92 results on '"MacKenzie TC"'
Search Results
2. Intrauterine Molekulartherapien für Monogenetische Erkrankungen
- Author
-
Herzeg, A, additional, Wallwiener, S, additional, and MacKenzie, TC, additional
- Published
- 2022
- Full Text
- View/download PDF
3. Multilineage differentiation of human MSC after in utero transplantation.
- Author
-
Mackenzie, TC and Flake, AW
- Subjects
- *
STEM cells , *TRANSPLANTATION of organs, tissues, etc. , *HEMATOPOIETIC stem cells , *BONE marrow cells , *HEMATOPOIETIC system - Abstract
Prenatal transplantation of stem cells is an exciting frontier for the treatment of many congenital diseases. The fetus may be an ideal recipient for stem cells, as it is immunologically immature and has rapidly proliferating cellular compartments that may support the engraftment of transplanted cells. Mesenchymal stem cells (MSC), given their ability to differentiate among multiple lineages, could potentially be used to treat diseases such as osteogenesis imperfecta, muscular dystrophy, and a variety of others that can be diagnosed in utero. We have shown, using a human-sheep in utero xenotransplantation model, that human MSC have the ability to engraft, differentiate into many tissue types, and survive for over 1 year in fetal lamb recipients. This observation warrants further studies of the behavior of MSC following systemic or site-directed transplantation. [ABSTRACT FROM AUTHOR]
- Published
- 2001
- Full Text
- View/download PDF
4. In utero hematopoietic stem cell transplantation for Fanconi anemia.
- Author
-
Swartzrock L, Dib C, Denis M, Willner H, Ho K, Haslett E, Han J, Pan W, Byrne-Steele M, Brown B, Krampf MR, Girsen A, Blumenfeld YJ, El-Sayed YY, Roncarolo MG, MacKenzie TC, and Czechowicz AD
- Subjects
- Humans, Female, Pregnancy, Fanconi Anemia therapy, Hematopoietic Stem Cell Transplantation methods, Hematopoietic Stem Cell Transplantation adverse effects
- Published
- 2024
- Full Text
- View/download PDF
5. The Conundrum of Mechanics Versus Genetics in Congenital Hydrocephalus and Its Implications for Fetal Therapy Approaches: A Scoping Review.
- Author
-
Herzeg A, Borges B, Diafos LN, Gupta N, MacKenzie TC, and Sanders SJ
- Abstract
Recent advances in gene therapy, particularly for single-gene disorders (SGDs), have led to significant progress in developing innovative precision medicine approaches that hold promise for treating conditions such as primary hydrocephalus (CH), which is characterized by increased cerebrospinal fluid (CSF) volumes and cerebral ventricular dilation as a result of impaired brain development, often due to genetic causes. CH is a significant contributor to childhood morbidity and mortality and a driver of healthcare costs. In many cases, prenatal ultrasound can readily identify ventriculomegaly as early as 14-20 weeks of gestation, with severe cases showing poor neurodevelopmental outcomes. Postnatal surgical approaches, such as ventriculoperitoneal shunts, do not address the underlying genetic causes, have high complication rates, and result in a marginal improvement of neurocognitive deficits. Prenatal somatic cell gene therapy (PSCGT) promises a novel approach to conditions such as CH by targeting genetic mutations in utero, potentially improving long-term outcomes. To better understand the pathophysiology, genetic basis, and molecular pathomechanisms of CH, we conducted a scoping review of the literature that identified over 160 published genes linked to CH. Mutations in L1CAM, TRIM71, MPDZ, and CCDC88C play a critical role in neural stem cell development, subventricular zone architecture, and the maintenance of the neural stem cell niche, driving the development of CH. Early prenatal interventions targeting these genes could curb the development of the expected CH phenotype, improve neurodevelopmental outcomes, and possibly limit the need for surgical approaches. However, further research is needed to establish robust genotype-phenotype correlations and develop safe and effective PSCGT strategies for CH., (© 2024 The Author(s). Prenatal Diagnosis published by John Wiley & Sons Ltd.)
- Published
- 2024
- Full Text
- View/download PDF
6. Dual α-globin and truncated EPO receptor knockin restores hemoglobin production in α-thalassemia-derived red blood cells.
- Author
-
Chu SN, Soupene E, Wienert B, Yin H, Sharma D, McCreary T, Jia K, Homma S, Hampton JP, Gardner JM, Conklin BR, MacKenzie TC, Porteus MH, and Cromer MK
- Abstract
Alpha-thalassemia is an autosomal recessive disease with increasing worldwide prevalence. The molecular basis is due to mutation or deletion of one or more duplicated α-globin genes, and disease severity is directly related to the number of allelic copies compromised. The most severe form, α-thalassemia major (αTM), results from loss of all four copies of α-globin and has historically resulted in fatality in utero . However, in utero transfusions now enable survival to birth. Postnatally, patients face challenges similar to β-thalassemia, including severe anemia and erythrotoxicity due to imbalance of β-globin and α-globin chains. While curative, hematopoietic stem cell transplantation (HSCT) is limited by donor availability and potential transplant-related complications. Despite progress in genome editing treatments for β-thalassemia, there is no analogous curative option for patients suffering from α-thalassemia. To address this, we designed a novel Cas9/AAV6-mediated genome editing strategy that integrates a functional α-globin gene into the β-globin locus in αTM patient-derived hematopoietic stem and progenitor cells (HSPCs). Incorporation of a truncated erythropoietin receptor transgene into the α-globin integration cassette dramatically increased erythropoietic output from edited HSPCs and led to the most robust production of α-globin, and consequently normal hemoglobin. By directing edited HSPCs toward increased production of clinically relevant RBCs instead of other divergent cell types, this approach has the potential to mitigate the limitations of traditional HSCT for the hemoglobinopathies, including low genome editing and low engraftment rates. These findings support development of a definitive ex vivo autologous genome editing strategy that may be curative for α-thalassemia., Competing Interests: M.H.P. is a member of the scientific advisory board of Allogene Therapeutics. M.H.P. is on the Board of Directors of Graphite Bio. M.H.P. has equity in CRISPR Tx. T.C.M. is on the scientific advisory board of Acrigen and receives grant funding from Novartis, BioMarin, and Biogen. M.K.C., B.W., T.C.M., and M.H.P. hold patent US-20220280571-A1 and provisional patent no. 63/236,178.
- Published
- 2024
- Full Text
- View/download PDF
7. Prenatal AAV9-GFP administration in fetal lambs results in transduction of female germ cells and maternal exposure to virus.
- Author
-
Borges B, Varthaliti A, Schwab M, Clarke MT, Pivetti C, Gupta N, Cadwell CR, Guibinga G, Phillips S, Del Rio T, Ozsolak F, Imai-Leonard D, Kong L, Laird DJ, Herzeg A, Sumner CJ, and MacKenzie TC
- Abstract
Prenatal somatic cell gene therapy (PSCGT) could potentially treat severe, early-onset genetic disorders such as spinal muscular atrophy (SMA) or muscular dystrophy. Given the approval of adeno-associated virus serotype 9 (AAV9) vectors in infants with SMA by the U.S. Food and Drug Administration, we tested the safety and biodistribution of AAV9-GFP (clinical-grade and dose) in fetal lambs to understand safety and efficacy after umbilical vein or intracranial injection on embryonic day 75 (E75) . Umbilical vein injection led to widespread biodistribution of vector genomes in all examined lamb tissues and in maternal uteruses at harvest (E96 or E140; term = E150). There was robust GFP expression in brain, spinal cord, dorsal root ganglia (DRGs), without DRG toxicity and excellent transduction of diaphragm and quadriceps muscles. However, we found evidence of systemic toxicity (fetal growth restriction) and maternal exposure to the viral vector (transient elevation of total bilirubin and a trend toward elevation in anti-AAV9 antibodies). There were no antibodies against GFP in ewes or lambs. Analysis of fetal gonads demonstrated GFP expression in female (but not male) germ cells, with low levels of integration-specific reads, without integration in select proto-oncogenes. These results suggest potential therapeutic benefit of AAV9 PSCGT for neuromuscular disorders, but warrant caution for exposure of female germ cells., Competing Interests: G.G., S.P., T.D.R., and F.O. are employees and stockholders of Novartis. C.J.S. receives grant support from Roche Ltd., Biogen, and Actio Bio and has served as a paid advisor, consultant, and/or speaker to Biogen, Roche/Genentech, and Novartis; these arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies. T.C.M. receives grant funding from Novartis, BioMarin, and Biogen and is on the SAB of Acrigen; these arrangements have been reviewed and approved by UCSF in accordance with its conflict of interest policies., (© 2024 The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
8. Prenatal delivery of a therapeutic antisense oligonucleotide achieves broad biodistribution in the brain and ameliorates Angelman syndrome phenotype in mice.
- Author
-
Clarke MT, Remesal L, Lentz L, Tan DJ, Young D, Thapa S, Namuduri SR, Borges B, Kirn G, Valencia J, Lopez ME, Lui JH, Shiow LR, Dindot S, Villeda S, Sanders SJ, and MacKenzie TC
- Subjects
- Animals, Mice, Oligonucleotides, Antisense therapeutic use, Tissue Distribution, Brain metabolism, Phenotype, Ubiquitin-Protein Ligases genetics, Disease Models, Animal, Angelman Syndrome therapy, Angelman Syndrome drug therapy
- Abstract
Angelman syndrome (AS), an early-onset neurodevelopmental disorder characterized by abnormal gait, intellectual disabilities, and seizures, occurs when the maternal allele of the UBE3A gene is disrupted, since the paternal allele is silenced in neurons by the UBE3A antisense (UBE3A-AS) transcript. Given the importance of early treatment, we hypothesized that prenatal delivery of an antisense oligonucleotide (ASO) would downregulate the murine Ube3a-AS, resulting in increased UBE3A protein and functional rescue. Using a mouse model with a Ube3a-YFP allele that reports on-target ASO activity, we found that in utero, intracranial (IC) injection of the ASO resulted in dose-dependent activation of paternal Ube3a, with broad biodistribution. Accordingly, in utero injection of the ASO in a mouse model of AS also resulted in successful restoration of UBE3A and phenotypic improvements in treated mice on the accelerating rotarod and fear conditioning. Strikingly, even intra-amniotic (IA) injection resulted in systemic biodistribution and high levels of UBE3A reactivation throughout the brain. These findings offer a novel strategy for early treatment of AS using an ASO, with two potential routes of administration in the prenatal window. Beyond AS, successful delivery of a therapeutic ASO into neurons has implications for a clinically feasible prenatal treatment for numerous neurodevelopmental disorders., Competing Interests: Declaration of interests D.J.T., S.T., L.R.S., M.E.L., and J.H.L. are employees of and stockholders in BioMarin Pharmaceutical, Inc. S.V. is an employee of Ultragenyx Pharmaceutical. T.C.M. is on the Scientific Advisory Board of Acrigen., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
9. Intrauterine enzyme replacement therapies for lysosomal storage disorders: Current developments and promising future prospects.
