301 results on '"Byrne, Bj"'
Search Results
2. Complete correction of acid α-glucosidase deficiency in Pompe disease fibroblasts in vitro, and lysosomally targeted expression in neonatal rat cardiac and skeletal muscle
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Pauly, DF, Johns, DC, Matelis, LA, Lawrence, JH, Byrne, BJ, and Kessler, PD
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- 1998
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3. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy
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By:mendell, Jr, Goemans, N, Lowes, Lp, Alfano, Ln, Berry, K, Shao, J, Kaye, Em, Mercuri, E, Hamid, Ha, Byrne, Bj, Connolly, Am, Dracker, Ra, Frank, Lm, Heydemann, Pt, O'Brien, Kc, Sparks, Se, Specht, La, Rodino Klapac, L, Sahenk, Z, Al Zaidy, S, Cripe, Lh, Lewis, S, Pane, M, Mazzone, E, Messina, S, Vita, Gl, D'Amico, A, Bertini, Es, Berardinelli, A, Torrente, Y, Magri, F, Comi, Gp, Baranello, G, Mongini, T, Pini, A, Battini, R, Pegoraro, E, Bruno, C, Previtali, S., POLITANO, Luisa, By:mendell, Jr, Goemans, N, Lowes, Lp, Alfano, Ln, Berry, K, Shao, J, Kaye, Em, Mercuri, E, Hamid, Ha, Byrne, Bj, Connolly, Am, Dracker, Ra, Frank, Lm, Heydemann, Pt, O'Brien, Kc, Sparks, Se, Specht, La, Rodino Klapac, L, Sahenk, Z, Al Zaidy, S, Cripe, Lh, Lewis, S, Pane, M, Mazzone, E, Messina, S, Vita, Gl, D'Amico, A, Bertini, E, Berardinelli, A, Torrente, Y, Magri, F, Comi, Gp, Baranello, G, Mongini, T, Pini, A, Battini, R, Pegoraro, E, Bruno, C, Politano, Luisa, and Previtali, S.
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Male ,Adolescent ,Exon ,Longitudinal Studie ,Walking ,Morpholino ,Muscular Dystrophy, Duchenne ,Alternative Splicing ,Outcome Assessment (Health Care) ,Neurology ,Oligonucleotide ,Disease Progression ,Exercise Test ,Neurology (clinical) ,Mobility Limitation ,Child ,Human - Abstract
Objective To continue evaluation of the long-term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy (DMD). Three-year progression of eteplirsen-treated patients was compared to matched historical controls (HC). Methods Ambulatory DMD patients who were ≥7 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks. Thereafter, all received eteplirsen on an open-label basis. The primary functional assessment in this study was the 6-Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype. Results At 36 months, eteplirsen-treated patients (n = 12) demonstrated a statistically significant advantage of 151m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n = 13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen-treated patients. Eteplirsen was well tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping. Interpretation Over 3 years of follow-up, eteplirsen-treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC.
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- 2016
4. Longitudinal effect of eteplirsen vs. historical control on ambulation in DMD
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Mendell, Jerry R, Goemans, Nathalie, Lowes, Linda P, Alfano, Lindsay N, Berry, Katherine, Shao, James, Kaye, Edward M, Mercuri, Eugenio, Pane, M, Mazzone, E, Messina, S, Vita, Gl, D'Amico, A, Berardinelli, A, Torrente, Y, Magri, F, Comi, Gp, Baranello, G, Mongini, Tiziana Enrica, Pini, A, Battini, R, Pegoraro, E, Bruno, C, Politano, L, Previtali, S, Hamid, Ha, Byrne, Bj, Connolly, Am, Dracker, Ra, Frank, Lm, Heydemann, Pt, O'Brien, Kc, Sparks, Se, Specht, La, Rodino Klapac, L, Sahenk, Z, Al Zaidy, S, Cripe, Lh, and Lewis, S.
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2'O-methyl-ribonucleoside phosphorothioate ,6MWT ,Duchenne muscular dystrophy (DMD) ,eteplirsen ,phosphorodiamidate morpholino oligomer (PMO) ,exon skipping ,historical control - Published
- 2015
5. B-cell depletion is protective against anti-AAV capsid immune response: a human subject case study
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Corti, M, primary, Elder, ME, additional, Falk, DJ, additional, Lawson, L, additional, Smith, BK, additional, Nayak, S, additional, Conlon, TJ, additional, Clément, N, additional, Erger, K, additional, Lavassani, E, additional, Green, MM, additional, Doerfler, PA, additional, Herzog, RW, additional, and Byrne, BJ, additional
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- 2014
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6. Translating the genomics revolution: The need for an international gene therapy consortium for monogenic diseases
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Tremblay, JP, Xiao, X, Aartsma-Rus, A, Barbas, C, Blau, HM, Bogdanove, AJ, Boycott, K, Braun, S, Breakefield, XO, Bueren, JA, Buschmann, M, Byrne, BJ, Calos, M, Cathomen, T, Chamberlain, J, Chuah, M, Cornetta, K, Davies, KE, Dickson, JG, Duchateau, P, Flotte, TR, Gaudet, D, Gersbach, CA, Gilbert, R, Glorioso, J, Herzog, RW, High, KA, Huang, W, Huard, J, Joung, JK, Liu, D, Lochmüller, H, Lustig, L, Martens, J, Massie, B, Mavilio, F, Mendell, JR, Nathwani, A, Ponder, K, Porteus, M, Puymirat, J, Samulski, J, Takeda, S, Thrasher, A, Vandendriessche, T, Wei, Y, Wilson, JM, Wilton, SD, Wolfe, JH, Gao, G, Tremblay, JP, Xiao, X, Aartsma-Rus, A, Barbas, C, Blau, HM, Bogdanove, AJ, Boycott, K, Braun, S, Breakefield, XO, Bueren, JA, Buschmann, M, Byrne, BJ, Calos, M, Cathomen, T, Chamberlain, J, Chuah, M, Cornetta, K, Davies, KE, Dickson, JG, Duchateau, P, Flotte, TR, Gaudet, D, Gersbach, CA, Gilbert, R, Glorioso, J, Herzog, RW, High, KA, Huang, W, Huard, J, Joung, JK, Liu, D, Lochmüller, H, Lustig, L, Martens, J, Massie, B, Mavilio, F, Mendell, JR, Nathwani, A, Ponder, K, Porteus, M, Puymirat, J, Samulski, J, Takeda, S, Thrasher, A, Vandendriessche, T, Wei, Y, Wilson, JM, Wilton, SD, Wolfe, JH, and Gao, G
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- 2013
7. SUSTAINED VESSEL DILATION INDUCED BY INCREASED PULSATILE PERFUSION OF PORCINE CAROTID ARTERIES IN VITRO
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Recchia, FABIO ANASTASIO, Byrne, Bj, and Kass, D. A.
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- 1999
8. Vasorelaxant effect of physiologic arterial pulsatility in isolated vessels
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Recchia, FABIO ANASTASIO, Byrne, Bj, and Kass, Da
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- 1994
9. Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial.
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Traverse JH, Henry TD, Ellis SG, Pepine CJ, Willerson JT, Zhao DX, Forder JR, Byrne BJ, Hatzopoulos AK, Penn MS, Perin EC, Baran KW, Chambers J, Lambert C, Raveendran G, Simon DI, Vaughan DE, Simpson LM, Gee AP, and Taylor DA
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Context: Clinical trial results suggest that intracoronary delivery of autologous bone marrow mononuclear cells (BMCs) may improve left ventricular (LV) function when administered within the first week following myocardial infarction (MI). However, because a substantial number of patients may not present for early cell delivery, the efficacy of autologous BMC delivery 2 to 3 weeks post-MI warrants investigation.Objective: To determine if intracoronary delivery of autologous BMCs improves global and regional LV function when delivered 2 to 3 weeks following first MI.Design, Setting, and Patients: A randomized, double-blind, placebo-controlled trial (LateTIME) of the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network of 87 patients with significant LV dysfunction (LV ejection fraction [LVEF] ≤45%) following successful primary percutaneous coronary intervention (PCI) between July 8, 2008, and February 28, 2011.Interventions: Intracoronary infusion of 150 × 10(6) autologous BMCs (total nucleated cells) or placebo (BMC:placebo, 2:1) was performed within 12 hours of bone marrow aspiration after local automated cell processing.Main Outcome Measures: Changes in global (LVEF) and regional (wall motion) LV function in the infarct and border zone between baseline and 6 months, measured by cardiac magnetic resonance imaging. Secondary end points included changes in LV volumes and infarct size.Results: A total of 87 patients were randomized (mean [SD] age, 57 [11] years; 83% men). Harvesting, processing, and intracoronary delivery of BMCs in this setting was feasible. Change between baseline and 6 months in the BMC group vs placebo for mean LVEF (48.7% to 49.2% vs 45.3% to 48.8%; between-group mean difference, -3.00; 95% CI, -7.05 to 0.95), wall motion in the infarct zone (6.2 to 6.5 mm vs 4.9 to 5.9 mm; between-group mean difference, -0.70; 95% CI, -2.78 to 1.34), and wall motion in the border zone (16.0 to 16.6 mm vs 16.1 to 19.3 mm; between-group mean difference, -2.60; 95% CI, -6.03 to 0.77) were not statistically significant. No significant change in LV volumes and infarct volumes was observed; both groups decreased by a similar amount at 6 months vs baseline.Conclusion: Among patients with MI and LV dysfunction following reperfusion with PCI, intracoronary infusion of autologous BMCs vs intracoronary placebo infusion, 2 to 3 weeks after PCI, did not improve global or regional function at 6 months.Trial Registration: clinicaltrials.gov Identifier: NCT00684060. [ABSTRACT FROM AUTHOR]- Published
- 2011
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10. Limb-girdle muscular dystrophy type 2D gene therapy restores alpha-sarcoglycan and associated proteins.
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Mendell JR, Rodino-Klapac LR, Rosales-Quintero X, Kota J, Coley BD, Galloway G, Craenen JM, Lewis S, Malik V, Shilling C, Byrne BJ, Conlon T, Campbell KJ, Bremer WG, Viollet L, Walker CM, Sahenk Z, Clark KR, Mendell, Jerry R, and Rodino-Klapac, Louise R
- Abstract
Objective: alpha-Sarcoglycan deficiency results in a severe form of muscular dystrophy (limb-girdle muscular dystrophy type 2D [LGMD2D]) without treatment. Gene replacement represents a strategy for correcting the underlying defect. Questions related to this approach were addressed in this clinical trial, particularly the need for immunotherapy and persistence of gene expression.Methods: A double-blind, randomized controlled trial using rAAV1.tMCK.hSGCA injected into the extensor digitorum brevis muscle was conducted. Control sides received saline. A 3-day course of methylprednisolone accompanied gene transfer without further immune suppression.Results: No adverse events were encountered. SGCA gene expression increased 4-5-fold over control sides when examined at 6 weeks (2 subjects) and 3 months (1 subject). The full sarcoglycan complex was restored in all subjects, and muscle fiber size was increased in the 3-month subject. Adeno-associated virus serotype 1 (AAV1)-neutralizing antibodies were seen as early as 2 weeks. Neither CD4+ nor CD8+ cells were increased over contralateral sides. Scattered foci of inflammation could be found, but showed features of programmed cell death. Enzyme-linked immunospot (ELISpot) showed no interferon-gamma response to alpha-SG or AAV1 capsid peptide pools, with the exception of a minimal capsid response in 1 subject. Restimulation to detect low-frequency capsid-specific T cells by ELISpot assays was negative. Results of the first 3 subjects successfully achieved study aims, precluding the need for additional enrollment.Interpretation: The finding of this gene replacement study in LGMD2D has important implications for muscular dystrophy. Sustained gene expression was seen, but studies over longer time periods without immunotherapy will be required for design of vascular delivery gene therapy trials. [ABSTRACT FROM AUTHOR]- Published
- 2009
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11. Dosage-response relationships for methyl methanesulfonate in Drosophila melanogaster spermatozoa: DNA methylation per nucleotide vs. sex-linked recessive lethal frequency
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Byrne Bj, William R. Lee, and Beranek Dt
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Male ,Guanine ,Health, Toxicology and Mutagenesis ,Mutagen ,Genes, Recessive ,Biology ,medicine.disease_cause ,Methylation ,chemistry.chemical_compound ,Genetics ,medicine ,Animals ,AP site ,Nucleotide ,Molecular Biology ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,DNA ,Methyl Methanesulfonate ,Molecular biology ,Spermatozoa ,Methyl methanesulfonate ,Drosophila melanogaster ,chemistry ,Biochemistry ,Genes, Lethal ,Nucleotide excision repair - Abstract
Two different mechanisms for mutagenesis following treatment with methyl methanesulfonate (MMS) are suggested from the dose-response curve that is best fit by the linear quadratic model where m = 0.130 D + 0.038 D 2 ( D = dose measured as alkylations per nucleotide × 10 3 , APdN; m = percent sex-linked recessive lethals, SRL). A predominant component of the dose-response curve at moderate to high dose is the quadratic component which is interpreted as the result of two single-strand breaks. The distribution of methyl adducts in vivo is consistent with the previously determined in vitro distribution of methyl adducts on DNA following treatmment with MMS. With the use of HPLC, 82% of the 3 H-labeled adducts are found on the N −7 of guanine. It has previously been shown by both in vitro studies and in vivo correlation with mutagenesis that the N −7 alkyl guanine is not in itself a predominately genetoxic lesion; however, N −7 alkyl guanine destabilizes guanine resulting in an increased rate of hydrolysis producing apurinic sites. In data presented in this paper, the loss of labeled adducts is shown to be at a rate consistent with hydrolysis of the destabilized alkyl guanine. The apurinic site thus produced should be converted to single-strand breaks by AP endonucleases once sperm has fertilized the egg. Single-strand breaks are repaired by excision repair which is not errot-prone; however, multiple breaks producing a proximity effect should lead to double-strand breaks that are repaired by an error-prone process. Mutations that are induced by a proximity effect would account for the quadratic term. It is hypothesized that a proximity effect is produced when two breaks are suffuciently close together to prevent using the complementary strand as a template. The linear component of the dose-response curve is probably due to akylation of oxygens in the purine or pyrimidine ring leading to mispairing. However, due to the low frequency of ring-oxygen alkylation following treatment with MMS, this important genotoxic site is not the predominant one observed at experimental levels normally used in the laboratory. From the dose-response curve, it is calculated that at mutation frequencies of 10 times the spontaneous frequency or higher, the predominant mechanism is the multi-hit component; however, at mutation induced frequencies of 0.1 of the spontaneous frequency, which are levels more likely to be encountered in man's exposure to environmental mutagens, the dominant mechanism is the linear component. Therefore, because of the quadratic term of the dose-response curve for MMS, studies with this mutagen at levels of mutagenesis of 10-fold or higher required for the specific locus test do not yield and analysis of the mechanism of mutagenesis important at environmental levels of 0.1 of the spontaneous frequency.
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- 1989
12. Relative Biological Effectiveness of Tritiated Water to γ Radiation for Germ Line Mutations
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Lee Wr and Byrne Bj
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Radiation ,Tritiated water ,Chemistry ,Radiochemistry ,Biophysics ,Linear energy transfer ,Gene mutation ,Ionizing radiation ,chemistry.chemical_compound ,Beta particle ,Relative biological effectiveness ,Lethal allele ,Radiology, Nuclear Medicine and imaging ,Tritium - Abstract
The relative biological effectiveness was determined using sex-linked recessive lethals induced in Drosophila spermatozoa as the biological effect. The sex-linked recessive lethal test, a measure of mutations induced in germ cells and transmitted through successive generations, yields a linear dose-response curve in the range used in these experiments. A dose-response curve was determined from three exposures to tritiated water and three exposures to 60Co gamma radiation. The ratio of the slopes of these two response curves is 2.7 +/- 0.3, yielding a relative biological effectiveness that suggests the tritium beta particle is 2.7 times more effective per unit of energy absorbed in inducing gene mutations transmitted to successive generations than 60Co gamma radiation. The increase in relative biological effectiveness with higher linear energy transfer for tritium beta radiation strongly suggests that single-strand breaks are repaired by a nearly error-free repair mechanism. Ion tracks with a high density of ions (high linear energy transfer) are more efficient than tracks with a low ion density (low linear energy transfer) in inducing transmissible mutations, suggesting interaction among products of ionization. Since most transmitted mutations induced by ionizing radiation result from strand breakage, interaction probably occurs at this level with double-strand breaks being repaired by an error-prone mechanism yielding transmissible mutations.
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- 1989
13. Cardiac and clinical phenotype in Barth syndrome.
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Spencer CT, Bryant RM, Day J, Gonzalez IL, Colan SD, Thompson WR, Berthy J, Redfearn SP, and Byrne BJ
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- 2006
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14. Switching treatment to cipaglucosidase alfa plus miglustat positively affects patient-reported outcome measures in patients with late-onset Pompe disease.
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Kishnani PS, Byrne BJ, Claeys KG, Díaz-Manera J, Dimachkie MM, Kushlaf H, Mozaffar T, Roberts M, Schoser B, Hummel N, Kopiec A, Holdbrook F, Shohet S, and Toscano A
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- Humans, Male, Female, Middle Aged, Adult, Drug Therapy, Combination, Treatment Outcome, Aged, Glycogen Storage Disease Type II drug therapy, Patient Reported Outcome Measures, Quality of Life, alpha-Glucosidases therapeutic use, alpha-Glucosidases administration & dosage, Enzyme Replacement Therapy methods, 1-Deoxynojirimycin analogs & derivatives, 1-Deoxynojirimycin therapeutic use, 1-Deoxynojirimycin administration & dosage
- Abstract
Background: Late-onset Pompe disease (LOPD), a rare autosomal recessive multisystemic disorder, substantially impacts patients' day-to-day activities, outcomes, and health-related quality of life (HRQoL). The PROPEL trial compared cipaglucosidase alfa plus miglustat (cipa+mig) with alglucosidase alfa plus placebo (alg+pbo) in adult patients with LOPD over 52 weeks and showed improved motor and respiratory function in patients switching treatment from standard-of-care enzyme replacement therapy (ERT) to cipa+mig at baseline. This study evaluated the impact of cipa+mig on patient-reported outcomes (PROs), including HRQoL in ERT-experienced patients, using data from PROPEL., Methods: PROs evaluated included the Subject's Global Impression of Change (SGIC), Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 20a, PROMIS Fatigue Short Form 8a, Rasch-built Pompe-specific Activity (R-PAct), and European Quality of Life-5 Dimensions 5 Response Levels (EQ-5D-5L). The proportions of responders in the cipa+mig arm and the alg+pbo arm were compared via chi-squared or Fisher's exact test (patient-level responder analysis), and least squares (LS) mean differences were calculated for change from baseline at Week 52 of the PRO measures (group-level analysis)., Results: At Week 52, patient-level SGIC responder and group-level SGIC analyses favored cipa+mig compared with alg+pbo across all SGIC domains (e.g. 90 vs. 59% responders in the cipa+mig vs. the alg+pbo group for SGIC ability to move around; P = 0.0005; and LS mean difference 0.385; P = 0.02). Similarly, PROMIS Physical Function and Fatigue domains numerically favored cipa+mig in both analyses (e.g. 50 vs. 40% responders in the cipa+mig vs. alg+pbo arm for PROMIS Physical Function; P = 0.37; and LS mean difference 3.1; P = 0.11). R-PAct for both treatment groups was similar in the patient-level responder analysis, but numerically favored alg+pbo in the group-level analysis (35% responders in both arms; P = 0.95; and LS mean difference -0.8; P = 0.48). Self-care, usual activities, and depression/anxiety domains of EQ-5D-5L numerically favored cipa+mig in both analyses (e.g. 20 vs. 12% responders in the cipa+mig vs. alg+pbo arm for EQ-5D-5L self-care; P = 0.54; and LS mean difference -0.108; P = 0.52)., Conclusions: Overall, switching treatment from alglucosidase alfa to cipa+mig positively impacted PRO measurements during the double-blind period of PROPEL., Trial Registration: NCT03729362; Registration date: November 1, 2018; https://clinicaltrials.gov/study/NCT03729362., Competing Interests: Declarations Ethics approval and consent to participate PROPEL was approved by the appropriate independent ethics committees and institutional review boards at each study site and was conducted according to international guidelines for clinical studies, such as the Declaration of Helsinki and Good Clinical Practice Guidelines. All participants provided written informed consent before participating in the study. Consent for publication Not applicable. Competing interests KGC received research funding from Alnylam, Biogen, Pfizer, Roche, Sanofi Genzyme; advisory board member honoraria from Alexion, Alnylam, Amicus Therapeutics, Inc., argenx, Biogen, Ipsen, Janssen Pharmaceutics, Lupin, Pfizer, Roche, Sanofi Genzyme and UCB; and is Chairholder of the Emil von Behring Chair for Neuromuscular and Neurodegenerative Disorders by CSL Behring. BJB reports consultant/advisory board membership for Pfizer, Amicus Therapeutics, Inc., and Sanofi; and owns stocks in Lacerta Therapeutics. JD-M reports consulting fees/honoraria from Sarepta, Sanofi, Audentes; has received grant support from Sanofi, Spark and Boehringer Ingelheim; and payment for speaking from Sanofi, Sarepta and Lupin. MMD serves or recently served as a consultant for Abata/Third Rock, Abcuro, Amicus Therapeutics, Inc., argenx, Astellas, Cabaletta Bio, Catalyst, CNSA, Covance/Labcorp, CSL Behring, Dianthus, Horizon, EMD Serono/Merck, Ig Society, Inc, Janssen Pharmaceuticals, Medlink, Octapharma, Priovant, Sanofi Genzyme, Shire Takeda, TACT/Treat NMD, UCB Biopharma, Valenza Bio and Wolters Kluwer Health/UpToDate; and has received research grants or contracts, or educational grants from Alexion/AstraZeneca, Alnylam Pharmaceuticals, Amicus Therapeutics, Inc., argenx, Bristol-Myers Squibb, Catalyst, CSL Behring, FDA/OOPD, GlaxoSmithKline, Genentech, Grifols, Mitsubishi Tanabe Pharma, MDA, NIH, Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi Genzyme, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, The Myositis Association, and UCB Biopharma/RaPharma. PSK has received research/grant support from Sanofi Genzyme and Amicus Therapeutics, Inc., and has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Inc., JCR Pharmaceuticals, Bayer and Asklepios Biopharmaceutical, Inc. (AskBio). She is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Pompe Disease Advisory Board for Amicus Therapeutics, Inc., and Advisory Board for Baebies. She has held equity in Asklepios Biopharmaceuticals and may receive milestone payments related to that equity in the future. HK served as a consultant for Alexion AstraZeneca Rare disease, argenx, UCB, Immunovant, Sanofi, and has received research grants or educational grants from Sanofi, MDA, and Healey ALS platform trial. TM has participated in an advisory capacity for Abbvie, Alexion, Amicus Therapeutics, Inc., Annji, argenx, Arvinas, Audentes, Cabaletta, Maze Therapeutics, Momenta, Ra Pharmaceuticals, Sanofi Genzyme, Sarepta, Spark Therapeutics, and UCB. He is a member of the medical advisory board for the Myositis Association, Neuromuscular Disease Foundation, Myasthenia Gravis Foundation of California and Myasthenia Gravis Foundation of America. He has received research funding from the Myositis Association, the Muscular Dystrophy Association, the NIH and from the following sponsors: Alexion, Amicus Therapeutics, Inc., Annji, argenx, Audentes, Bristol-Myers Squib, Cabaletta, Cartesian Therapeutics, Grifols, Momenta, Ra Pharmaceuticals, Sanofi Genzyme, Spark Therapeutics, UCB, and Valerion. He is a member of the data safety monitoring board for Acceleron, Applied Therapeutics, Sarepta, and the NIH. MR has received honoraria for educational symposia from Sanofi Genzyme and Amicus Therapeutics, Inc., and for participation on advisory boards for Sanofi, and Amicus Therapeutics, Inc. BS has received unrestricted research grants from Amicus Therapeutics, Inc., Astellas, Roche, Marigold Foundation, AMDA Foundation and speaker’s honoraria from Amicus Therapeutics, Inc., Alexion, Kedrion, and Sanofi. He has participated as a scientific adviser for Amicus Therapeutics, Inc., argenx, Astellas, Bayer, Maze, Pepgen, Sanofi, and Spark. He declares no stocks or shares. NH and AK are employees of Certara, which is a paid consultant to Amicus Therapeutics, Inc. FH and SS are employees of and hold stock in Amicus Therapeutics, Inc. AT has received honorarium for educational talks from Sanofi Genzyme and Amicus Therapeutics, Inc. and for participation on advisory boards for Sanofi, Amicus Therapeutics, Inc., Aro and Spark. He is a member of the European Reference Network for Neuromuscular Disorders (EU-NMD)– Project ID 739543., (© 2024. The Author(s).)