- Author
-
Herzeg A, Borges B, Lianoglou BR, Gonzalez-Velez J, Canepa E, Munar D, Young SP, Bali D, Gelb MH, Chakraborty P, Kishnani PS, Harmatz P, Cohen JL, and MacKenzie TC
- Subjects
- Pregnancy, Female, Humans, Central Nervous System, Lysosomes, Enzyme Replacement Therapy methods, Lysosomal Storage Diseases therapy, Lysosomal Storage Diseases complications
- Abstract
Lysosomal storage disorders (LSDs) are a group of monogenic condition, with many characterized by an enzyme deficiency leading to the accumulation of an undegraded substrate within the lysosomes. For those LSDs, postnatal enzyme replacement therapy (ERT) represents the standard of care, but this treatment has limitations when administered only postnatally because, at that point, prenatal disease sequelae may be irreversible. Furthermore, most forms of ERT, specifically those administered systemically, are currently unable to access certain tissues, such as the central nervous system (CNS), and furthermore, may initiate an immune response. In utero enzyme replacement therapy (IUERT) is a novel approach to address these challenges evaluated in a first-in-human clinical trial for IUERT in LSDs (NCT04532047). IUERT has numerous advantages: in-utero intervention may prevent early pathology; the CNS can be accessed before the blood-brain barrier forms; and the unique fetal immune system enables exposure to new proteins with the potential to prevent an immune response and may induce sustained tolerance. However, there are challenges and limitations for any fetal procedure that involves two patients. This article reviews the current state of IUERT for LSDs, including its advantages, limitations, and potential future directions for definitive therapies., (© 2023 John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
10. Systematic evaluation of genome sequencing for the diagnostic assessment of autism spectrum disorder and fetal structural anomalies.
- Author
-
Lowther C, Valkanas E, Giordano JL, Wang HZ, Currall BB, O'Keefe K, Pierce-Hoffman E, Kurtas NE, Whelan CW, Hao SP, Weisburd B, Jalili V, Fu J, Wong I, Collins RL, Zhao X, Austin-Tse CA, Evangelista E, Lemire G, Aggarwal VS, Lucente D, Gauthier LD, Tolonen C, Sahakian N, Stevens C, An JY, Dong S, Norton ME, MacKenzie TC, Devlin B, Gilmore K, Powell BC, Brandt A, Vetrini F, DiVito M, Sanders SJ, MacArthur DG, Hodge JC, O'Donnell-Luria A, Rehm HL, Vora NL, Levy B, Brand H, Wapner RJ, and Talkowski ME
- Subjects
- Female, Pregnancy, Humans, Pregnancy Trimester, First, Ultrasonography, Prenatal, Chromosome Mapping, Exome, Autism Spectrum Disorder diagnosis, Autism Spectrum Disorder genetics
- Abstract
Short-read genome sequencing (GS) holds the promise of becoming the primary diagnostic approach for the assessment of autism spectrum disorder (ASD) and fetal structural anomalies (FSAs). However, few studies have comprehensively evaluated its performance against current standard-of-care diagnostic tests: karyotype, chromosomal microarray (CMA), and exome sequencing (ES). To assess the clinical utility of GS, we compared its diagnostic yield against these three tests in 1,612 quartet families including an individual with ASD and in 295 prenatal families. Our GS analytic framework identified a diagnostic variant in 7.8% of ASD probands, almost 2-fold more than CMA (4.3%) and 3-fold more than ES (2.7%). However, when we systematically captured copy-number variants (CNVs) from the exome data, the diagnostic yield of ES (7.4%) was brought much closer to, but did not surpass, GS. Similarly, we estimated that GS could achieve an overall diagnostic yield of 46.1% in unselected FSAs, representing a 17.2% increased yield over karyotype, 14.1% over CMA, and 4.1% over ES with CNV calling or 36.1% increase without CNV discovery. Overall, GS provided an added diagnostic yield of 0.4% and 0.8% beyond the combination of all three standard-of-care tests in ASD and FSAs, respectively. This corresponded to nine GS unique diagnostic variants, including sequence variants in exons not captured by ES, structural variants (SVs) inaccessible to existing standard-of-care tests, and SVs where the resolution of GS changed variant classification. Overall, this large-scale evaluation demonstrated that GS significantly outperforms each individual standard-of-care test while also outperforming the combination of all three tests, thus warranting consideration as the first-tier diagnostic approach for the assessment of ASD and FSAs., Competing Interests: Declaration of interests M.E.T. and H.R. receive research funding from Microsoft Inc and/or research reagents from Illumina Inc. M.E.T. also received research funding from Levo Therapeutics and research reagents from Ionis Therapeutics for unrelated research projects., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
11. The impact of in utero transfusions on perinatal outcomes in patients with alpha thalassemia major: the UCSF registry.
- Author
-
Schwab ME, Lianoglou BR, Gano D, Gonzalez Velez J, Allen IE, Arvon R, Baschat A, Bianchi DW, Bitanga M, Bourguignon A, Brown RN, Chen B, Chien M, Davis-Nelson S, de Laat MWM, Ekwattanakit S, Gollin Y, Hirata G, Jelin A, Jolley J, Meyer P, Miller J, Norton ME, Ogasawara KK, Panchalee T, Schindewolf E, Shaw SW, Stumbaugh T, Thompson AA, Towner D, Tsai PS, Viprakasit V, Volanakis E, Zhang L, Vichinsky E, and MacKenzie TC
- Subjects
- Pregnancy, Infant, Newborn, Female, Humans, Blood Transfusion, Blood Transfusion, Intrauterine adverse effects, Blood Transfusion, Intrauterine methods, Gestational Age, Edema etiology, alpha-Thalassemia complications, alpha-Thalassemia therapy
- Abstract
Alpha thalassemia major (ATM) is a hemoglobinopathy that usually results in perinatal demise if in utero transfusions (IUTs) are not performed. We established an international registry (NCT04872179) to evaluate the impact of IUTs on survival to discharge (primary outcome) as well as perinatal and neurodevelopmental secondary outcomes. Forty-nine patients were diagnosed prenatally, 11 were diagnosed postnatally, and all 11 spontaneous survivor genotypes had preserved embryonic zeta-globin levels. We compared 3 groups of patients; group 1, prenatally diagnosed and alive at hospital discharge (n = 14), group 2, prenatally diagnosed and deceased perinatally (n = 5), and group 3, postnatally diagnosed and alive at hospital discharge (n = 11). Group 1 had better outcomes than groups 2 and 3 in terms of the resolution of hydrops, delivery closer to term, shorter hospitalizations, and more frequent average or greater neurodevelopmental outcomes. Earlier IUT initiation was correlated with higher neurodevelopmental (Vineland-3) scores (r = -0.72, P = .02). Preterm delivery after IUT was seen in 3/16 (19%) patients who continued their pregnancy. When we combined our data with those from 2 published series, patients who received ≥2 IUTs had better outcomes than those with 0 to 1 IUT, including resolution of hydrops, delivery at ≥34 weeks gestation, and 5-minute appearance, pulse, grimace, activity, and respiration scores ≥7. Neurodevelopmental assessments were normal in 17/18 of the ≥2 IUT vs 5/13 of the 0 to 1 IUT group (OR 2.74; P = .01). Thus, fetal transfusions enable the survival of patients with ATM and normal neurodevelopment, even in those patients presenting with hydrops. Nondirective prenatal counseling for expectant parents should include the option of IUTs., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
12. In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe's Disease.
- Author
-
Cohen JL, Chakraborty P, Fung-Kee-Fung K, Schwab ME, Bali D, Young SP, Gelb MH, Khaledi H, DiBattista A, Smallshaw S, Moretti F, Wong D, Lacroix C, El Demellawy D, Strickland KC, Lougheed J, Moon-Grady A, Lianoglou BR, Harmatz P, Kishnani PS, and MacKenzie TC
- Subjects
- Humans, Infant, Glycogen Storage Disease Type II drug therapy
- Abstract
Patients with early-onset lysosomal storage diseases are ideal candidates for prenatal therapy because organ damage starts in utero. We report the safety and efficacy results of in utero enzyme-replacement therapy (ERT) in a fetus with CRIM (cross-reactive immunologic material)-negative infantile-onset Pompe's disease. The family history was positive for infantile-onset Pompe's disease with cardiomyopathy in two previously affected deceased siblings. After receiving in utero ERT and standard postnatal therapy, the current patient had normal cardiac and age-appropriate motor function postnatally, was meeting developmental milestones, had normal biomarker levels, and was feeding and growing well at 13 months of age., (Copyright © 2022 Massachusetts Medical Society.)
- Published
- 2022
- Full Text
- View/download PDF
13. Prenatal Somatic Cell Gene Therapies: Charting a Path Toward Clinical Applications (Proceedings of the CERSI-FDA Meeting).
- Author
-
Herzeg A, Almeida-Porada G, Charo RA, David AL, Gonzalez-Velez J, Gupta N, Lapteva L, Lianoglou B, Peranteau W, Porada C, Sanders SJ, Sparks TN, Stitelman DH, Struble E, Sumner CJ, and MacKenzie TC
- Subjects
- Female, Humans, Parturition, Pregnancy, United States, United States Food and Drug Administration, Fetus, Genetic Therapy
- Abstract
We are living in a golden age of medicine in which the availability of prenatal diagnosis, fetal therapy, and gene therapy/editing make it theoretically possible to repair almost any defect in the genetic code. Furthermore, the ability to diagnose genetic disorders before birth and the presence of established surgical techniques enable these therapies to be delivered safely to the fetus. Prenatal therapies are generally used in the second or early third trimester for severe, life-threatening disorders for which there is a clear rationale for intervening before birth. While there has been promising work for prenatal gene therapy in preclinical models, the path to a clinical prenatal gene therapy approach is complex. We recently held a conference with the University of California, San Francisco-Stanford Center of Excellence in Regulatory Science and Innovation, researchers, patient advocates, regulatory (members of the Food and Drug Administration), and other stakeholders to review the scientific background and rationale for prenatal somatic cell gene therapy for severe monogenic diseases and initiate a dialogue toward a safe regulatory path for phase 1 clinical trials. This review represents a summary of the considerations and discussions from these conversations., (© 2022, The American College of Clinical Pharmacology.)
- Published
- 2022
- Full Text
- View/download PDF
14. Thymic and extrathymic Aire-expressing cells in maternal-fetal tolerance.
- Author
-
Sun IH, Gillis-Buck E, Mackenzie TC, and Gardner JM
- Subjects
- Antigens, Epithelial Cells metabolism, Female, Humans, Immune Tolerance, Pregnancy, T-Lymphocytes, Thymus Gland, Placenta, Pregnancy Complications metabolism
- Abstract
Healthy pregnancy requires maternal immune tolerance to both fetal and placental tissues which contain a range of self- and non-self-antigens. While many of the components and mechanisms of maternal-fetal tolerance have been investigated in detail and previously and thoroughly reviewed (Erlebacher A. Annu Rev Immunol. 2013;31:387-411), the role of autoimmune regulator (Aire), a critical regulator of central tolerance expressed by medullary thymic epithelial cells (mTECs), has been less explored. Aire is known to facilitate the expression of a range of otherwise tissue-specific antigens (TSAs) in mTECs, and here we highlight recent work showing a role for mTEC-mediated thymic selection in maintaining maternal-fetal tolerance. Recently, however, our group and others have identified additional populations of extrathymic Aire-expressing cells (eTACs) in the secondary lymphoid organs. These hematopoietic antigen-presenting cells possess the ability to induce functional inactivation and/or deletion of cognate T cells, and deletion of maternal eTACs during pregnancy increases T-cell activation in the lymph nodes and lymphocytic infiltration of the uterus, leading to pregnancy complications including intrauterine growth restriction (IUGR) and fetal resorption. In this review, we briefly summarize findings related to essential Aire biology, discuss the known roles of Aire-deficiency related to pregnancy complications and infertility, review the newly discovered role for eTACs in the maintenance of maternal-fetal tolerance-as well as recent work defining eTACs at the single-cell level-and postulate potential mechanisms by which eTACs may regulate this process., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2022
- Full Text
- View/download PDF
15. Fetal therapies and trials for lysosomal storage diseases: a survey of attitudes of parents and patients.
- Author
-
Schwab ME, Brown JEH, Lianoglou B, Jin C, Conroy PC, Gallagher RC, Harmatz P, and MacKenzie TC
- Subjects
- Attitude, Clinical Trials, Phase I as Topic, Enzyme Replacement Therapy, Female, Humans, Parents, Pregnancy, Surveys and Questionnaires, Fetal Therapies, Glycogen Storage Disease Type II drug therapy, Lysosomal Storage Diseases genetics
- Abstract
Background: Lysosomal storage diseases (LSDs) are inherited metabolic disorders that may lead to severe multi-organ disease. Current ERTs are limited by anti-drug antibodies, the blood-brain barrier, and early disease onset and progression before ERT is started. We have opened a phase I clinical trial of enzyme replacement therapy (ERT) for fetuses with LSDs (NCT04532047). We evaluated the attitudes of parents and patients with LSDs towards fetal clinical trials and therapies., Methods: A multidisciplinary team designed a survey which was distributed by five international patient advocacy groups. We collected patients' demographic, diagnostic, and treatment information. Associations between respondent characteristics and attitudes towards fetal therapies/trials were analyzed using multivariate ordinal logistic regression., Results: The survey was completed by 181 adults from 19 countries. The majority of respondents were mothers from the United States. The most common diseases were MPS1 (26%), MPS3 (19%), and infantile-onset Pompe (14%). Most patients (88%) were diagnosed after birth, at a median of 21 months. Altogether, 65% of participating patients and children of participants had received ERT, 27% a stem cell transplant, and 4% gene therapy. We found that half (49%) of respondents were unlikely to terminate a future affected pregnancy, 55% would enroll in a phase I clinical trial for fetal ERT, and 46% would enroll in a fetal gene therapy trial. Respondents who received postnatal ERT were significantly more likely enroll in a trial for fetal ERT or gene therapy (ERT OR 4.48, 95% CI 2.13-9.44, p < 0.0001; gene therapy OR 3.03, 95% CI 1.43-6.43, p = 0.0038). Respondents who used clinicaltrials.gov as a main source of information were more likely to choose to participate in a fetal trial (ERT OR 2.43, 95% CI 1.18-5.01, p = 0.016; gene therapy OR 2.86, 95% CI 1.27-6.46, p = 0.011)., Conclusions: Familiarity with postnatal ERT increased respondents' likelihood of pursuing fetal therapies. Families who use clinicaltrials.gov may be more receptive to innovative fetal treatments. The patient community has a favorable attitude towards fetal therapy; over half of respondents would enroll in a phase I clinical trial to assess the safety and efficacy of fetal ERT., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
16. Exome sequencing of fetuses with congenital diaphragmatic hernia supports a causal role for NR2F2, PTPN11, and WT1 variants.
- Author
-
Schwab ME, Dong S, Lianoglou BR, Aguilar Lucero AF, Schwartz GB, Norton ME, MacKenzie TC, and Sanders SJ
- Subjects
- Exome genetics, Female, Fetus abnormalities, Fetus diagnostic imaging, Genetic Testing methods, Genetic Testing statistics & numerical data, Hernias, Diaphragmatic, Congenital diagnosis, Humans, Male, Pregnancy, Ultrasonography, Prenatal, COUP Transcription Factor II genetics, Hernias, Diaphragmatic, Congenital genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 11 genetics, WT1 Proteins genetics
- Abstract
Background: To identify genes associated with congenital diaphragmatic hernia (CDH) to help understand the etiology and inform prognosis., Methods: We performed exome sequencing on fetuses with CDH and their parents to identify rare genetic variants likely to mediate risk. We reviewed prenatal characteristics and neonatal outcomes., Results: Data were generated for 22 parent-offspring trios. Six Likely Damaging (LD) variants were identified in five families (23 %). Three LD variants were in genes that contain variants in other CDH cohorts (NR2F2, PTPN11, WT1), while three were in genes that do not (CTR9, HDAC6, TP53). Integrating these data bolsters the evidence of association of NR2F2, PTPN11, and WT1 with CDH in humans. Of the five fetuses with a genetic diagnosis, one was terminated, two underwent perinatal demise, while two survived until repair., Conclusions: Exome sequencing expands the diagnostic yield of genetic testing in CDH. Correlating CDH patients' exomes with clinical outcomes may enable personalized counseling and therapies., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
17. Consensus statement for the perinatal management of patients with α thalassemia major.
- Author
-
MacKenzie TC, Amid A, Angastiniotis M, Butler C, Gilbert S, Gonzalez J, Keller RL, Kharbanda S, Kirby-Allen M, Koenig BA, Kyono W, Lal A, Lianoglou BR, Norton ME, Ogasawara KK, Panchalee T, Rosner M, Schwab M, Thompson A, Waye JS, and Vichinsky E
- Subjects
- Female, Genotype, Humans, Pregnancy, alpha-Thalassemia diagnosis, alpha-Thalassemia epidemiology, alpha-Thalassemia genetics, beta-Thalassemia diagnosis, beta-Thalassemia epidemiology, beta-Thalassemia therapy
- Published
- 2021
- Full Text
- View/download PDF
18. Prenatal Gene Therapy.
- Author
-
Schwab ME and MacKenzie TC
- Subjects
- Female, Fetus, Humans, Pregnancy, Fetal Therapies, Genetic Therapy
- Abstract
Prenatal gene therapy could provide a cure for many monogenic diseases. Prenatal gene therapy has multiple potential advantages over postnatal therapy, including treating before the onset of disease, the ability to induce tolerance and cross the blood-brain barrier. In this chapter, we will describe in utero gene therapy and its rationale, clinical trials of postnatal gene therapy, preclinical studies of in utero gene therapy, and potential risks to the mother and fetus., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
19. Maternal and Infant Immune Repertoire Sequencing Analysis Identifies Distinct Ig and TCR Development in Term and Preterm Infants.
- Author
-
Le BL, Sper R, Nielsen SCA, Pineda S, Nguyen QH, Lee JY, Boyd SD, MacKenzie TC, and Sirota M
- Subjects
- Complementarity Determining Regions immunology, Female, Humans, Infant, Premature immunology, Pregnancy, Immunoglobulin Heavy Chains immunology, Infant, Newborn immunology, Obstetric Labor, Premature immunology, Premature Birth immunology, Receptors, Antigen, T-Cell immunology
- Abstract
Preterm labor (PTL) is the leading cause of neonatal morbidity and mortality worldwide. Whereas many studies have investigated the maternal immune responses that cause PTL, fetal immune cell activation has recently been raised as an important contributor to the pathogenesis of PTL. In this study, we analyzed lymphocyte receptor repertoires in maternal and cord blood from 14 term and 10 preterm deliveries, hypothesizing that the high prevalence of infection in patients with PTL may result in specific changes in the T cell and B cell repertoires. We analyzed TCR β-chain (TCR-β) and IgH diversity, CDR3 lengths, clonal sharing, and preferential usage of variable and joining gene segments. Both TCR-β and IgH repertoires had shorter CDR3s compared with those in maternal blood. In cord blood samples, we found that CDR3 lengths correlated with gestational age, with shorter CDR3s in preterm neonates suggesting a less developed repertoire. Preterm cord blood displayed preferential usage of a number of genes. In preterm pregnancies, we observed significantly higher prevalence of convergent clones between mother/baby pairs than in term pregnancies. Together, our results suggest the repertoire of preterm infants displays a combination of immature features and convergence with maternal TCR-β clones compared with that of term infants. The higher clonal convergence in PTL could represent mother and fetus both responding to a shared stimulus like an infection. These data provide a detailed analysis of the maternal-fetal immune repertoire in term and preterm patients and contribute to a better understanding of neonate immune repertoire development and potential changes associated with PTL., (Copyright © 2021 by The American Association of Immunologists, Inc.)