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- 2024
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15. Differences in Pediatricians' Income by Sex Over Time.
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Frintner MP, Freed GL, Byrne BJ, Leslie LK, Starmer AJ, Gottschlich EA, and Olson LM
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- Humans, Male, Female, Longitudinal Studies, Sex Factors, United States, Adult, Middle Aged, Physicians, Women economics, Physicians, Women statistics & numerical data, Income, Pediatricians economics, Pediatricians statistics & numerical data
- Abstract
Objective: Previous Pediatrician Life and Career Experience Study (PLACES) 2016 data revealed that female pediatricians reported earning ∼94% of what male pediatricians reported, after adjusting for factors that might impact income. Has this disparity persisted?, Methods: Data from PLACES, a national longitudinal study, was used to examine pediatrician-reported income from 2017 to 2022. A regression analysis estimated the adjusted differences in female and male pediatricians' annual income for each survey year. Models included sex and other key personal and practice characteristics for which female and male pediatricians' careers might differ. A mixed effects regression for longitudinal analysis examined income across years for female and male pediatricians and if time-variant characteristics are associated with increased or decreased income., Results: PLACES participation ranged from 83.6% in 2017% to 75.5% in 2022 (analytic n = 1251 in 2017 and 1077 in 2022). The unadjusted mean annual income in 2022 was $237 168, $220 374 for female pediatricians and $284 286 for male pediatricians. Adjusting for key characteristics, female pediatrician income was ∼93% of male pediatrician income, a gap of ∼$ 11 000 annually. Income increased across years (coefficient = 0.03, P < .001). The year-sex interaction was not significant, indicating that the female-male disparity did not change over time. Three time-variant characteristics associated with increased income over time included increased portion of continuous full-time work, work hours, and time in administrative work., Conclusions: A national longitudinal study revealed that female pediatricians reported earning ∼93% of what their male colleagues reported, with a consistent gap from 2017 to 2022., (Copyright © 2024 by the American Academy of Pediatrics.)
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- 2024
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16. Cipaglucosidase alfa plus miglustat: linking mechanism of action to clinical outcomes in late-onset Pompe disease.
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Byrne BJ, Parenti G, Schoser B, van der Ploeg AT, Do H, Fox B, Goldman M, Johnson FK, Kang J, Mehta N, Mondick J, Sheikh MO, Sitaraman Das S, Tuske S, Brudvig J, Weimer JM, and Mozaffar T
- Abstract
Enzyme replacement therapy (ERT) is the only approved disease-modifying treatment modality for Pompe disease, a rare, inherited metabolic disorder caused by a deficiency in the acid α -glucosidase (GAA) enzyme that catabolizes lysosomal glycogen. First-generation recombinant human GAA (rhGAA) ERT (alglucosidase alfa) can slow the progressive muscle degeneration characteristic of the disease. Still, most patients experience diminished efficacy over time, possibly because of poor uptake into target tissues. Next-generation ERTs aim to address this problem by increasing bis-phosphorylated high mannose (bis-M6P) N -glycans on rhGAA as these moieties have sufficiently high receptor binding affinity at the resultant low interstitial enzyme concentrations after dosing to drive uptake by the cation-independent mannose 6-phosphate receptor on target cells. However, some approaches introduce bis-M6P onto rhGAA via non-natural linkages that cannot be hydrolyzed by natural human enzymes and thus inhibit the endolysosomal glycan trimming necessary for complete enzyme activation after cell uptake. Furthermore, all rhGAA ERTs face potential inactivation during intravenous delivery (and subsequent non-productive clearance) as GAA is an acid hydrolase that is rapidly denatured in the near-neutral pH of the blood. One new therapy, cipaglucosidase alfa plus miglustat, is hypothesized to address these challenges by combining an enzyme enriched with naturally occurring bis-M6P N -glycans with a small-molecule stabilizer. Here, we investigate this hypothesis by analyzing published and new data related to the mechanism of action of the enzyme and stabilizer molecule. Based on an extensive collection of in vitro , preclinical, and clinical data, we conclude that cipaglucosidase alfa plus miglustat successfully addresses each of these challenges to offer meaningful advantages in terms of pharmacokinetic exposure, target-cell uptake, endolysosomal processing, and clinical benefit., Competing Interests: BB reports consultant/advisory board membership for Pfizer, Amicus Therapeutics, Inc., and Sanofi; and owns stocks in Lacerta Therapeutics. GP received honoraria, travel reimbursement and research support from Sanofi, Takeda, Piam Farmaceutici, and Spark Therapeutics. BS has received unrestricted research grants from AMDA Foundation, Amicus Therapeutics, Inc., EU Horizon programs COMPASS and PaLaDIn, Marigold Foundation, Roche Diagnostics, and speaker’s honoraria from Alexion, Amicus Therapeutics, Inc., Argenx, Kedrion, and Sanofi. He has also been a scientific advisor for Amicus Therapeutics, Inc., Alexion, Astellas, Sanofi, and Taysha. He declares no stocks or shares. AP is an advisory board member of Amicus Therapeutics, Inc., BioMarin, Sanofi Genzyme, and Spark Therapeutics. She provided consultancies for Amicus Therapeutics, Inc., BioMarin, Sanofi Genzyme, and Spark Therapeutics; and contracted research for Amicus Therapeutics, Inc., BioMarin, Sanofi Genzyme, and Spark Therapeutics. All collaborations were carried out under an agreement between Erasmus MC and these industries. HD is a former employee of Amicus Therapeutics, Inc. and a current employee of 6MP-Therapeutics. BF, MG, FJ, NM, OS, SS, ST, JB, and JW are current employees of and holds stock in Amicus Therapeutics, Inc. JK is an employee of Metrum Research Group, which was contracted by Amicus to perform the PK/PD analysis, and has no other competing interests to declare. JM was a paid consultant as an employee of Metrum Research Group when the modeling work was carried out JM was employed by Incyte Corporation at the time the manuscript was developed.TM has advised for Abbvie, Alexion, Amicus Therapeutics, Inc., Annji, Argenx, Arvinas, Audentes, Cabaletta, Maze Therapeutics, Momenta, Ra Pharmaceuticals, Sanofi Genzyme, Sarepta, Spark Therapeutics, and UCB. He participates on the speaker’s bureau for Sanofi Genzyme and the medical advisory boards for the Myositis Association, Neuromuscular Disease Foundation, Myasthenia Gravis Foundation of California and Myasthenia Gravis Foundation of America. He has received research funding from the Myositis Association, the Muscular Dystrophy Association, the NIH and from the following sponsors: Alexion, Amicus Therapeutics, Inc., Annji, Argenx, Audentes, Bristol-Myers Squibb, Cabaletta, Cartesian Therapeutics, Grifols, Momenta, Ra Pharmaceuticals, Sanofi Genzyme, Spark Therapeutics, UCB, and Valerion; and is on the data safety monitoring board for Acceleron, Applied Therapeutics, Sarepta, and the NIH. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Byrne, Parenti, Schoser, van der Ploeg, Do, Fox, Goldman, Johnson, Kang, Mehta, Mondick, Sheikh, Sitaraman Das, Tuske, Brudvig, Weimer and Mozaffar.)
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- 2024
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17. Codon-Optimized and de novo-Synthesized E-Selectin/AAV2 Dose-Response Study for Vascular Regeneration Gene Therapy.
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Voza FA, Byrne BJ, Ortiz YY, Li Y, Le N, Osafo L, Ribieras AC, Shao H, Huerta CT, Wei Y, Falero-Diaz G, Franco-Bravo A, Lassance-Soares RM, Vazquez-Padron RI, Liu ZJ, and Velazquez OC
- Subjects
- Animals, Mice, Dependovirus genetics, Genetic Vectors, Disease Models, Animal, Neovascularization, Physiologic, Male, Regeneration, Genetic Therapy methods, E-Selectin, Ischemia therapy, Hindlimb blood supply, Codon
- Abstract
Objective: This study focuses on dose-response investigation using a codon-optimized and de novo-synthesized E-Selectin/AAV2 (E-Sel/AAV2) vector in preparation for Investigational New Drug enabling of subsequent clinical studies., Background: Gene therapy is a potential solution for patients suffering from chronic limb-threatening ischemia. Understanding the dose for effective gene delivery is crucial for future Investigational New Drug-enabling studies., Methods: Expression of the codon-optimized E-Selectin gene was assessed by flow cytometry following in vitro cell transfection assay and RT-qPCR for murine limbs injected in vivo with AAV-m-E-Selectin (E-Sel/AAV2). Dose-response studies involved 3 cohorts of FVB/NJ mice (n=6/group) with escalating log doses of E-Selectin/AAV2 injected intramuscularly in divided aliquots, ranging from 2 × 10 9 VG to 2 × 10 11 VG, into ischemic limbs created by left femoral artery/vein ligation/excision and administration of nitric oxide synthase inhibitor, L-NAME. Limb perfusion, extent of gangrene free limb, functional limb recovery, and therapeutic angiogenesis were assessed., Results: Codon-optimized E-Sel/AAV2 gene therapy exhibits a superior expression level than WT E-Sel/AAV2 gene therapy both in vitro and in vivo. Mice treated with a high dose (2 × 10 11 VG) of E-Sel/AAV2 showed significantly improved perfusion indices, lower Faber scores, increased running stamina, and neovascularization compared with lower doses tested with control groups, indicating a distinct dose-dependent response. No toxicity was detected in any of the animal groups studied., Conclusions: E-Sel/AAV2 Vascular Regeneration Gene Therapy holds promise for enhancing the recovery of ischemic hindlimb perfusion and function, with the effective dose identified in this study as 2 × 10 11 VG aliquots injected intramuscularly., Competing Interests: Z.J.L. and O.C.V. declare the following potential conflicts of interest with respect to the research, authorship, and/or presentation and/or publication of some aspects of this work: the E-Selectin gene modification technologies were developed in our research laboratory and patented/licensed by the University of Miami. O.C.V. and Z.J.L. are co-inventors of this technology. This technology is fully owned by University of Miami and is Licensed with exclusivity to Ambulero Inc . This technology is currently under preclinical development by Ambulero Inc., a new incubator company spin out from the University of Miami that focuses on developing new vascular treatments for ischemic tissue conditions, wound healing, and limb salvage. Co-authors, Z.J.L. and O.C.V., serve as consultants and chief scientific and medical advisory officers to Ambulero Inc. ; are co-inventors of the technologies; and are minority shareholders in Ambulero Inc. Co-authors, Z.J.L. and O.C.V. are also funded for this work by the NIH/NHLBI and Philanthropy (Eloise & David Kimmelman Foundation) in ongoing preclinical investigations of these technologies. The remaining authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2024
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18. Taldefgrobep Alfa and the Phase 3 RESILIENT Trial in Spinal Muscular Atrophy.
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Servais L, Lair LL, Connolly AM, Byrne BJ, Chen KS, Coric V, Qureshi I, Durham S, Campbell DJ, Maclaine G, Marin J, and Bechtold C
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- Humans, Clinical Trials, Phase III as Topic, Activin Receptors, Type II metabolism, Activin Receptors, Type II therapeutic use, Animals, Recombinant Proteins therapeutic use, Myostatin metabolism, Myostatin antagonists & inhibitors, Muscular Atrophy, Spinal metabolism, Muscular Atrophy, Spinal drug therapy, Muscular Atrophy, Spinal genetics
- Abstract
Spinal muscular atrophy (SMA) is a rare, genetic neurodegenerative disorder caused by insufficient production of survival motor neuron (SMN) protein. Diminished SMN protein levels lead to motor neuron loss, causing muscle atrophy and weakness that impairs daily functioning and reduces quality of life. SMN upregulators offer clinical improvements and increased survival in SMA patients, although significant unmet needs remain. Myostatin, a TGF-β superfamily signaling molecule that binds to the activin II receptor, negatively regulates muscle growth; myostatin inhibition is a promising therapeutic strategy for enhancing muscle. Combining myostatin inhibition with SMN upregulation, a comprehensive therapeutic strategy targeting the whole motor unit, offers promise in SMA. Taldefgrobep alfa is a novel, fully human recombinant protein that selectively binds to myostatin and competitively inhibits other ligands that signal through the activin II receptor. Given a robust scientific and clinical rationale and the favorable safety profile of taldefgrobep in patients with neuromuscular disease, the RESILIENT phase 3, randomized, placebo-controlled trial is investigating taldefgrobep as an adjunct to SMN upregulators in SMA (NCT05337553). This manuscript reviews the role of myostatin in muscle, explores the preclinical and clinical development of taldefgrobep and introduces the phase 3 RESILIENT trial of taldefgrobep in SMA.
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- 2024
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19. Neurological glycogen storage diseases and emerging therapeutics.
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Colpaert M, Singh PK, Donohue KJ, Pires NT, Fuller DD, Corti M, Byrne BJ, Sun RC, Vander Kooi CW, and Gentry MS
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- Humans, Animals, Glycogen metabolism, Enzyme Replacement Therapy methods, Nervous System Diseases therapy, Nervous System Diseases metabolism, Glycogen Storage Disease therapy, Glycogen Storage Disease metabolism, Glycogen Storage Disease genetics, Genetic Therapy methods, Genetic Therapy trends
- Abstract
Glycogen storage diseases (GSDs) comprise a group of inherited metabolic disorders characterized by defects in glycogen metabolism, leading to abnormal glycogen accumulation in multiple tissues, most notably affecting the liver, skeletal muscle, and heart. Recent findings have uncovered the importance of glycogen metabolism in the brain, sustaining a myriad of physiological functions and linking its perturbation to central nervous system (CNS) pathology. This link resulted in classification of neurological-GSDs (n-GSDs), a group of diseases with shared deficits in neurological glycogen metabolism. The n-GSD patients exhibit a spectrum of clinical presentations with common etiology while requiring tailored therapeutic approaches from the traditional GSDs. Recent research has elucidated the genetic and biochemical mechanisms and pathophysiological basis underlying different n-GSDs. Further, the last decade has witnessed some promising developments in novel therapeutic approaches, including enzyme replacement therapy (ERT), substrate reduction therapy (SRT), small molecule drugs, and gene therapy targeting key aspects of glycogen metabolism in specific n-GSDs. This preclinical progress has generated noticeable success in potentially modifying disease course and improving clinical outcomes in patients. Herein, we provide an overview of current perspectives on n-GSDs, emphasizing recent advances in understanding their molecular basis, therapeutic developments, underscore key challenges and the need to deepen our understanding of n-GSDs pathogenesis to develop better therapeutic strategies that could offer improved treatment and sustainable benefits to the patients., Competing Interests: Declaration of competing interest R.C.S. has received research support and consultancy fees from Maze Therapeutics and is a member of the Medical Advisory Board for Little Warrior Foundation. M.S.G. has received research support, research compounds, or consultancy fees from Maze Therapeutics, Valerion Therapeutics, Ionis Pharmaceuticals, PTC Therapeutics, and the Glut1-Deficiency Syndrome Foundation. R.C.S. and M.S.G. are co-founders of Attrogen LLC. M.Corti has received research support from Sanofi, Friedreich Ataxia Research Alliance (FARA), Amicus, AavantiBio, Lacerta, Provention Bio, Sarepta, Duchenne Research Fund, Muscular Dystrophy Association (MDA), GoFAR, Cydan, Audentes. M.Corti has received consulting fees from AavantiBio, Reata, Lilly, Avexis and Gilbert foundation, SwanBio and PCT Therapeutics. B.J.B. has received research support from SolidBio, ProventionBio, Barth Syndrome Foundation. B.J.B. has received consulting fees from AavantiBio, Amicus Therapeutics, Rocket Pharma, Pfizer, Sanofi, and Sarepta Therapeutics. M.Corti and B.J.B. are co-founders of Ventura, LLC., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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20. Innate Immune Sensing of Adeno-Associated Virus Vectors.
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Cao D, Byrne BJ, de Jong YP, Terhorst C, Duan D, Herzog RW, and Kumar SRP
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- Humans, Animals, Dendritic Cells immunology, Genetic Therapy, Toll-Like Receptor 9 metabolism, Toll-Like Receptor 9 immunology, Signal Transduction, Dependovirus genetics, Dependovirus immunology, Immunity, Innate, Genetic Vectors immunology, Genetic Vectors genetics
- Abstract
Adeno-associated virus (AAV) based viral vectors are widely used in human gene therapy and form the basis of approved treatments for several genetic diseases. Immune responses to vector and transgene products, however, substantially complicate these applications in clinical practice. The role of innate immune recognition of AAV vectors was initially unclear, given that inflammatory responses early after vector administration were typically mild in animal models. However, more recent research continues to identify innate immune pathways that are triggered by AAV vectors and that serve to provide activation signals for antigen-presenting cells and initiation of adaptive immune responses. Sensing of the AAV genome by the endosomal DNA receptor toll-like receptor 9 (TLR9) promotes early inflammatory response and interferon expression. Thus, activation of the TLR9>MyD88 pathway in plasmacytoid dendritic cells (pDCs) leads to the conditioning of antigen cross-presenting DCs through type I interferon (IFN-I) and ultimately CD8
+ T cell activation. Alternatively, pDCs may also promote CD8+ T cell responses in a TLR9-independent manner by the production of IL-1 cytokines, thereby activating the IL-1R1>MyD88 signaling pathway. AAV can induce cytokine expression in monocyte-derived DCs, which in turn increases antibody formation. Binding of AAV capsid to complement components likely further elevates B cell activation. At high systemic vector doses in humans and in non-human primates, AAV vectors can trigger complement activation, with contributions by classical and alternative pathways, leading to severe toxicities. Finally, evidence for activation of TLR2 by the capsid and of additional innate receptors for nucleic acids has been presented. These observations show that AAV vectors can initiate several and likely redundant innate immune pathways resulting in an exaggerated adaptive immune response.- Published
- 2024
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21. Longitudinal changes of swallowing safety and efficiency in infants with spinal muscular atrophy who received disease modifying therapies.
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Leon-Astudillo C, Brooks O, Salabarria SM, Coker M, Corti M, Lammers J, Plowman EK, Byrne BJ, and Smith BK
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- Humans, Male, Infant, Female, Infant, Newborn, Longitudinal Studies, Muscular Atrophy, Spinal physiopathology, Muscular Atrophy, Spinal drug therapy, Fluoroscopy, Child, Preschool, Deglutition Disorders physiopathology, Deglutition Disorders etiology, Deglutition physiology
- Abstract
Background: Dysphagia is a common feature of the natural history of patients with spinal muscular atrophy (SMA). Literature regarding swallowing safety and efficiency is scarce in patients with SMA, particularly in the era of newborn screening programs and disease-modifying therapies., Objective: To describe the longitudinal changes of swallowing safety and efficiency in children with SMA who received one or more disease modifying therapies METHODS: Case series of patients with SMA followed at the University of Florida from 1 May 2019 to 31 December 2022 who had two or more videofluoroscopy swallowing studies (VFSS), with the first being within 30 days of their first treatment. Data extracted from the electronic health record included: neuromotor outcomes, VFSS penetration aspiration scores (PAS), presence of abrnormal oral or pharyngeal residue, clinical history, and timing of disease-modifying therapies administration., Results: Seven subjects were included (five male); three were diagnosed via newborn screen. Median age at diagnosis was 10 days (range: 4-250). Median age at initial VFSS was 29 days (range: 9-246), and age at the last VFSS was 26.1 months (range: 18.2-36.2). All subjects received onasemnogene-abeparvovec (OA); four received additional therapies. PAS at diagnosis was abnormal in four subjects. Six subjects required feeding modifications after VFSS results. Of these, three had silent aspiration (PAS 8) and three of them improved after treatment., Conclusions: Swallowing safety and efficiency can be impaired in patients with SMA despite early treatment. Larger, prospective studies are needed to define optimal timiing of longitudinal instrumental evaluations., (© 2024 Wiley Periodicals LLC.)
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- 2024
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22. 104-week efficacy and safety of cipaglucosidase alfa plus miglustat in adults with late-onset Pompe disease: a phase III open-label extension study (ATB200-07).
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Schoser B, Kishnani PS, Bratkovic D, Byrne BJ, Claeys KG, Díaz-Manera J, Laforêt P, Roberts M, Toscano A, van der Ploeg AT, Castelli J, Goldman M, Holdbrook F, Sitaraman Das S, Wasfi Y, and Mozaffar T
- Subjects
- Humans, Male, Female, Middle Aged, Adult, Double-Blind Method, alpha-Glucosidases adverse effects, alpha-Glucosidases administration & dosage, alpha-Glucosidases therapeutic use, Drug Therapy, Combination, Treatment Outcome, Aged, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors adverse effects, Glycogen Storage Disease Type II drug therapy, 1-Deoxynojirimycin analogs & derivatives, 1-Deoxynojirimycin administration & dosage, 1-Deoxynojirimycin adverse effects, 1-Deoxynojirimycin therapeutic use, Enzyme Replacement Therapy methods
- Abstract
The phase III double-blind PROPEL study compared the novel two-component therapy cipaglucosidase alfa + miglustat (cipa + mig) with alglucosidase alfa + placebo (alg + pbo) in adults with late-onset Pompe disease (LOPD). This ongoing open-label extension (OLE; NCT04138277) evaluates long-term safety and efficacy of cipa + mig. Outcomes include 6-min walk distance (6MWD), forced vital capacity (FVC), creatine kinase (CK) and hexose tetrasaccharide (Hex4) levels, patient-reported outcomes and safety. Data are reported as change from PROPEL baseline to OLE week 52 (104 weeks post-PROPEL baseline). Of 118 patients treated in the OLE, 81 continued cipa + mig treatment from PROPEL (cipa + mig group; 61 enzyme replacement therapy [ERT] experienced prior to PROPEL; 20 ERT naïve) and 37 switched from alg + pbo to cipa + mig (switch group; 29 ERT experienced; 8 ERT naive). Mean (standard deviation [SD]) change in % predicted 6MWD from baseline to week 104 was + 3.1 (8.1) for cipa + mig and - 0.5 (7.8) for the ERT-experienced switch group, and + 8.6 (8.6) for cipa + mig and + 8.9 (11.7) for the ERT-naïve switch group. Mean (SD) change in % predicted FVC was - 0.6 (7.5) for cipa + mig and - 3.8 (6.2) for the ERT-experienced switch group, and - 4.8 (6.5) and - 3.1 (6.7), respectively, in ERT-naïve patients. CK and Hex4 levels improved in both treatment groups by week 104 with cipa + mig treatment. Three patients discontinued the OLE due to infusion-associated reactions. No new safety signals were identified. Cipa + mig treatment up to 104 weeks was associated with overall maintained improvements (6MWD, biomarkers) or stabilization (FVC) from baseline with continued durability, and was well tolerated, supporting long-term benefits for patients with LOPD.Trial registration number: NCT04138277; trial start date: December 18, 2019., (© 2024. The Author(s).)