- Published
- 2021
- Full Text
- View/download PDF
20. Extrathymic Aire -expressing cells support maternal-fetal tolerance.
- Author
-
Gillis-Buck E, Miller H, Sirota M, Sanders SJ, Ntranos V, Anderson MS, Gardner JM, and MacKenzie TC
- Subjects
- Animals, Female, Fetal Growth Retardation immunology, Fetus immunology, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Placenta immunology, Pregnancy, Thymus Gland immunology, Transcription Factors genetics, AIRE Protein, Epithelial Cells immunology, Immune Tolerance, Transcription Factors immunology
- Abstract
Healthy pregnancy requires tolerance to fetal alloantigens as well as syngeneic embryonic and placental antigens. Given the importance of the autoimmune regulator ( Aire ) gene in self-tolerance, we investigated the role of Aire -expressing cells in maternal-fetal tolerance. We report that maternal ablation of Aire -expressing ( Aire
+ ) cells during early mouse pregnancy caused intrauterine growth restriction (IUGR) in both allogeneic and syngeneic pregnancies. This phenotype is immune mediated, as IUGR was rescued in Rag1-deficient mice, and involved a memory response, demonstrated by recurrence of severe IUGR in second pregnancies. Single-cell RNA sequencing demonstrated that Aire+ cell depletion in pregnancy results in expansion of activated T cells, particularly T follicular helper cells. Unexpectedly, selective ablation of either Aire -expressing medullary thymic epithelial cells or extrathymic Aire -expressing cells (eTACs) mapped the IUGR phenotype exclusively to eTACs. Thus, we report a previously undescribed mechanism for the maintenance of maternal-fetal immune homeostasis and demonstrate that eTACs protect the conceptus from immune-mediated IUGR., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2021
- Full Text
- View/download PDF
21. Forever Connected: The Lifelong Biological Consequences of Fetomaternal and Maternofetal Microchimerism.
- Author
-
Bianchi DW, Khosrotehrani K, Way SS, MacKenzie TC, Bajema I, and O'Donoghue K
- Subjects
- Animals, Female, Fetal Blood cytology, Humans, Male, Pregnancy, Chimerism, Fetus cytology, Genetic Diseases, Inborn diagnosis, Maternal-Fetal Exchange, Prenatal Diagnosis
- Abstract
Background: Originally studied as a mechanism to understand eclampsia-related deaths during pregnancy, fetal cells in maternal blood have more recently garnered attention as a noninvasive source of fetal material for prenatal testing. In the 21st century, however, intact fetal cells have been largely supplanted by circulating cell-free placental DNA for aneuploidy screening. Instead, interest has pivoted to the ways in which fetal cells influence maternal biology. In parallel, an increasing appreciation of the consequences of maternal cells in the developing fetus has occurred., Content: In this review, we highlight the potential clinical applications and functional consequences of the bidirectional trafficking of intact cells between a pregnant woman and her fetus. Fetal cells play a potential role in the pathogenesis of maternal disease and tissue repair. Maternal cells play an essential role in educating the fetal immune system and as a factor in transplant acceptance. Naturally occurring maternal microchimerism is also being explored as a source of hematopoietic stem cells for transplant in fetal hematopoietic disorders., Summary: Future investigations in humans need to include complete pregnancy histories to understand maternal health and transplant success or failure. Animal models are useful to understand the mechanisms underlying fetal wound healing and/or repair associated with maternal injury and inflammation. The lifelong consequences of the exchange of cells between a mother and her child are profound and have many applications in development, health, and disease. This intricate exchange of genetically foreign cells creates a permanent connection that contributes to the survival of both individuals., (Published by Oxford University Press on behalf of the American Association for Clinical Chemistry 2021.)
- Published
- 2021
- Full Text
- View/download PDF
22. Fetal and Maternal Safety Considerations for In Utero Therapy Clinical Trials: iFeTiS Consensus Statement.
- Author
-
Sagar R, Almeida-Porada G, Blakemore K, Chan JKY, Choolani M, Götherström C, Jaulent A, MacKenzie TC, Mattar C, Porada CD, Peranteau WH, Schneider H, Shaw SW, Waddington SN, Westgren M, and David AL
- Subjects
- Cell- and Tissue-Based Therapy, Female, Fetal Therapies standards, Genetic Therapy, Humans, Pregnancy, Prenatal Care, Clinical Trials as Topic, Fetal Therapies adverse effects, Fetal Therapies methods
- Published
- 2020
- Full Text
- View/download PDF
23. Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis.
- Author
-
Sparks TN, Lianoglou BR, Adami RR, Pluym ID, Holliman K, Duffy J, Downum SL, Patel S, Faubel A, Boe NM, Field NT, Murphy A, Laurent LC, Jolley J, Uy C, Slavotinek AM, Devine P, Hodoglugil U, Van Ziffle J, Sanders SJ, MacKenzie TC, and Norton ME
- Subjects
- Female, Humans, Pregnancy, Prognosis, Genetic Variation, Hydrops Fetalis diagnosis, Hydrops Fetalis genetics, Prenatal Diagnosis, Exome Sequencing
- Abstract
Background: The cause of most fetal anomalies is not determined prenatally. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Nonimmune hydrops fetalis (NIHF), a fetal abnormality that is often lethal, has numerous genetic causes; the extent to which exome sequencing can aid in its diagnosis is unclear., Methods: We evaluated a series of 127 consecutive unexplained cases of NIHF that were defined by the presence of fetal ascites, pleural or pericardial effusions, skin edema, cystic hygroma, increased nuchal translucency, or a combination of these conditions. The primary outcome was the diagnostic yield of exome sequencing for detecting genetic variants that were classified as either pathogenic or likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics. Secondary outcomes were the percentage of cases associated with specific genetic disorders and the proportion of variants that were inherited., Results: In 37 of the 127 cases (29%), we identified diagnostic genetic variants, including those for disorders affecting the RAS-MAPK cell-signaling pathway (known as RASopathies) (30% of the genetic diagnoses); inborn errors of metabolism and musculoskeletal disorders (11% each); lymphatic, neurodevelopmental, cardiovascular, and hematologic disorders (8% each); and others. Prognoses ranged from a relatively mild outcome to death during the perinatal period. Overall, 68% of the cases (25 of 37) with diagnostic variants were autosomal dominant (of which 12% were inherited and 88% were de novo), 27% (10 of 37) were autosomal recessive (of which 95% were inherited and 5% were de novo), 1 was inherited X-linked recessive, and 1 was of uncertain inheritance. We identified potentially diagnostic variants in an additional 12 cases., Conclusions: In this large case series of 127 fetuses with unexplained NIHF, we identified a diagnostic genetic variant in approximately one third of the cases. (Funded by the UCSF Center for Maternal-Fetal Precision Medicine and others; ClinicalTrials.gov number, NCT03412760.)., (Copyright © 2020 Massachusetts Medical Society.)
- Published
- 2020
- Full Text
- View/download PDF
24. Detection of microbial cell-free DNA in maternal and umbilical cord plasma in patients with chorioamnionitis using next generation sequencing.
- Author
-
Witt RG, Blair L, Frascoli M, Rosen MJ, Nguyen QH, Bercovici S, Zompi S, Romero R, and Mackenzie TC
- Subjects
- Adult, Chorioamnionitis microbiology, Cohort Studies, Female, Fetal Blood chemistry, Fetal Blood metabolism, Fetal Blood microbiology, Gestational Age, Humans, Infant, Newborn, Mycoplasma genetics, Mycoplasma pathogenicity, Neonatal Sepsis blood, Neonatal Sepsis diagnosis, Neonatal Sepsis microbiology, Pregnancy, Streptococcus mitis genetics, Streptococcus mitis pathogenicity, Umbilical Cord pathology, Ureaplasma genetics, Ureaplasma pathogenicity, Young Adult, Cell-Free Nucleic Acids blood, Chorioamnionitis diagnosis, High-Throughput Nucleotide Sequencing methods, Sequence Analysis, DNA methods, Umbilical Cord microbiology
- Abstract
Background: Chorioamnionitis has been linked to spontaneous preterm labor and complications such as neonatal sepsis. We hypothesized that microbial cell-free (cf) DNA would be detectable in maternal plasma in patients with chorioamnionitis and could be the basis for a non-invasive method to detect fetal exposure to microorganisms., Objective: The purpose of this study was to determine whether next generation sequencing could detect microbial cfDNA in maternal plasma in patients with chorioamnionitis., Study Design: Maternal plasma (n = 94) and umbilical cord plasma (n = 120) were collected during delivery at gestational age 28-41 weeks. cfDNA was extracted and sequenced. Umbilical cord plasma samples with evidence of contamination were excluded. The prevalence of microorganisms previously implicated in choriomanionitis, neonatal sepsis and intra-amniotic infections, as described in the literature, were examined to determine if there was enrichment of these microorganisms in this cohort. Specific microbial cfDNA associated with chorioamnionitis was first detected in umbilical cord plasma and confirmed in the matched maternal plasma samples (n = 77 matched pairs) among 14 cases of histologically confirmed chorioamnionitis and one case of clinical chorioamnionitis; 63 paired samples were used as controls. A correlation of rank of a given microorganism across maternal plasma and matched umbilical cord plasma was used to assess whether signals found in umbilical cord plasma were also present in maternal plasma., Results: Microbial DNA sequences associated with clinical and/or histological chorioamnionitis were enriched in maternal plasma in cases with suspected chorioamnionitis when compared to controls (12/14 microorganisms, p = 0.02). Analysis of the microbial cfDNA in umbilical cord plasma among the 1,251 microorganisms detectable with this assay identified Streptococcus mitis, Ureaplasma spp., and Mycoplasma spp. in cases of suspected chorioamnionitis. This assay also detected cfDNA from Lactobacillus spp. in controls. Comparison between maternal plasma and umbilical cord plasma confirmed these signatures were also present in maternal plasma. Unbiased analysis of microorganisms with significantly correlated signal between matched maternal plasma and umbilical cord plasma identified the above listed 3 microorganisms, all of which have previously been implicated in patients with chorioamnionitis (Mycoplasma hominis p = 0.0001; Ureaplasma parvum p = 0.002; Streptococcus mitis p = 0.007). These data show that the pathogen signal relevant for chorioamnionitis can be identified in both maternal and umbilical cord plasma., Conclusion: This is the first report showing the detection of relevant microbial cell-free cfDNA in maternal plasma and umbilical cord plasma in patients with clinical and/or histological chorioamnionitis. These results may lead to the development of a specific assay to detect perinatal infections for targeted therapy to reduce early neonatal sepsis complications., Competing Interests: LB, MJR, SB and SZ are or were employees of Karius, Inc. MJR is also employed by D2G Oncology. RGW, MF, QHN, RR and TCM have no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
- Published
- 2020
- Full Text
- View/download PDF
25. Tolerance induction and microglial engraftment after fetal therapy without conditioning in mice with Mucopolysaccharidosis type VII.
- Author
-
Nguyen QH, Witt RG, Wang B, Eikani C, Shea J, Smith LK, Boyle G, Cadaoas J, Sper R, MacKenzie JD, Villeda S, and MacKenzie TC
- Subjects
- Animals, Female, Immune Tolerance, Mice, Microglia, Pregnancy, Fetal Therapies, Hematopoietic Stem Cell Transplantation, Mucopolysaccharidosis VII therapy
- Abstract
Mucopolysaccharidosis type VII (MPS7) is a lysosomal storage disorder (LSD) resulting from mutations in the β-glucuronidase gene, leading to multiorgan dysfunction and fetal demise. While postnatal enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation have resulted in some phenotypic improvements, prenatal treatment might take advantage of a unique developmental window to penetrate the blood-brain barrier or induce tolerance to the missing protein, addressing two important shortcomings of postnatal therapy for multiple LSDs. We performed in utero ERT (IUERT) at E14.5 in MPS7 mice and improved survival of affected mice to birth. IUERT penetrated brain microglia, whereas postnatal administration did not, and neurological testing (after IUERT plus postnatal administration) showed decreased microglial inflammation and improved grip strength in treated mice. IUERT prevented antienzyme antibody development even after multiple repeated postnatal challenges. To test a more durable treatment strategy, we performed in utero hematopoietic stem cell transplantation (IUHCT) using congenic CX3C chemokine receptor 1-green fluorescent protein (CX3CR1-GFP) mice as donors, such that donor-derived microglia are identified by GFP expression. In wild-type recipients, hematopoietic chimerism resulted in microglial engraftment throughout the brain without irradiation or conditioning; the transcriptomes of donor and host microglia were similar. IUHCT in MPS7 mice enabled cross-correction of liver Kupffer cells and improved phenotype in multiple tissues. Engrafted microglia were seen in chimeric mice, with decreased inflammation near donor microglia. These results suggest that fetal therapy with IUERT and/or IUHCT could overcome the shortcomings of current treatment strategies to improve phenotype in MPS7 and other LSDs., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2020
- Full Text
- View/download PDF
26. CD161 contributes to prenatal immune suppression of IFNγ-producing PLZF+ T cells.
- Author
-
Halkias J, Rackaityte E, Hillman SL, Aran D, Mendoza VF, Marshall LR, MacKenzie TC, and Burt TD
- Subjects
- CD4-Positive T-Lymphocytes cytology, Case-Control Studies, Female, Fetal Blood cytology, Fetus immunology, Gene Expression Regulation, Humans, Immunologic Memory, Immunosuppression Therapy, Infant, Newborn, Inflammation, Interferon-gamma metabolism, Intestines immunology, Leukocytes, Mononuclear cytology, Lymphocyte Activation, Phenotype, Pregnancy, Promyelocytic Leukemia Zinc Finger Protein metabolism, T-Lymphocytes metabolism, Gene Expression Regulation, Developmental, Immune System, Intestines embryology, Lymphoid Tissue embryology, Mucous Membrane embryology, NK Cell Lectin-Like Receptor Subfamily B metabolism, T-Lymphocytes cytology
- Abstract
Background: While the human fetal immune system defaults to a program of tolerance, there is concurrent need for protective immunity to meet the antigenic challenges encountered after birth. Activation of T cells in utero is associated with the fetal inflammatory response with broad implications for the health of the fetus and of the pregnancy. However, the characteristics of the fetal effector T cells that contribute to this process are largely unknown., Methods: We analyzed primary human fetal lymphoid and mucosal tissues and performed phenotypic, functional, and transcriptional analysis to identify T cells with pro-inflammatory potential. The frequency and function of fetal-specific effector T cells was assessed in the cord blood of infants with localized and systemic inflammatory pathologies and compared to healthy term controls., Results: We identified a transcriptionally distinct population of CD4+ T cells characterized by expression of the transcription factor Promyelocytic Leukemia Zinc Finger (PLZF). PLZF+ CD4+ T cells were specifically enriched in the fetal intestine, possessed an effector memory phenotype, and rapidly produced pro-inflammatory cytokines. Engagement of the C-type lectin CD161 on these cells inhibited TCR-dependent production of IFNγ in a fetal-specific manner. IFNγ-producing PLZF+ CD4+ T cells were enriched in the cord blood of infants with gastroschisis, a natural model of chronic inflammation originating from the intestine, as well as in preterm birth, suggesting these cells contribute to fetal systemic immune activation., Conclusion: Our work reveals a fetal-specific program of protective immunity whose dysregulation is associated with fetal and neonatal inflammatory pathologies.
- Published
- 2019
- Full Text
- View/download PDF
27. Evaluation of Clinical Outcomes of Sutureless vs Sutured Closure Techniques in Gastroschisis Repair.
- Author
-
Witt RG, Zobel M, Padilla B, Lee H, MacKenzie TC, and Vu L
- Subjects
- Enteral Nutrition statistics & numerical data, Female, Humans, Infant, Newborn, Length of Stay statistics & numerical data, Male, Postoperative Care methods, Retrospective Studies, San Francisco, Treatment Outcome, Wound Closure Techniques statistics & numerical data, Gastroschisis surgery, Suture Techniques
- Abstract
Importance: Sutureless gastroschisis repair offers an alternative to the traditional sutured method and has been associated with decreased intubation time. Published study results are inconsistent regarding the advantages of sutureless closure., Objective: To compare the clinical outcomes of sutureless and sutured gastroschisis repair., Design, Setting, and Participants: A single-center cohort review was performed of all consecutive patients (n = 97) who underwent gastroschisis repair from February 1, 2007, to April 30, 2017, at the University of California, San Francisco. Patients' medical records were evaluated for clinical characteristics and outcomes. Cases with incomplete data during initial hospitalization were excluded., Main Outcomes and Measures: Length of hospital stay, time to full enteral feeds, total parenteral nutrition duration, days requiring intravenous analgesia, days intubated, wound infection rate, antibiotic treatment duration, rate of umbilical hernias that required an operation, and readmission rate., Results: In total, 97 patients (47 [48%] were female and 50 [52%] were male with a mean [SD] age of 2.8 [2.8] days) underwent gastroschisis repair, of which 7 were excluded for incomplete medical record. Of the 90 patients included in the study, 50 (56%) underwent sutured closure and 40 (44%) underwent sutureless closure. No statistical difference was found between the sutured and sutureless groups in length of hospital stay (mean [SD] days, 43.9 [40.4] vs 36.7 [21.2]; P = .71), time to full enteral feeds (mean [SD] days, 31.4 [20.2] vs 27.9 [17.3]; P = .22), total parenteral nutrition duration (mean [SD] days, 33.5 [29.8] vs 27.4 [18.2]; P = .23), wound infection rates (14 [28%] vs 10 [25%]; P = .81), and readmission rates (5 [10%] vs 7 [18%]; P = .36). The sutureless group, compared with the sutured group, had substantially fewer days receiving antibiotics (mean [SD], 7.2 [6.4] vs 12.4 [13.2]; P = .003), fewer days intubated (mean [SD], 2.8 [3.3] vs 6.8 [1.3]; P = .001), fewer days receiving intravenous analgesia (mean [SD], 4.2 [4.0] vs 7.1 [4.5]; P = .003), and fewer patients that required silo reduction (25 [63%] vs 48 [96%]; P < .001). Sutureless closures, compared with the sutured technique, had considerably more umbilical hernias requiring surgical repair (5 [13%] vs 0; P = .02)., Conclusions and Relevance: Sutureless repair of gastroschisis appears to be associated with a statistically significant reduction in mechanical ventilation duration and pain medication requirements but may increase umbilical hernia risk. Multicenter randomized clinical trials are necessary to determine the true advantages of the sutureless approach.
- Published
- 2019
- Full Text
- View/download PDF
28. Depletion of murine fetal hematopoietic stem cells with c-Kit receptor and CD47 blockade improves neonatal engraftment.
- Author
-
Witt RG, Wang B, Nguyen QH, Eikani C, Mattis AN, and MacKenzie TC
- Subjects
- Animals, Animals, Newborn, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal immunology, CD47 Antigen immunology, Female, Fetal Stem Cells immunology, Fetal Therapies, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells cytology, Mice, Mice, Inbred C57BL, Pregnancy, Proto-Oncogene Proteins c-kit immunology, Receptors, Immunologic metabolism, Transplantation Conditioning, CD47 Antigen metabolism, Fetal Stem Cells cytology, Graft Survival physiology, Hematopoietic Stem Cells metabolism, Proto-Oncogene Proteins c-kit metabolism
- Published
- 2018
- Full Text
- View/download PDF
29. Large Differences in Small RNA Composition Between Human Biofluids.
- Author
-
Godoy PM, Bhakta NR, Barczak AJ, Cakmak H, Fisher S, MacKenzie TC, Patel T, Price RW, Smith JF, Woodruff PG, and Erle DJ
- Subjects
- Adult, Amino Acids genetics, Anticodon genetics, Female, Humans, Male, MicroRNAs metabolism, Middle Aged, RNA, Small Interfering genetics, RNA, Transfer metabolism, Sequence Analysis, RNA, Body Fluids metabolism, MicroRNAs genetics, RNA, Transfer genetics
- Abstract
Extracellular microRNAs (miRNAs) and other small RNAs are implicated in cellular communication and may be useful as disease biomarkers. We systematically compared small RNAs in 12 human biofluid types using RNA sequencing (RNA-seq). miRNAs and tRNA-derived RNAs (tDRs) accounted for the majority of mapped reads in all biofluids, but the ratio of miRNA to tDR reads varied from 72 in plasma to 0.004 in bile. miRNA levels were highly correlated across all biofluids, but levels of some miRNAs differed markedly between biofluids. tDR populations differed extensively between biofluids. Y RNA fragments were seen in all biofluids and accounted for >10% of reads in blood plasma, serum, and cerebrospinal fluid (CSF). Reads mapping exclusively to Piwi-interacting RNAs (piRNAs) were very rare, except in seminal plasma. These results demonstrate extensive differences in small RNAs between human biofluids and provide a useful resource for investigating extracellular RNA biology and developing biomarkers., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
30. Future AAVenues for In Utero Gene Therapy.
- Author
-
MacKenzie TC
- Subjects
- Female, Fetus, Genetic Therapy, Genetic Vectors, Humans, Infant, Pregnancy, Neurodegenerative Diseases
- Abstract
Fetal gene therapy using safe and effective viral vectors no longer remains a distant prospect. Recently in Nature Medicine, Massaro et al. (2018) demonstrated that prenatal intracranial injection of a viral vector results in improved neurologic function, raising the intriguing possibility that in utero gene therapy may be approaching clinical applications., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