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- 2024
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23. Ventilatory Assistance Before Umbilical Cord Clamping in Extremely Preterm Infants: A Randomized Clinical Trial.
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Fairchild KD, Petroni GR, Varhegyi NE, Strand ML, Josephsen JB, Niermeyer S, Barry JS, Warren JB, Rincon M, Fang JL, Thomas SP, Travers CP, Kane AF, Carlo WA, Byrne BJ, Underwood MA, Poulain FR, Law BH, Gorman TE, Leone TA, Bulas DI, Epelman M, Kline-Fath BM, Chisholm CA, and Kattwinkel J
- Subjects
- Humans, Infant, Newborn, Female, Male, Canada, Respiration, Artificial methods, Cerebral Intraventricular Hemorrhage prevention & control, Umbilical Cord, Continuous Positive Airway Pressure methods, Gestational Age, Time Factors, United States, Infant, Extremely Premature, Umbilical Cord Clamping methods
- Abstract
Importance: Providing assisted ventilation during delayed umbilical cord clamping may improve outcomes for extremely preterm infants., Objective: To determine whether assisted ventilation in extremely preterm infants (23 0/7 to 28 6/7 weeks' gestational age [GA]) followed by cord clamping reduces intraventricular hemorrhage (IVH) or early death., Design, Setting, and Participants: This phase 3, 1:1, parallel-stratified randomized clinical trial conducted at 12 perinatal centers across the US and Canada from September 2, 2016, through February 21, 2023, assessed IVH and early death outcomes of extremely preterm infants randomized to receive 120 seconds of assisted ventilation followed by cord clamping vs delayed cord clamping for 30 to 60 seconds with ventilatory assistance afterward. Two analysis cohorts, not breathing well and breathing well, were specified a priori based on assessment of breathing 30 seconds after birth., Intervention: After birth, all infants received stimulation and suctioning if needed. From 30 to 120 seconds, infants randomized to the intervention received continuous positive airway pressure if breathing well or positive-pressure ventilation if not, with cord clamping at 120 seconds. Control infants received 30 to 60 seconds of delayed cord clamping followed by standard resuscitation., Main Outcomes and Measures: The primary outcome was any grade IVH on head ultrasonography or death before day 7. Interpretation by site radiologists was confirmed by independent radiologists, all masked to study group. To estimate the association between study group and outcome, data were analyzed using the stratified Cochran-Mantel-Haenszel test for relative risk (RR), with associations summarized by point estimates and 95% CIs., Results: Of 1110 women who consented to participate, 548 were randomized and delivered infants at GA less than 29 weeks. A total of 570 eligible infants were enrolled (median [IQR] GA, 26.6 [24.9-27.7] weeks; 297 male [52.1%]). Intraventricular hemorrhage or death occurred in 34.9% (97 of 278) of infants in the intervention group and 32.5% (95 of 292) in the control group (adjusted RR, 1.02; 95% CI, 0.81-1.27). In the prespecified not-breathing-well cohort (47.5% [271 of 570]; median [IQR] GA, 26.0 [24.7-27.4] weeks; 152 male [56.1%]), IVH or death occurred in 38.7% (58 of 150) of infants in the intervention group and 43.0% (52 of 121) in the control group (RR, 0.91; 95% CI, 0.68-1.21). There was no evidence of differences in death, severe brain injury, or major morbidities between the intervention and control groups in either breathing cohort., Conclusions and Relevance: This study did not show that providing assisted ventilation before cord clamping in extremely preterm infants reduces IVH or early death. Additional study around the feasibility, safety, and efficacy of assisted ventilation before cord clamping may provide additional insight., Trial Registration: ClinicalTrials.gov Identifier: NCT02742454.
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- 2024
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24. The multifaceted roles of the brain glycogen.
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Markussen KH, Corti M, Byrne BJ, Vander Kooi CW, Sun RC, and Gentry MS
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- Animals, Humans, Glycogen Storage Disease metabolism, Brain metabolism, Glycogen metabolism
- Abstract
Glycogen is a biologically essential macromolecule that is directly involved in multiple human diseases. While its primary role in carbohydrate storage and energy metabolism in the liver and muscle is well characterized, recent research has highlighted critical metabolic and non-metabolic roles for glycogen in the brain. In this review, the emerging roles of glycogen homeostasis in the healthy and diseased brain are discussed with a focus on advancing our understanding of the role of glycogen in the brain. Innovative technologies that have led to novel insights into glycogen functions are detailed. Key insights into how cellular localization impacts neuronal and glial function are discussed. Perturbed glycogen functions are observed in multiple disorders of the brain, including where it serves as a disease driver in the emerging category of neurological glycogen storage diseases (n-GSDs). n-GSDs include Lafora disease (LD), adult polyglucosan body disease (APBD), Cori disease, Glucose transporter type 1 deficiency syndrome (G1D), GSD0b, and late-onset Pompe disease (PD). They are neurogenetic disorders characterized by aberrant glycogen which results in devastating neurological and systemic symptoms. In the most severe cases, rapid neurodegeneration coupled with dementia results in death soon after diagnosis. Finally, we discuss current treatment strategies that are currently being developed and have the potential to be of great benefit to patients with n-GSD. Taken together, novel technologies and biological insights have resulted in a renaissance in brain glycogen that dramatically advanced our understanding of both biology and disease. Future studies are needed to expand our understanding and the multifaceted roles of glycogen and effectively apply these insights to human disease., (© 2023 International Society for Neurochemistry.)
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- 2024
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25. Video-Assisted Informed Consent in a Clinical Trial of Resuscitation of Extremely Preterm Infants: Lessons Learned.
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Odackal NJ, Caruso CG, Klitzman M, Rincon M, Byrne BJ, Winter J, Petroni GR, Fairchild KD, and Warren JB
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- Humans, Female, Infant, Newborn, Adult, Surveys and Questionnaires, Informed Consent, Infant, Extremely Premature, Video Recording, Resuscitation methods
- Abstract
Objective: Obtaining informed consent for clinical trials is challenging in acute clinical settings. For the VentFirst randomized clinical trial (assisting ventilation during delayed cord clamping for infants <29 weeks' gestation), we created an informational video that sites could choose to use to supplement the standard in-person verbal and written consent. Using a postconsent survey, we sought to describe the impact of the video on patient recruitment, satisfaction with the consent process, and knowledge about the study., Study Design: This is a descriptive survey-based substudy., Results: Of the sites participating in the VentFirst trial that obtained institutional review board (IRB) approval to allow use of the video to supplement the standard informed consent process, three elected to participate in the survey substudy. From February 2018 to January 2021, 82 women at these three sites were offered the video and completed the postconsent survey. Overall, 73 of these 82 women (89%) consented to participate in the primary study, 78 (95%) indicated the study was explained to them very well or extremely well, and the range of correct answers on five knowledge questions about the study was 63 to 98%. Forty-six (56%) of the 82 women offered the video chose to watch it. There were no major differences in study participation, satisfaction with the consent process, or knowledge about the study between the women who chose to watch or not watch the video., Conclusion: Watching an optional video to supplement the standard informed consent process did not have a major impact on outcomes in this small substudy. The ways in which audiovisual tools might modify the traditional informed consent process deserve further study., Key Points: · Informed consent in acute clinical contexts is difficult.. · Videos offer an alternative communication tool.. · Continued research is necessary to optimize the consent process.., Competing Interests: None declared., (Thieme. All rights reserved.)
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- 2024
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26. Improving Accuracy for Initial Endotracheal Tube Size Selection for Newborns.
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Byrne BJ and Kapadia V
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- Humans, Infant, Newborn, Intubation, Intratracheal
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- 2024
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27. Long-term safety and efficacy of cipaglucosidase alfa plus miglustat in individuals living with Pompe disease: an open-label phase I/II study (ATB200-02).
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Byrne BJ, Schoser B, Kishnani PS, Bratkovic D, Clemens PR, Goker-Alpan O, Ming X, Roberts M, Vorgerd M, Sivakumar K, van der Ploeg AT, Goldman M, Wright J, Holdbrook F, Jain V, Benjamin ER, Johnson F, Das SS, Wasfi Y, and Mozaffar T
- Subjects
- Adult, Humans, Treatment Outcome, alpha-Glucosidases therapeutic use, Indoles, Enzyme Replacement Therapy methods, Glycogen Storage Disease Type II therapy, Propionates, 1-Deoxynojirimycin analogs & derivatives
- Abstract
Cipaglucosidase alfa plus miglustat (cipa + mig) is a novel, two-component therapy for Pompe disease. We report data from the Phase I/II ATB200-02 study for up to 48 months of treatment. Four adult cohorts, including one non-ambulatory ERT-experienced (n = 6) and three ambulatory cohorts, (two enzyme replacement therapy [ERT]-experienced cohorts [2-6 years (n = 11) and ≥ 7 years (n = 6)]), one ERT-naïve cohort (n = 6), received 20 mg/kg intravenous-infused cipa plus 260 mg oral mig biweekly. Change from baseline (CFBL) for multiple efficacy endpoints at 12, 24, 36, and 48 months, pharmacodynamics, pharmacokinetics, safety, and immunogenicity data were assessed. Six-minute walking distance (% predicted) improved at 12, 24, 36, and 48 months: pooled ambulatory ERT-experienced cohorts, mean(± standard deviation [SD]) CFBL: 6.1(± 7.84), n = 16; 5.4(± 10.56), n = 13; 3.4(± 14.66), n = 12; 5.9(± 17.36), n = 9, respectively; ERT-naïve cohort: 10.7(± 3.93), n = 6; 11.0(± 5.06), n = 6; 9.0(± 7.98), n = 5; 11.7(± 7.69), n = 4, respectively. Percent predicted forced vital capacity was generally stable in ERT-experienced cohorts, mean(± SD) CFBL - 1.2(± 5.95), n = 16; 1.0(± 7.96), n = 13; - 0.3(± 6.68), n = 10; 1.0(± 6.42), n = 6, respectively, and improved in the ERT-naïve cohort: 3.2(± 8.42), n = 6; 4.7(± 5.09), n = 6; 6.2(± 3.35), n = 5; 8.3(± 4.50), n = 4, respectively. Over 48 months, CK and Hex4 biomarkers improved in ambulatory cohorts. Overall, cipa + mig was well tolerated with a safety profile like alglucosidase alfa. ATB200-02 results show the potential benefits of cipa + mig as a long-term treatment option for Pompe disease. Trial registration number: NCT02675465 January 26, 2016., (© 2023. The Author(s).)