31. Alloreactive fetal T cells promote uterine contractility in preterm labor via IFN-γ and TNF-α.
- Author
-
Frascoli M, Coniglio L, Witt R, Jeanty C, Fleck-Derderian S, Myers DE, Lee TH, Keating S, Busch MP, Norris PJ, Tang Q, Cruz G, Barcellos LF, Gomez-Lopez N, Romero R, and MacKenzie TC
- Subjects
- Animals, Female, Fetus, Mice, Mice, Inbred C57BL, Pregnancy, Uterus physiology, Interferon-gamma metabolism, Obstetric Labor, Premature etiology, Obstetric Labor, Premature metabolism, T-Lymphocytes metabolism, Tumor Necrosis Factor-alpha metabolism, Uterus metabolism
- Abstract
Healthy pregnancy is the most successful form of graft tolerance, whereas preterm labor (PTL) may represent a breakdown in maternal-fetal tolerance. Although maternal immune responses have been implicated in pregnancy complications, fetal immune responses against maternal antigens are often not considered. To examine the fetal immune system in the relevant clinical setting, we analyzed maternal and cord blood in patients with PTL and healthy term controls. We report here that the cord blood of preterm infants has higher amounts of inflammatory cytokines and a greater activation of dendritic cells. Moreover, preterm cord blood is characterized by the presence of a population of central memory cells with a type 1 T helper phenotype, which is absent in term infants, and an increase in maternal microchimerism. T cells from preterm infants mount a robust proliferative, proinflammatory response to maternal antigens compared to term infants yet fail to respond to third-party antigens. Furthermore, we show that T cells from preterm infants stimulate uterine myometrial contractility through interferon-γ and tumor necrosis factor-α. In parallel, we found that adoptive transfer of activated T cells directly into mouse fetuses resulted in pregnancy loss. Our findings indicate that fetal inflammation and rejection of maternal antigens can contribute to the signaling cascade that promotes uterine contractility and that aberrant fetal immune responses should be considered in the pathogenesis of PTL., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2018
- Full Text
- View/download PDF
32. Systemic multilineage engraftment in mice after in utero transplantation with human hematopoietic stem cells.
- Author
-
Witt RG, Kreger EM, Buckman LB, Moradi PW, Ho PT, Derderian SC, Tsai P, Baker C, Schramm N, Cleary R, Garcia JV, and MacKenzie TC
- Subjects
- Animals, Antibodies administration & dosage, Antibodies pharmacology, Cell Differentiation, Chimerism, Fetal Blood transplantation, Humans, Mice, Mice, SCID, Models, Animal, Proto-Oncogene Proteins c-kit immunology, Cell Lineage, Fetal Diseases therapy, Graft Survival drug effects, Hematopoietic Stem Cell Transplantation methods, Transplantation, Heterologous methods
- Abstract
IUHCT of human cord blood-derived CD34
+ cells into fetal NSG mice results in systemic multilineage engraftment with human cells.Preconditioning with in utero injection of an anti-c-Kit receptor antibody (ACK2) results in an improved rate of engraftment., Competing Interests: Conflict-of-interest disclosure: The authors declare no competing financial interests.- Published
- 2018
- Full Text
- View/download PDF
33. Esophagoesophagopexy technique for assisted fistulization of esophageal atresia.
- Author
-
Chumfong I, Lee H, Padilla BE, MacKenzie TC, and Vu LT
- Subjects
- Cohort Studies, Dilatation, Esophageal Fistula etiology, Esophageal Fistula surgery, Female, Fundoplication, Humans, Infant, Infant, Newborn, Male, Postoperative Complications, Retrospective Studies, Esophageal Atresia surgery, Esophagus surgery
- Abstract
Purpose: We describe our experience using a modified suture fistula technique for addressing tension in longer gap esophageal atresia (EA). Esophagoesophagopexy (EEP) is the tacking of the proximal and distal ends of esophageal pouches without formal anastomosis. In this retrospective cohort, we review the outcomes of patients with EA after EEP., Methods: We reviewed the operative reports of EA cases treated at our institution from 1997 to 2016 and identified all patients described as having EEP., Results: Of 129 EA cases, five patients underwent EEP. Formal anastomosis was not done due to patient's instability, prematurity, or long gap. Median birth weight was 1.4 kg (0.6-2.2 kg), and median gestational age at birth was 29 weeks (25-34 weeks). Age at time of EEP ranged 0-5 months. Esophagoesophageal fistula was confirmed in three patients. All three had strictures requiring weekly dilations. One of these patients died. The two surviving patients underwent fundoplication., Conclusion: We describe an alternative technique for esophageal anastomosis in patients for whom a standard anastomosis is not possible. EEP can lead to a functional anastomosis through fistulization and avoid the morbidity of multiple thoracotomies and lengthening procedures. Families should be educated on the potential need for dilations and antireflux procedures.
- Published
- 2018
- Full Text
- View/download PDF
34. Fetal stem cell and gene therapy.
- Author
-
Witt R, MacKenzie TC, and Peranteau WH
- Subjects
- Animals, Female, Humans, Pregnancy, Fetal Diseases therapy, Fetal Therapies methods, Genetic Therapy, Hematopoietic Stem Cell Transplantation
- Abstract
Advances in our understanding of stem cells, gene editing, prenatal imaging and fetal interventions have opened up new opportunities for the treatment of congenital diseases either through in-utero stem cell transplantation or in-utero gene therapy. Improvements in ultrasound-guided access to the fetal vasculature have also enhanced the safety and efficacy of cell delivery. The fetal environment offers accessible stem cell niches, localized cell populations with large proliferative potential, and an immune system that is able to acquire donor-specific tolerance. In-utero therapy seeks to take advantage of these factors and has the potential to cure diseases prior to the onset of symptoms, a strategy that offers substantial social and economic benefits. In this article, we examine previous studies in animal models as well as clinical attempts at in-utero therapy. We also discuss the barriers to successful in-utero therapy and future strategies for overcoming these obstacles., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
35. Favorable outcomes after in utero transfusion in fetuses with alpha thalassemia major: a case series and review of the literature.
- Author
-
Kreger EM, Singer ST, Witt RG, Sweeters N, Lianoglou B, Lal A, Mackenzie TC, and Vichinsky E
- Subjects
- Female, Fetal Development, Follow-Up Studies, Gestational Age, Hematopoietic Stem Cell Transplantation, Humans, Hydrops Fetalis etiology, Male, Neurodevelopmental Disorders epidemiology, Neurodevelopmental Disorders etiology, Pregnancy, Pregnancy Outcome, alpha-Thalassemia complications, Blood Transfusion, Intrauterine adverse effects, Blood Transfusion, Intrauterine methods, Fetal Diseases therapy, Treatment Outcome, alpha-Thalassemia embryology, alpha-Thalassemia therapy
- Abstract
Objective: Alpha thalassemia major (ATM) is often fatal in utero due to severe hydrops fetalis. Although in utero transfusions (IUTs) are increasingly used to allow fetal survival in ATM, prenatal and postnatal outcomes are not well described., Methods: We retrospectively reviewed cases of ATM at our institution treated with consecutive IUT. Clinical records were reviewed for transfusion history, neurodevelopmental outcomes, anatomic abnormalities, survival to hematopoietic cell transplantation, and transfusion independence. A systematic review was performed, and additional reported cases are discussed., Results: Three patients who underwent IUT for ATM were identified, and review of the literature revealed 17 reported cases. Of patients who received IUT, reported neurodevelopmental deficits occurred in 29% (4/14) and anatomic abnormalities in 55% (11/20). Four patients eventually underwent successful hematopoietic cell transplantation. Transfusion volumes were less than suggested guidelines for other causes of fetal anemia in 91.7% of the transfusions., Conclusion: This series demonstrates the potential for achieving full fetal development with normal neurologic outcomes in those affected by ATM. It provides support for continued patient and provider education about current benefits and risks of active prenatal therapy for fetuses with ATM, as well as continued research to optimize therapeutic strategies such as in utero transplantation. © 2016 John Wiley & Sons, Ltd., (© 2016 John Wiley & Sons, Ltd.)
- Published
- 2016
- Full Text
- View/download PDF
36. Heightened Immune Activation in Fetuses with Gastroschisis May Be Blocked by Targeting IL-5.
- Author
-
Frascoli M, Jeanty C, Fleck S, Moradi PW, Keating S, Mattis AN, Tang Q, and MacKenzie TC
- Subjects
- Amniotic Fluid immunology, Animals, Antibodies, Neutralizing administration & dosage, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Chemokine CCL11 blood, Cytokines blood, Disease Models, Animal, Eosinophilia therapy, Eosinophils immunology, Eosinophils physiology, Female, Fetal Blood cytology, Fetal Blood immunology, Fetal Therapies, Humans, Immunologic Memory, Infant, Newborn, Inflammation therapy, Interleukin-5 antagonists & inhibitors, Interleukin-5 blood, Intestines immunology, Intestines pathology, Lymphocytes immunology, Mice, Mothers, Pregnancy, Fetal Diseases immunology, Fetal Diseases therapy, Gastroschisis immunology, Gastroschisis therapy, Interleukin-5 immunology, Intestines drug effects
- Abstract
The development of the fetal immune system during pregnancy is a well-orchestrated process with important consequences for fetal and neonatal health, but prenatal factors that affect immune activation are poorly understood. We hypothesized that chronic fetal inflammation may lead to alterations in development of the fetal immune system. To test this hypothesis, we examined neonates with gastroschisis, a congenital abdominal wall defect that leads to exposure of the fetal intestines to amniotic fluid, with resultant intestinal inflammation. We determined that patients with gastroschisis show high systemic levels of inflammatory cytokines and chemokines such as eotaxin, as well as earlier activation of CD4(+) and CD8(+) effector and memory T cells in the cord blood compared with controls. Additionally, increased numbers of T cells and eosinophils infiltrate the serosa and mucosa of the inflamed intestines. Using a mouse model of gastroschisis, we observed higher numbers of eosinophils and both type 2 and type 3 innate lymphoid cells (ILC2 and ILC3), specifically in the portion of organs exposed to the amniotic fluid. Given the role of IL-5 produced by ILC2 in regulating eosinophil development and survival, we determined that maternal or fetal administration of the anti-IL-5 neutralizing Ab, or a depleting Ab against ILCs, can both effectively reduce intestinal eosinophilia. Thus, a congenital anomaly causing chronic inflammation can alter the composition of circulating and tissue-resident fetal immune cells. Given the high rate of prenatal and neonatal complications in these patients, such changes have clinical significance and might become targets for fetal therapy., (Copyright © 2016 by The American Association of Immunologists, Inc.)