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- 2024
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28. Pediatricians' Career Satisfaction and Wellbeing by Sex Before and During the COVID-19 Pandemic.
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Frintner MP, Leslie LK, Gottschlich EA, Starmer AJ, Byrne BJ, and Freed GL
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- Humans, Child, Female, Male, Cohort Studies, Job Satisfaction, Pandemics, Pediatricians, COVID-19 epidemiology
- Abstract
Objective: To compare pediatrician career satisfaction and wellbeing by sex during the coronavirus disease 2019 pandemic with prepandemic years using longitudinal survey data., Methods: Data from a cohort study, the American Academy of Pediatrics Pediatrician Life and Career Experience Study, were used to examine career satisfaction and wellbeing from 2012 to 2021 among 2002-2004 and 2009-2011 residency graduates (n = 1760). Mixed effects logistic regression, including key pediatrician characteristics, examined career satisfaction and wellbeing measures for sex (female vs male), pandemic year (2012-2019 vs 2020-2021), and their interaction effect. Adjusted predicted percentage values (PVs) were determined., Results: In total, 73.4% of participants identified as female. Adjusting for key pediatrician characteristics, differences were found by sex for satisfaction and 4 of 5 wellbeing measures, by pandemic year for 2 wellbeing measures, and the interaction of sex and pandemic year for 3 wellbeing measures. Female pediatricians reported higher levels of anxiety, sadness, and work stress, with greater differences during the pandemic. For example, female pediatricians (PV = 22.6, confidence interval [CI] = 21.0-24.3) were more likely than male pediatricians (PV = 14.2, CI = 12.0-16.4) to report anxiety during pre-pandemic years, and the difference between female pediatricians (PV = 29.3, CI = 26.7-32.0) and male pediatricians (PV = 12.4, CI = 9.3-15.5) increased during pandemic years (sex by pandemic year interaction, P < .001)., Conclusions: Compared with male pediatricians, female pediatricians reported worse anxiety, sadness, and stress at work, and the differences were more pronounced during the pandemic., (Copyright © 2024 by the American Academy of Pediatrics.)
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- 2024
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29. Kenneth I. Berns, MD, PhD [1938-2024].
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Byrne BJ, Flotte TR, Herzog RW, and Srivastava A
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- 2024
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30. B cell focused transient immune suppression protocol for efficient AAV readministration to the liver.
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Rana J, Herzog RW, Muñoz-Melero M, Yamada K, Kumar SRP, Lam AK, Markusic DM, Duan D, Terhorst C, Byrne BJ, Corti M, and Biswas M
- Abstract
Adeno-associated virus (AAV) vectors are used for correcting multiple genetic disorders. Although the goal is to achieve lifelong correction with a single vector administration, the ability to redose would enable the extension of therapy in cases in which initial gene transfer is insufficient to achieve a lasting cure, episomal vector forms are lost in growing organs of pediatric patients, or transgene expression is diminished over time. However, AAV typically induces potent and long-lasting neutralizing antibodies (NAbs) against capsid that prevents re-administration. To prevent NAb formation in hepatic AAV8 gene transfer, we developed a transient B cell-targeting protocol using a combination of monoclonal Ab therapy against CD20 (for B cell depletion) and BAFF (to slow B cell repopulation). Initiation of immunosuppression before (rather than at the time of) vector administration and prolonged anti-BAFF treatment prevented immune responses against the transgene product and abrogated prolonged IgM formation. As a result, vector re-administration after immune reconstitution was highly effective. Interestingly, re-administration before the immune system had fully recovered achieved further elevated levels of transgene expression. Finally, this immunosuppression protocol reduced Ig-mediated AAV uptake by immune cell types with implications to reduce the risk of immunotoxicities in human gene therapy with AAV., Competing Interests: R.W.H. serves on the scientific advisory boards and committees of Regeneron Pharmaceuticals, Pfizer, Biomarin, Spark Therapeutics, Hoffman-La Roche, and Prevail Therapeutics. D.D. serves on the scientific advisory boards of Solid Biosciences and Sardocor Corporation. M.B. serves on the steering committee of Pfizer., (© 2024 The Author(s).)
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- 2024
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31. The Clinical Development of Taldefgrobep Alfa: An Anti-Myostatin Adnectin for the Treatment of Duchenne Muscular Dystrophy.
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Muntoni F, Byrne BJ, McMillan HJ, Ryan MM, Wong BL, Dukart J, Bansal A, Cosson V, Dreghici R, Guridi M, Rabbia M, Staunton H, Tirucherai GS, Yen K, Yuan X, and Wagner KR
- Abstract
Introduction: Duchenne muscular dystrophy (DMD) is a genetic muscle disorder that manifests during early childhood and is ultimately fatal. Recently approved treatments targeting the genetic cause of DMD are limited to specific subpopulations of patients, highlighting the need for therapies with wider applications. Pharmacologic inhibition of myostatin, an endogenous inhibitor of muscle growth produced almost exclusively in skeletal muscle, has been shown to increase muscle mass in several species, including humans. Taldefgrobep alfa is an anti-myostatin recombinant protein engineered to bind to and block myostatin signaling. Preclinical studies of taldefgrobep alfa demonstrated significant decreases in myostatin and increased lower limb volume in three animal species, including dystrophic mice., Methods: This manuscript reports the cumulative data from three separate clinical trials of taldefgrobep alfa in DMD: a phase 1 study in healthy adult volunteers (NCT02145234), and two randomized, double-blind, placebo-controlled studies in ambulatory boys with DMD-a phase 1b/2 trial assessing safety (NCT02515669) and a phase 2/3 trial including the North Star Ambulatory Assessment (NSAA) as the primary endpoint (NCT03039686)., Results: In healthy adult volunteers, taldefgrobep alfa was generally well tolerated and resulted in a significant increase in thigh muscle volume. Treatment with taldefgrobep alfa was associated with robust dose-dependent suppression of free myostatin. In the phase 1b/2 trial, myostatin suppression was associated with a positive effect on lean body mass, though effects on muscle mass were modest. The phase 2/3 trial found that the effects of treatment did not meet the primary endpoint pre-specified futility analysis threshold (change from baseline of ≥ 1.5 points on the NSAA total score)., Conclusions: The futility analysis demonstrated that taldefgrobep alfa did not result in functional change for boys with DMD. The program was subsequently terminated in 2019. Overall, there were no safety concerns, and no patients were withdrawn from treatment as a result of treatment-related adverse events or serious adverse events., Trial Registration: NCT02145234, NCT02515669, NCT03039686., (© 2024. The Author(s).)
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- 2024
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32. Thrombotic microangiopathy following systemic AAV administration is dependent on anti-capsid antibodies.
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Salabarria SM, Corti M, Coleman KE, Wichman MB, Berthy JA, D'Souza P, Tifft CJ, Herzog RW, Elder ME, Shoemaker LR, Leon-Astudillo C, Tavakkoli F, Kirn DH, Schwartz JD, and Byrne BJ
- Subjects
- Humans, Immunoglobulin M, Immunoglobulin G, Dependovirus genetics, Thrombotic Microangiopathies therapy
- Abstract
BACKGROUNDSystemic administration of adeno-associated virus (AAV) can trigger life-threatening inflammatory responses, including thrombotic microangiopathy (TMA), acute kidney injury due to atypical hemolytic uremic syndrome-like complement activation, immune-mediated myocardial inflammation, and hepatic toxicity.METHODSWe describe the kinetics of immune activation following systemic AAV serotype 9 (AAV9) administration in 38 individuals following 2 distinct prophylactic immunomodulation regimens. Group 1 received corticosteroids and Group 2 received rituximab plus sirolimus in addition to steroids to prevent anti-AAV antibody formation.RESULTSGroup 1 participants had a rapid increase in immunoglobulin M (IgM) and IgG. Increase in D-dimer, decline in platelet count, and complement activation are indicative of TMA. All Group 1 participants demonstrated activation of both classical and alternative complement pathways, as indicated by depleted C4 and elevated soluble C5b-9, Ba, and Bb antigens. Group 2 patients did not have a significant change in IgM or IgG and had minimal complement activation.CONCLUSIONSThis study demonstrates that TMA in the setting of AAV gene therapy is antibody dependent (classical pathway) and amplified by the alternative complement pathway. Critical time points and interventions are identified to allow for management of immune-mediated events that impact the safety and efficacy of systemic gene therapy.
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- 2024
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33. Meeting Report: 2023 Muscular Dystrophy Association Summit on 'Safety and Challenges in Gene Therapy of Neuromuscular Diseases'.
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Lek A, Atas E, Lin B, Hesterlee SE, Abbott JK, Byrne BJ, and Bönnemann CG
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- Humans, Muscular Dystrophies therapy, Muscular Dystrophies genetics, Genetic Therapy methods, Neuromuscular Diseases therapy, Neuromuscular Diseases genetics
- Abstract
This meeting report summarizes the presentations and discussions held at the summit on Challenges in Gene Therapy hosted by the Muscular Dystrophy Association (MDA) in 2023. Topics covered include safety issues, mitigation strategies and practical considerations pertaining to the clinical translation of gene therapies for neuromuscular disease. The listing of actionable recommendations will assist in overall efforts in the field to achieve safe and efficacious translation of gene therapies for neuromuscular disease patients.
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- 2024
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34. Fetal Injury from Maternal Penetrating Abdominal Trauma in Pregnancy.
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Barron E, Jeffries A, Pelton S, Vogel K, and Byrne BJ
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- Pregnancy, Female, Humans, Abdominal Injuries diagnosis, Pregnancy Complications diagnosis, Fetal Diseases
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- 2024
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35. Perspectives of the Friedreich ataxia community on gene therapy clinical trials.
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Trantham SJ, Coker MA, Norman S, Crowley E, Berthy J, Byrne BJ, Subramony S, Lou X, and Corti M
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Gene therapy is a potential treatment for Friedreich ataxia, with multiple programs on the horizon. The purpose of this study was to collect opinions about gene therapy from individuals 14 years or older with Friedreich ataxia or parents/caregivers of Friedreich ataxia patients who were diagnosed as children 17 or younger. Participants were asked to complete a survey after reading brief educational materials regarding gene therapy. Most of the patients captured in this survey have an early-onset (classical) presentation of the disease. Participants expressed urgency in participating in gene therapy clinical trials despite the associated risks. About half of the respondents believed that gene therapy would cease progression or minimize symptoms, whereas nearly one-fourth expected to be cured. The survey also revealed how participants perceive their symptom burden, because a substantial majority reported that balance/walking issues most interfere with their quality of life and would be the symptom they would prioritize treating. Although not statistically significant, more caregivers prioritized treating cardiomyopathy than patients. This study provides valuable information on priorities, beliefs, and expectations regarding gene therapy and serves to guide future gene therapy opinion studies and gene therapy trial design., Competing Interests: M.C. and B.J.B. are co-founders of AavantiBio, which supported the employee at ClinicalMind who provided graphical support for the educational material written by the study team. The survey was completed before the acquisition of AavantiBio by Solid Biosciences. None of the authors have any financial, commercial, legal, or professional relationship with Solid Biosciences. There was no commercial support for this study. The study was developed and conducted by the academic team at the University of Florida. Thus, the authors declare that they have no competing interests., (© 2023 The Author(s).)
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- 2023
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36. Evolving Horizons: Adenovirus Vectors' Timeless Influence on Cancer, Gene Therapy and Vaccines.
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Trivedi PD, Byrne BJ, and Corti M
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- Humans, COVID-19 Vaccines, Virus Replication genetics, Genetic Vectors genetics, Adenoviridae genetics, Genetic Therapy, Neoplasms genetics, Neoplasms therapy, Vaccines
- Abstract
Efficient and targeted delivery of a DNA payload is vital for developing safe gene therapy. Owing to the recent success of commercial oncolytic vector and multiple COVID-19 vaccines, adenovirus vectors are back in the spotlight. Adenovirus vectors can be used in gene therapy by altering the wild-type virus and making it replication-defective; specific viral genes can be removed and replaced with a segment that holds a therapeutic gene, and this vector can be used as delivery vehicle for tissue specific gene delivery. Modified conditionally replicative-oncolytic adenoviruses target tumors exclusively and have been studied in clinical trials extensively. This comprehensive review seeks to offer a summary of adenovirus vectors, exploring their characteristics, genetic enhancements, and diverse applications in clinical and preclinical settings. A significant emphasis is placed on their crucial role in advancing cancer therapy and the latest breakthroughs in vaccine clinical trials for various diseases. Additionally, we tackle current challenges and future avenues for optimizing adenovirus vectors, promising to open new frontiers in the fields of cell and gene therapies.
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- 2023
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37. Development of capsid- and genome-modified optimized AAVrh74 vectors for muscle gene therapy.
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Shoti J, Qing K, Keeler GD, Duan D, Byrne BJ, and Srivastava A
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The first generation of adeno-associated virus (AAV) vectors composed of the naturally occurring capsids and genomes, although effective in some instances, are unlikely to be optimal for gene therapy in humans. The use of the first generation of two different AAV serotype vectors (AAV9 and AAVrh74) in four separate clinical trials failed to be effective in patients with Duchenne muscular dystrophy, although some efficacy was observed in a subset of patients with AAVrh74 vectors leading to US Food and Drug Administration approval (Elevidys). In two trials with the first generation of AAV9 vectors, several serious adverse events were observed, including the death of a patient in one trial, and more recently, in the death of a second patient in an N-of-1 clinical trial. In a fourth trial with the first generation of AAVrh74 vectors, myositis and myocarditis were also observed. Here, we report that capsid- and genome-modified optimized AAVrh74 vectors are significantly more efficient in transducing primary human skeletal muscle cells in vitro and in all major muscle tissues in vivo following systemic administration in a murine model. The availability of optimized AAVrh74 vectors promises to be safe and effective in the potential gene therapy of muscle diseases in humans., Competing Interests: A.S. is a cofounder of, and has equity in, Lacerta Therapeutics. He also serves on the scientific advisory board of 4D Molecular Therapeutics. He is an inventor on several issued and filed patents on recombinant AAV vectors that have been or are being licensed to various AAV gene therapy companies. B.J.B. is an inventor of AAV-related patents that have been licensed to various AAV gene therapy companies. He is a co-founder and equity holder in Lacerta Therapeutics. D.D. is a member of the scientific advisory board for Solid Biosciences and equity holder in Solid Biosciences. He is also a member of the scientific advisory board of Sardocor Corporation. All of the other authors declare no competing interests., (© 2023 The Authors.)
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- 2023
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38. Current avenues of gene therapy in Pompe disease.
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Leon-Astudillo C, Trivedi PD, Sun RC, Gentry MS, Fuller DD, Byrne BJ, and Corti M
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- Humans, Genetic Therapy, Central Nervous System, Dependovirus genetics, Glycogen, Glycogen Storage Disease Type II genetics, Glycogen Storage Disease Type II therapy
- Abstract
Purpose of Review: Pompe disease is a rare, inherited, devastating condition that causes progressive weakness, cardiomyopathy and neuromotor disease due to the accumulation of glycogen in striated and smooth muscle, as well as neurons. While enzyme replacement therapy has dramatically changed the outcome of patients with the disease, this strategy has several limitations. Gene therapy in Pompe disease constitutes an attractive approach due to the multisystem aspects of the disease and need to address the central nervous system manifestations. This review highlights the recent work in this field, including methods, progress, shortcomings, and future directions., Recent Findings: Recombinant adeno-associated virus (rAAV) and lentiviral vectors (LV) are well studied platforms for gene therapy in Pompe disease. These products can be further adapted for safe and efficient administration with concomitant immunosuppression, with the modification of specific receptors or codon optimization. rAAV has been studied in multiple clinical trials demonstrating safety and tolerability., Summary: Gene therapy for the treatment of patients with Pompe disease is feasible and offers an opportunity to fully correct the principal pathology leading to cellular glycogen accumulation. Further work is needed to overcome the limitations related to vector production, immunologic reactions and redosing., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2023
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39. Elevated liver glycogenolysis mediates higher blood glucose during acute exercise in Barth syndrome.
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Schweitzer GG, Ditzenberger GL, Hughey CC, Finck BN, Martino MR, Pacak CA, Byrne BJ, and Cade WT
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- Humans, Male, Animals, Mice, Blood Glucose, Liver, Glucose, Mice, Transgenic, Muscle, Skeletal, Glycogenolysis, Barth Syndrome genetics, Hyperglycemia, Genetic Diseases, X-Linked
- Abstract
Barth syndrome (BTHS) is an X-linked recessive genetic disorder due to mutations in the Tafazzin (TAFAZZIN) gene that lead to cardiac and skeletal muscle mitochondrial dysfunction. Previous studies in humans with BTHS demonstrate that the defects in muscle mitochondrial oxidative metabolism result in an enhanced reliance on anaerobic metabolism during exercise to meet energy demands of muscular work. During exercise, the liver normally increases glucose production via glycogenolysis and gluconeogenesis to match the elevated rate of muscle glucose uptake and meet the ATP requirements of working muscle. However, the impact of Tafazzin deficiency on hepatic glucose production and the pathways contributing to hepatic glucose production during exercise is unknown. Therefore, the purpose of this study was to quantify in vivo liver gluconeogenesis and glycogenolysis in Tafazzin knockdown mice at rest and during acute exercise., Methods: Male TAFAZZIN shRNA transgenic (TG) and wild-type (WT) mice completed exhaustive treadmill running protocols to test exercise tolerance. Mice underwent 2H- and 13C-stable isotope infusions at rest and during a 30-minute treadmill running bout to quantify hepatic glucose production and associated nutrient fluxes under sedentary conditions and during acute exercise. Circulating and tissue (skeletal muscle and liver) samples were obtained during and following exercise to assess static metabolite levels., Results: TG mice reached exhaustion sooner during exhaustive treadmill running protocols and exhibited higher plasma lactate concentrations after exhaustive exercise compared to WT mice. Arterial glucose levels were comparable between genotypes at rest, but higher in TG mice compared to WT mice during exercise. Consistent with the higher blood glucose, TG mice showed increased endogenous glucose production owing to elevated glycogenolysis compared to WT mice during exercise. Total gluconeogenesis, gluconeogenesis from glycerol, gluconeogenesis from phosphoenolpyruvate, pyruvate cycling, total cataplerosis, and anaplerotic fluxes were similar between TG and WT mice at rest and during exercise. However, lactate dehydrogenase flux and TCA cycle fluxes trended higher in TG mice during exercise. Liver glycogen content in TG was higher in TG vs. controls., Conclusion: Our data in the Tafazzin knockdown mouse suggest that elevated anaerobic metabolism during rest and exercise previously reported in humans with BTHS are supported by the finding of higher hepatic glycogenolysis., Competing Interests: The authors declared no conflict of interest., (Copyright: © 2023 Schweitzer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2023
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40. Diaphragm pacing and independent breathing in individuals with severe Pompe disease.
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Liberati C, Byrne BJ, Fuller DD, Croft C, Pitts T, Ehrbar J, Leon-Astudillo C, and Smith BK
- Abstract
Introduction: Pompe disease is an inherited disease characterized by a deficit in acid-α-glucosidase (GAA), an enzyme which degrades lysosomal glycogen. The phrenic-diaphragm motor system is affected preferentially, and respiratory failure often occurs despite GAA enzyme replacement therapy. We hypothesized that the continued use of diaphragm pacing (DP) might improve ventilator-dependent subjects' respiratory outcomes and increase ventilator-free time tolerance., Methods: Six patients (3 pediatric) underwent clinical DP implantation and started diaphragm conditioning, which involved progressively longer periods of daily, low intensity stimulation. Longitudinal respiratory breathing pattern, diaphragm electromyography, and pulmonary function tests were completed when possible, to assess feasibility of use, as well as diaphragm and ventilatory responses to conditioning., Results: All subjects were eventually able to undergo full-time conditioning via DP and increase their maximal tolerated time off-ventilator, when compared to pre-implant function. Over time, 3 of 6 subjects also demonstrated increased or stable minute ventilation throughout the day, without positive-pressure ventilation assistance., Discussion: Respiratory insufficiency is one of the main causes of death in patients with Pompe disease. Our results indicate that DP in Pompe disease was feasible, led to few adverse events and stabilized breathing for up to 7 years., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Liberati, Byrne, Fuller, Croft, Pitts, Ehrbar, Leon-Astudillo and Smith.)
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- 2023
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41. Adeno-associated virus-mediated gene therapy in a patient with Canavan disease using dual routes of administration and immune modulation.
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Corti M, Byrne BJ, Gessler DJ, Thompson G, Norman S, Lammers J, Coleman KE, Liberati C, Elder ME, Escolar ML, Tuna IS, Mesaros C, Kleiner GI, Barbouth DS, Gray-Edwards HL, Clement N, Cleaver BD, and Gao G
- Abstract
Gene replacement therapy is a rational therapeutic strategy and clinical intervention for neurodegenerative disorders like Canavan disease, a leukodystrophy caused by biallelic mutations in the aspartoacylase ( ASPA ) gene. We aimed to investigate whether simultaneous intravenous (i.v.) and intracerebroventricular (i.c.v.) administration of rAAV9-CB6-ASPA provides a safe and effective therapeutic strategy in an open-label, individual-patient, expanded-access trial for Canavan disease. Immunomodulation was given prophylactically prior to adeno-associated virus (AAV) treatment to prevent an immune response to ASPA or the vector capsid. The patient served as his own control, and change from baseline was assessed by clinical pathology tests, vector genomes in the blood, antibodies against ASPA and AAV capsids, levels of cerebrospinal fluid (CSF) N -acetylaspartate (NAA), brain water content and morphology, clinical status, and motor function tests. Two years post treatment, the patient's white matter myelination had increased, motor function was improved, and he remained free of typical severe epilepsy. NAA level was reduced at 3 months and remained stable up to 4 years post treatment. Immunomodulation prior to AAV exposure enables repeat dosing and has prevented an anti-transgene immune response. Dual-route administration of gene therapy may improve treatment outcomes., Competing Interests: G.G. and D.J.G. are co-founders of ASPA Therapeutics., (© 2023.)
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- 2023
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42. Examining Early Career Pediatrician Characteristics, Sacrifices, and Satisfaction.
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Webber SA, Byrne BJ, Starmer AJ, Somberg CA, and Frintner MP
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- Child, Humans, Female, Pediatricians, Surveys and Questionnaires, Personal Satisfaction, Career Choice, Job Satisfaction, Physicians
- Abstract
Objective: Explore relationships between pediatrician characteristics, sacrifices made for career, and career and life satisfaction., Methods: Surveys of early career pediatricians (ECPs) who recently graduated residency (2016-18), as part of the AAP Pediatrician Life and Career Experience Study (PLACES) were administered in 2019. Logistic regression analyzed association of pediatrician characteristics with personal sacrifices (a lot vs some or no sacrifices) made for one's career and whether career was worth the sacrifices made to become a physician, and association of characteristics and sacrifices with overall career and life satisfaction., Results: Of 918 ECPs in the cohort, 90% responded to the 2019 survey. Seventy-seven percent agreed their career was worth the sacrifices and 40% reported they made a lot of personal sacrifices for their career. In multivariable analysis, female sex was associated with lower odds of viewing career as worth the sacrifices made [adjusted odds ratio [aOR] 0.45; 95% confidence interval [CI], 0.28-0.71], a higher odds of delaying starting a family [aOR 2.25; CI, 1.32-3.86] and making sacrifices in having children for career [aOR 2.60; CI, 1.48-4.58]. Those in fellowship training also reported making more sacrifices related to having children for their career [aOR 1.73; CI, 1.08-2.78]. ECPs who reported making a lot of sacrifices for their career were less likely to be satisfied with their overall career and life., Conclusions: Most ECPs believe their sacrifices to become a pediatrician were worth it. Female pediatricians were less likely to feel personal sacrifices were worth it and reported more sacrifices related to having children., (Copyright © 2023 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)
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- 2023
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43. Nicholas Muzyczka, PhD.