- Published
- 2016
- Full Text
- View/download PDF
37. Magnetic resonance imaging of Müllerian duct anomalies in children.
- Author
-
Li Y, Phelps A, Zapala MA, MacKenzie JD, MacKenzie TC, and Courtier J
- Subjects
- Female, Humans, Genital Diseases, Female diagnostic imaging, Magnetic Resonance Imaging methods, Mullerian Ducts abnormalities, Mullerian Ducts diagnostic imaging
- Abstract
Müllerian duct anomalies encompass a wide variety of disorders resulting from abnormalities in the embryological development of the Müllerian ducts. In the prepubertal pediatric population, Müllerian duct anomalies are often incidental findings on studies obtained for other reasons. The onset of menses can prompt more clinical symptoms. Proper characterization of Müllerian duct anomalies is important because these anomalies can affect the development of gynecological disorders as well as fertility. Müllerian duct anomalies also carry a high association with other congenital anomalies, particularly renal abnormalities. MRI is widely considered the best modality for assessing Müllerian duct anomalies; it provides multiplanar capability, clear anatomical detail and tissue characterization without ionizing radiation. MRI allows for careful description of Müllerian duct anomalies, often leading to classification into the most widely accepted classification system for Müllerian duct anomalies. This system, developed by the American Society of Reproductive Medicine, includes seven subtypes: uterine agenesis/hypoplasia, unicornuate, didelphys, bicornuate, septate, arcuate, and diethylstilbestrol (DES) drug-related uterus. In cases of complex anomalies that defy classification, MRI allows detailed depiction of all components of the anatomical abnormality, allowing for proper management and surgical planning.
- Published
- 2016
- Full Text
- View/download PDF
38. Fetal Surgical conditions and the unraveling of maternal-fetal tolerance.
- Author
-
MacKenzie TC
- Subjects
- Female, Fetal Diseases immunology, Humans, Obstetric Labor, Premature immunology, Pregnancy, Premature Birth immunology, Fetal Diseases therapy, Fetal Therapies adverse effects, Histocompatibility, Maternal-Fetal immunology, Obstetric Labor, Premature etiology, Premature Birth etiology
- Abstract
Fetal surgery is a fascinating field that will continue to evolve as we develop a more refined understanding of the underlying biology of various birth defects. Since preterm labor is a frequent outcome of fetal intervention, examining the mechanisms that lead to a breakdown in maternal-fetal tolerance is vital to developing strategies to overcome this limitation. The trafficking of cells between the mother and fetus during pregnancy plays a critical role in the education of the fetal immune system and may have implications for postnatal transplantation tolerance. Maternal cells may also be the ideal source for transplantation into the fetus to treat congenital stem cell disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
39. Mass Effect Alone May Not Explain Pulmonary Vascular Pathology in Severe Congenital Diaphragmatic Hernia.
- Author
-
Derderian SC, Jayme CM, Cheng LS, Keller RL, Moon-Grady AJ, and MacKenzie TC
- Subjects
- Echocardiography, Hernias, Diaphragmatic, Congenital diagnostic imaging, Hernias, Diaphragmatic, Congenital pathology, Humans, Hypertension, Pulmonary complications, Hypertension, Pulmonary diagnostic imaging, Hypertension, Pulmonary mortality, Hypertension, Pulmonary pathology, Pulmonary Artery diagnostic imaging, Pulmonary Artery embryology, Retrospective Studies, Ultrasonography, Doppler, Ultrasonography, Prenatal, Vascular Remodeling, Hernias, Diaphragmatic, Congenital complications, Pulmonary Artery pathology
- Abstract
Congenital diaphragmatic hernia (CDH) and congenital pulmonary airway malformation (CPAM) are diseases in which chest-occupying lesions can result in severe pulmonary hypoplasia. However, significant postnatal mortality due to pulmonary hypertension (PH) is more often seen in patients with CDH. We analyzed prenatal echocardiographic parameters of pulmonary vascular pathology in these groups to understand whether PH in patients with CDH is secondary to a mass effect or to underlying disease. We analyzed pre- and postnatal characteristics of 26 patients with severe CDH and 23 patients with severe CPAM from 2009 to 2012. Severe mediastinal compression, indicated by a low cardiothoracic ratio, was evident in both groups. However, fetuses with severe CDH had smaller pulmonary arteries bilaterally and higher pulsatility indices in the ipsilateral lung than those with severe CPAM. Prenatal modified McGoon indices were significantly lower in patients with CDH versus CPAM. Consistent with these prenatal measurements, postnatal PH was seen more frequently in patients with CDH compared to CPAM. Patients with severe CDH have prenatal evidence of pulmonary vascular remodeling compared to patients with severe CPAM. These results suggest a multifactorial origin for PH in CDH and support the idea of using prenatal medical therapies to promote vascular remodeling in these patients., (© 2015 S. Karger AG, Basel.)
- Published
- 2016
- Full Text
- View/download PDF
40. A booster shot to cure hemoglobinopathies.
- Author
-
Walters MC and MacKenzie TC
- Subjects
- Animals, Anemia, Sickle Cell surgery, Fetal Therapies methods, Hematopoietic Stem Cell Transplantation methods, Immune Tolerance immunology, beta-Thalassemia surgery
- Published
- 2015
- Full Text
- View/download PDF
41. Placental drug delivery for treatment of congenital hematopoietic disorders.
- Author
-
Derderian SC, Moradi PW, and MacKenzie TC
- Subjects
- Animals, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal therapeutic use, Bone Marrow drug effects, Female, Fetus cytology, Hematopoietic Stem Cells drug effects, Injections, Liver cytology, Mice, Mice, Inbred C57BL, Pregnancy, Proto-Oncogene Proteins c-kit immunology, Antibodies, Monoclonal administration & dosage, Fetal Therapies methods, Hematopoietic Stem Cell Transplantation methods, Placenta, Transplantation Conditioning methods
- Abstract
Objective: The success of in utero hematopoietic cell transplantation (IUHCTx) hinges on successful conditioning strategies of the host to overcome barriers to engraftment. The "space" barrier is a reflection of a finite number of hematopoietic stem cell (HSC) niches within the host. Independent of the number of donor HSCs transplanted, engraftment is frequently low. By conditioning fetal mice using a monoclonal antibody against the c-kit receptor (ACK2) found on HSCs, we can effectively increase space for donor HSC engraftment. We questioned whether simple placental injection of ACK2 early in gestation could effectively deplete host HSCs within the fetal liver and neonatal bone marrow., Methods: In this set of experiments, we injected mice with ACK2 (5 μg/fetus) or PBS at E11.5-12.5 and harvested the fetal liver at 2 and 4 days and the neonatal bone marrow at 7 days following injection. Survival and total number of HSCs within the fetal liver or bone marrow were quantified and compared., Results: Survival between the treated and control group was similar (73% and 71%, respectively). The total number of HSCs within the fetal liver was not significantly lower following ACK2 treatment compared to PBS injected fetuses at 2 days but was by 4 days. Additionally, ACK2 resulted in a significant reduction in the number of HSCs within neonatal mice 7 days after treatment., Conclusion: Survival following placental ACK2 injection is comparable to control animals and provides a simple non-invasive strategy to deliver ACK2 into the fetal circulation which successfully depletes the host HSCs., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
42. Maternal factors associated with the occurrence of gastroschisis.
- Author
-
Baer RJ, Chambers CD, Jones KL, Shew SB, MacKenzie TC, Shaw GM, and Jelliffe-Pawlowski LL
- Subjects
- Adult, Age Factors, California epidemiology, Female, Humans, Hypertension, Pregnancy-Induced physiopathology, Infant, Newborn, Logistic Models, Maternal Age, Obesity complications, Odds Ratio, Pregnancy, Prevalence, Risk Factors, Sexually Transmitted Diseases complications, Urinary Tract Infections complications, Virus Diseases complications, Gastroschisis epidemiology, Gastroschisis etiology, Maternal Health, Pregnancy Complications, Infectious
- Abstract
We sought to identify age group specific maternal risk factors for gastroschisis. Maternal characteristics and prenatal factors were compared for 1,279 live born infants with gastroschisis and 3,069,678 without. Data were obtained using the California database containing linked hospital discharge, birth certificate and death records from 1 year prior to the birth to 1 year after the birth. Backwards-stepwise logistic regression models were used with maternal factors where initial inclusion was determined by a threshold of p < 0.10 on initial crude analyses. Due to the strong association of gastroschisis with young maternal age, models were stratified by age groups and odds ratios were calculated. These final models identified maternal infection as the only risk factor common to all age groups and a protective effect of obesity and gestational hypertension. In addition, age specific risk factors were identified. Although gestation at the time of infection was not available, a sexually transmitted disease complicating pregnancy was associated with increased risk in the less than 20 years of age grouping whereas viral infection was associated with increased risk only in the 20-24 and more than 24 years of age groupings. Urinary tract infection remained in the final logistic model for women less than 20 years. Short interpregnancy interval was not found to be a risk factor for any age group. Our findings support the need to explore maternal infection by type and gestational timing., (© 2015 Wiley Periodicals, Inc.)
- Published
- 2015
- Full Text
- View/download PDF
43. Favorable outcomes in high-risk congenital pulmonary airway malformations treated with multiple courses of maternal betamethasone.
- Author
-
Derderian SC, Coleman AM, Jeanty C, Lim FY, Shaaban AM, Farrell JA, Hirose S, MacKenzie TC, and Lee H
- Subjects
- Adult, Dose-Response Relationship, Drug, Female, Glucocorticoids administration & dosage, Humans, Infant, Newborn, Injections, Intramuscular, Male, Pregnancy, Pregnancy Outcome, Respiratory System Abnormalities complications, Retrospective Studies, Betamethasone administration & dosage, Cystic Adenomatoid Malformation of Lung, Congenital drug therapy, Fetal Diseases drug therapy
- Abstract
Background/purpose: Congenital pulmonary airway malformations (CPAMs) are rare congenital lung lesions often diagnosed by prenatal ultrasound. High-risk cases can result in hydrops and prenatal or postnatal demise. Antenatal betamethasone has resulted in improved survival but it is unclear how to manage patients who do not respond to a single course., Methods: We present a bi-institutional retrospective review of patients treated with multiple courses of prenatal steroids for high-risk CPAMs between 2007 and 2013., Results: Nine patients met inclusion criteria. All but one either had an increased CPAM volume ratio (CVR) or number of fluid-containing compartments involved after a single course of antenatal betamethasone, prompting additional courses. Four patients stabilized, three improved and two progressed after the second course. The two cases with disease progression underwent an in utero resection. There were one in utero fetal demise and two deaths within the delivery room. Both fetuses that underwent a fetal resection died. All but one mother who delivered a viable fetus had complications of pregnancy., Conclusions: Multiple courses of antenatal betamethasone for high-risk fetal CPAMs often result in favorable short-term outcomes without the need for open fetal resection. Pregnancy complications are common and women within this cohort should be monitored closely., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
44. Consensus statement from the first international conference for in utero stem cell transplantation and gene therapy.
- Author
-
MacKenzie TC, David AL, Flake AW, and Almeida-Porada G
- Published
- 2015
- Full Text
- View/download PDF
45. In utero hematopoietic cell transplantation for hemoglobinopathies.
- Author
-
Derderian SC, Jeanty C, Walters MC, Vichinsky E, and MacKenzie TC
- Abstract
In utero hematopoietic cell transplantation (IUHCTx) is a promising strategy to circumvent the challenges of postnatal hematopoietic stem cell (HSC) transplantation. The goal of IUHCTx is to introduce donor cells into a naïve host prior to immune maturation, thereby inducing donor-specific tolerance. Thus, this technique has the potential of avoiding host myeloablative conditioning with cytotoxic agents. Over the past two decades, several attempts at IUHCTx have been made to cure numerous underlying congenital anomalies with limited success. In this review, we will briefly review the history of IUHCTx and give a perspective on alpha thalassemia major, one target disease for its clinical application.
- Published
- 2015
- Full Text
- View/download PDF
46. The many faces of hydrops.
- Author
-
Derderian SC, Jeanty C, Fleck SR, Cheng LS, Peyvandi S, Moon-Grady AJ, Farrell J, Hirose S, Gonzalez J, Keller RL, and MacKenzie TC
- Subjects
- Female, Fetal Therapies, Gestational Age, Humans, Pregnancy, Prognosis, Retrospective Studies, Ultrasonography, Prenatal, Hydrops Fetalis diagnostic imaging, Hydrops Fetalis etiology, Hydrops Fetalis physiopathology, Hydrops Fetalis therapy
- Abstract
Purpose: Fetal hydrops arises from multiple disease processes and can portend a grim prognosis. We reviewed our experience with hydropic fetuses to understand relevant antenatal anatomic and physiologic predictors of survival., Methods: We reviewed fetal ultrasounds and echocardiograms of hydropic fetuses evaluated from 1996 to 2013., Results: Overall neonatal survival in 167 fetuses was 44% (range, 0-75%) and was influenced by the underlying disease process. The anatomic distribution of fluid varied and was not significantly different between survivors and nonsurvivors. Univariate analysis indicated that resolution of hydrops and delivery at a later gestational age were predictive of survival (OR: 5.7 (95% CI: 2.5-13.2) and OR: 1.3 (95% CI: 1.1-1.4), respectively). Fetal intervention also improved survival in some diseases. Echocardiograms were reviewed to group fetuses with similar cardiac physiology and defined categories with high or low/normal cardiothoracic ratio (CTR). Among patients with a high CTR, the cardiovascular profile score was predictive of survival (p=0.009)., Conclusion: Survival in hydrops depends on the underlying disease, available fetal therapies to resolve hydrops, and the gestational age of delivery and not on the specific anatomic manifestations of hydrops. In hydropic fetuses with high CTRs, the cardiovascular profile score may be a useful prognostic indicator., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
47. Novel non-surgical prenatal approaches to treating congenital diaphragmatic hernia.
- Author
-
Jeanty C, Kunisaki SM, and MacKenzie TC
- Subjects
- Antioxidants therapeutic use, Female, Hernias, Diaphragmatic, Congenital drug therapy, Humans, Pregnancy, Prenatal Diagnosis, Stem Cell Transplantation, Steroids therapeutic use, Vitamin A therapeutic use, Fetal Therapies, Hernias, Diaphragmatic, Congenital therapy, Lung abnormalities
- Abstract
This review focuses on the emerging field of non-surgical in-utero therapies in the management of fetal pulmonary hypoplasia and pulmonary hypertension associated with congenital diaphragmatic hernia (CDH). These experimental approaches include pharmacologic as well as stem-cell-based strategies. Current barriers of non-surgical therapies toward clinical translation are emphasized. As the severity of CDH will likely influence the efficacy of any in-utero therapy, the current status of prenatal imaging and the role of novel biomarkers, especially those related to fetal inflammation, are also reviewed., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
48. In utero depletion of fetal hematopoietic stem cells improves engraftment after neonatal transplantation in mice.
- Author
-
Derderian SC, Togarrati PP, King C, Moradi PW, Reynaud D, Czechowicz A, Weissman IL, and MacKenzie TC
- Subjects
- Animals, Animals, Newborn, Female, Fetal Stem Cells immunology, Hematopoietic Stem Cells immunology, Mice, Mice, Inbred C57BL, Pregnancy, Proto-Oncogene Proteins c-kit administration & dosage, Proto-Oncogene Proteins c-kit antagonists & inhibitors, Proto-Oncogene Proteins c-kit immunology, Stem Cell Niche immunology, Fetal Stem Cells cytology, Fetal Therapies methods, Hematopoietic Stem Cell Transplantation methods, Hematopoietic Stem Cells cytology, Transplantation Conditioning methods
- Abstract
Although in utero hematopoietic cell transplantation is a promising strategy to treat congenital hematopoietic disorders, levels of engraftment have not been therapeutic for diseases in which donor cells have no survival advantage. We used an antibody against the murine c-Kit receptor (ACK2) to deplete fetal host hematopoietic stem cells (HSCs) and increase space within the hematopoietic niche for donor cell engraftment. Fetal mice were injected with ACK2 on embryonic days 13.5 to 14.5 and surviving pups were transplanted with congenic hematopoietic cells on day of life 1. Low-dose ACK2 treatment effectively depleted HSCs within the bone marrow with minimal toxicity and the antibody was cleared from the serum before the neonatal transplantation. Chimerism levels were significantly higher in treated pups than in controls; both myeloid and lymphoid cell chimerism increased because of higher engraftment of HSCs in the bone marrow. To test the strategy of repeated HSC depletion and transplantation, some mice were treated with ACK2 postnatally, but the increase in engraftment was lower than that seen with prenatal treatment. We demonstrate a successful fetal conditioning strategy associated with minimal toxicity. Such strategies could be used to achieve clinically relevant levels of engraftment to treat congenital stem cell disorders., (© 2014 by The American Society of Hematology.)
- Published
- 2014
- Full Text
- View/download PDF
49. Maternal-fetal cellular trafficking: clinical implications and consequences.
- Author
-
Jeanty C, Derderian SC, and Mackenzie TC
- Subjects
- Adult, Aneuploidy, Autoimmune Diseases genetics, Chimerism embryology, Female, Graft Rejection genetics, Humans, Immune Tolerance, Infant, Newborn, Pregnancy, Pregnancy Complications genetics, Pregnancy Complications immunology, Prenatal Diagnosis, Autoimmune Diseases diagnosis, Fetal Therapies methods, Graft Rejection immunology, Histocompatibility, Maternal-Fetal immunology, Maternal-Fetal Exchange immunology, Pregnancy Complications diagnosis
- Abstract
Purpose of Review: Maternal-fetal cellular trafficking (MFCT) is the bidirectional passage of cells between mother and fetus during pregnancy. This results in the presence of fetal cells in the maternal circulation, known as fetal microchimerism, and maternal cells in the fetal circulation, known as maternal microchimerism. The biologic role of this transplacental cellular trafficking during pregnancy is not known, although it has been implicated in development of the fetal immune system, tolerance mechanisms during pregnancy, tissue repair in autoimmune disease and cancer, and immune surveillance., Recent Findings: Clinical utility of MFCT has been identified in prenatal testing for aneuploidies and prediction of pregnancy complications. Additionally, this transplacental passage of cells has been implicated in the delicate balance between immunologic priming and tolerance, which can influence the occurrence of autoimmune disease and transplantation outcomes. Ongoing studies are evaluating the utility of microchimerism in predicting the risk of graft rejection in transplantation., Summary: In this review, we will discuss the clinical implications of MFCT in pregnancy, fetal surgery, autoimmune disease, transplantation, and cancer.
- Published
- 2014
- Full Text
- View/download PDF
50. Outcomes of fetal intervention for primary hydrothorax.
- Author
-
Derderian SC, Trivedi S, Farrell J, Keller RL, Rand L, Goldstein R, Feldstein VA, Hirose S, and MacKenzie TC
- Subjects
- California epidemiology, Female, Fetal Diseases diagnostic imaging, Fetal Diseases mortality, Follow-Up Studies, Gestational Age, Humans, Hydrothorax diagnostic imaging, Hydrothorax embryology, Infant, Newborn, Male, Pregnancy, Pregnancy Outcome, Retrospective Studies, Survival Rate trends, Treatment Outcome, Ultrasonography, Prenatal, Fetal Diseases therapy, Fetal Therapies methods, Hydrothorax therapy
- Abstract
Objective: Primary hydrothorax is a rare congenital anomaly with outcomes ranging from spontaneous resolution to fetal demise. We reviewed our experience with fetuses diagnosed with primary hydrothorax to evaluate prenatal management strategies., Methods: We reviewed the records of patients evaluated for fetal pleural effusions at our Fetal Treatment Center between 1996 and 2013. To define fetuses with primary hydrothorax, we excluded those with structural or genetic anomalies, diffuse lymphangiectasia, immune hydrops, and monochorionic diamniotic twin gestations., Results: We identified 31 fetuses with primary hydrothorax, of whom 24 had hydrops. Hydropic fetuses were more likely to present with bilateral effusions. Of all fetuses with primary hydrothorax, 21 had fetal interventions. Survival without hydrops was 7/7 (100%), whereas survival with hydrops depended on whether or not the patient had fetal intervention: 12/19 (63%) with intervention and 1/5 (20%) without intervention. Premature delivery was common (44%) among those who had fetal intervention., Conclusions: Fetal intervention for primary hydrothorax may lead to resolution of hydrops, but preterm birth and neonatal demise still occur. Understanding the pathophysiology of hydrops may provide insights into further prenatal management strategies, including targeted therapies to prevent preterm labor., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.