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Berns KI, Byrne BJ, Flotte TR, Samulski RJ, and Srivastava A
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- 2023
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44. Binding and neutralizing anti-AAV antibodies: Detection and implications for rAAV-mediated gene therapy.
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Schulz M, Levy DI, Petropoulos CJ, Bashirians G, Winburn I, Mahn M, Somanathan S, Cheng SH, and Byrne BJ
- Subjects
- Humans, Seroepidemiologic Studies, Genetic Vectors genetics, Genetic Therapy methods, Antibodies, Viral, Capsid Proteins genetics, Antibodies, Neutralizing, Dependovirus genetics
- Abstract
Assessment of anti-adeno-associated virus (AAV) antibodies in patients prior to systemic gene therapy administration is an important consideration regarding efficacy and safety of the therapy. Approximately 30%-60% of individuals have pre-existing anti-AAV antibodies. Seroprevalence is impacted by multiple factors, including geography, age, capsid serotype, and assay type. Anti-AAV antibody assays typically measure (1) transduction inhibition by detecting the neutralizing capacity of antibodies and non-antibody neutralizing factors, or (2) total anti-capsid binding antibodies, regardless of neutralizing activity. Presently, there is a paucity of head-to-head data and standardized approaches associating assay results with clinical outcomes. In addition, establishing clinically relevant screening titer cutoffs is complex. Thus, meaningful comparisons across assays are nearly impossible. Although complex, establishing screening assays in routine clinical practice to identify patients with antibody levels that may impact favorable treatment outcomes is achievable for both transduction inhibition and total antibody assays. Formal regulatory approval of such assays as companion diagnostic tests will confirm their suitability for specific recombinant AAV gene therapies. This review covers current approaches to measure anti-AAV antibodies in patient plasma or serum, their potential impact on therapeutic safety and efficacy, and investigative strategies to mitigate the effects of pre-existing anti-AAV antibodies in patients., Competing Interests: Declaration of interests S.H.C., M.S., S.S., G.B., I.W., M.M., and D.L. are employees of Pfizer. C.J.P. is an employee of Labcorp-Monogram Biosciences., (Copyright © 2023. Published by Elsevier Inc.)
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- 2023
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45. Optogenetic activation of the tongue in spontaneously breathing mice.
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Singer ML, Benevides ES, Rana S, Sunshine MD, Martinez RC, Barral BE, Byrne BJ, and Fuller DD
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- Mice, Animals, Mice, Inbred C57BL, Respiration, Tongue physiology, Optogenetics, Sleep Apnea, Obstructive
- Abstract
Inadequate tongue muscle activation contributes to dysarthria, dysphagia, and obstructive sleep apnea. Thus, treatments which increase tongue muscle activity have potential clinical benefit. We hypothesized that lingual injection of an adeno-associated virus (AAV) encoding channelrhodopsin-2 (ChR2) would enable light-induced activation of tongue motor units during spontaneous breathing. An AAV serotype 9 vector (pACAGW-ChR2-Venus-AAV9, 8.29 × 10
11 vg) was injected to the posterior tongue in adult C57BL/6J mice. After 12 weeks, mice were anesthetized and posterior tongue electromyographic (EMG) activity was recorded during spontaneous breathing; a light source was positioned near the injection site. Light-evoked EMG responses increased with the intensity and duration of pulses. Stimulus trains (250 ms) evoked EMG bursts that were comparable to endogenous (inspiratory) tongue muscle activation. Histology confirmed lingual myofiber transgene expression. We conclude that intralingual AAV9-ChR2 delivery enables light evoked lingual EMG activity. These proof-of-concept studies lay the groundwork for clinical application of this novel approach to lingual therapeutics., Competing Interests: Conflict of interest The authors declare no competing financial interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)- Published
- 2023
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46. Nicholas Muzyczka, PhD [1947-2023].
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Berns KI, Byrne BJ, Flotte TR, Samulski RJ, and Srivastava A
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- 2023
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47. Assessment of systemic AAV-microdystrophin gene therapy in the GRMD model of Duchenne muscular dystrophy.
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Birch SM, Lawlor MW, Conlon TJ, Guo LJ, Crudele JM, Hawkins EC, Nghiem PP, Ahn M, Meng H, Beatka MJ, Fickau BA, Prieto JC, Styner MA, Struharik MJ, Shanks C, Brown KJ, Golebiowski D, Bettis AK, Balog-Alvarez CJ, Clement N, Coleman KE, Corti M, Pan X, Hauschka SD, Gonzalez JP, Morris CA, Schneider JS, Duan D, Chamberlain JS, Byrne BJ, and Kornegay JN
- Subjects
- Animals, Dogs, Humans, Infant, Newborn, Mice, Dystrophin genetics, Dystrophin metabolism, Genetic Therapy, Heart, Muscle, Skeletal metabolism, Muscles metabolism, Muscular Dystrophy, Animal genetics, Muscular Dystrophy, Animal therapy, Muscular Dystrophy, Animal metabolism, Muscular Dystrophy, Duchenne genetics, Muscular Dystrophy, Duchenne therapy
- Abstract
Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by the absence of dystrophin, a membrane-stabilizing protein encoded by the DMD gene. Although mouse models of DMD provide insight into the potential of a corrective therapy, data from genetically homologous large animals, such as the dystrophin-deficient golden retriever muscular dystrophy (GRMD) model, may more readily translate to humans. To evaluate the clinical translatability of an adeno-associated virus serotype 9 vector (AAV9)-microdystrophin (μDys5) construct, we performed a blinded, placebo-controlled study in which 12 GRMD dogs were divided among four dose groups [control, 1 × 10
13 vector genomes per kilogram (vg/kg), 1 × 1014 vg/kg, and 2 × 1014 vg/kg; n = 3 each], treated intravenously at 3 months of age with a canine codon-optimized microdystrophin construct, rAAV9-CK8e-c-μDys5, and followed for 90 days after dosing. All dogs received prednisone (1 milligram/kilogram) for a total of 5 weeks from day -7 through day 28. We observed dose-dependent increases in tissue vector genome copy numbers; μDys5 protein in multiple appendicular muscles, the diaphragm, and heart; limb and respiratory muscle functional improvement; and reduction of histopathologic lesions. As expected, given that a truncated dystrophin protein was generated, phenotypic test results and histopathologic lesions did not fully normalize. All administrations were well tolerated, and adverse events were not seen. These data suggest that systemically administered AAV-microdystrophin may be dosed safely and could provide therapeutic benefit for patients with DMD.- Published
- 2023
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48. Meeting Report: 2022 Muscular Dystrophy Association Summit on 'Safety and Challenges in Gene Transfer Therapy'.
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Lek A, Atas E, Hesterlee SE, Byrne BJ, and Bönnemann CG
- Subjects
- Humans, Genetic Therapy adverse effects, Dependovirus genetics, Muscular Dystrophies genetics, Muscular Dystrophies therapy, Neuromuscular Diseases genetics, Neuromuscular Diseases therapy
- Abstract
Muscular Dystrophy Association (MDA) has invested over $125M in the development of gene therapy for neuromuscular disorders (NMD) over the past 20 years. As a lead initiator of progress in this important field of medicine and to help ensure continued progress towards therapies for patients, MDA organized a dedicated summit in January 2022 to address emerging challenges in safely delivering adeno-associated virus (AAV) mediated gene therapies with a focus on their application in NMD. In this meeting, chaired by Carsten Bönnemann (NINDS, NIH) and Barry Byrne (University of Florida), academic and industry experts and stakeholders convened to openly discuss adverse events linked to clinical trials, as well as other challenges emerging in preclinical studies associated with difficulties in the translation of AAV-mediated gene therapies.
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- 2023
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49. Polysomnography findings in children with spinal muscular atrophy after onasemnogene-abeparvovec.
- Author
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Leon-Astudillo C, Wagner M, Salabarria SM, Lammers J, Berthy J, Zingariello CD, Byrne BJ, and Smith BK
- Subjects
- Infant, Humans, Child, Female, Polysomnography, Cross-Sectional Studies, Sleep, Sleep Apnea Syndromes diagnosis, Muscular Atrophy, Spinal diagnosis
- Abstract
Background: Sleep disordered breathing (SDB) is common in patients with neuromuscular diseases, including spinal muscular atrophy (SMA). While polysomnography (PSG) findings have been described in natural history studies of patients with SMA, reports regarding PSG in treated children are limited to nusinersen. We aim to describe the sleep characteristics in a cohort of children treated with Onasemnogene-abeparvovec., Methods: We conducted a cross-sectional cohort study of children with SMA followed at the University of Florida Center for neuromuscular and rare diseases and had a diagnostic or split night PSG after SMA treatment., Results: Eight children were included in the cohort (four female), aged 5-250 days at diagnosis. Five children had two survival motor neuron 2 (SMN2) copies, two had three SMN2 copies and one subject had four SMN2 copies. Median age at the time of treatment was 46.5 days (range 20-257). All children received onasemnogene-abeparvovec (OA) before their PSG; in addition to OA, one received nusinersen and one received risdiplam. Apnea hypopnea index (AHI) ranged from 3.6 to 24.1/h. REM AHI was higher than NREM AHI. Median Children's Hospital of Philadelphia Infant test of neuromuscular disorders (CHOP-Intend) score at the time of PSG was 55 (range 33-64). There was no correlation between age at treatment, CHOP-Intend score and AHI., Conclusion: SDB is common in treated children with SMA, regardless of age at diagnosis, treatment and neuromotor scores. While AHI may not be the only indicator of SDB in this population, indications, timing of PSG in this cohort remain unknown., (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
50. Addressing the implementation gap in advanced therapeutics for spinal muscular atrophy in the era of newborn screening programs.
- Author
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Leon-Astudillo C, Byrne BJ, and Salloum RG
- Abstract
Spinal muscular atrophy (SMA) is a rare genetic disease that results in progressive neuromuscular weakness. Without therapy, the most common form of the disease, type 1, typically results in death or chronic respiratory failure in the first 2 years of life. Thanks to the recent introduction of newborn screening programs and the discovery of three disease-modifying therapies in the last decade, the outcomes of children with SMA have dramatically improved. Patients are able to achieve many, if not all, of the typical neuromotor milestones, such as sitting, standing and walking, as well as safe oral intake. As the natural history of treated patients is continuously evolving, children with SMA continue to require complex and multidisciplinary care, posing implementation and sustainability challenges. Accordingly, there is a significant need for the application and evaluation of implementation science to address the steps involved in the diagnosis and treatment of patients with SMA, ensuring that all pertinent stakeholders and systems are working effectively to deliver timely and appropriate care. In this manuscript, we discuss the current challenges and gaps in the care for children with SMA, as well as how implementation science can advance this field. In addition, we provide an adapted implementation science framework that includes the main domains and subdomains involved in the care of patients with SMA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Leon-Astudillo, Byrne and Salloum.)
- Published
- 2022
- Full Text
- View/download PDF
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