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1. The expanding application of antisense oligonucleotides to neurodegenerative diseases

Author

Sumner, Charlotte J. and Miller, Timothy M.

Subjects
Medical research, Medicine, Experimental, Gene therapy -- Research, Nervous system -- Degeneration, Health care industry
Abstract

Despite investment of billions of research dollars, neurodegenerative diseases have been largely resistant to therapeutics development because of incomplete understanding of molecular basis of disease, paucity of disease proximal targets, [...]

Published
2024
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2. Characterization of Low-noise Backshort-Under-Grid Kilopixel Transition Edge Sensor Arrays for PIPER

Author

Datta, Rahul, Dahal, Sumit, Switzer, Eric R., Brekosky, Regis P., Essinger-Hileman, Thomas, Fixsen, Dale J., Jhabvala, Christine A., Kogut, Alan J., Miller, Timothy M., Mirel, Paul, and Wollack, Edward J.

Subjects
Astrophysics - Instrumentation and Methods for Astrophysics
Abstract

We present laboratory characterization of kilo-pixel, filled backshort-under-grid (BUG) transition-edge sensor (TES) arrays developed for the Primordial Inflation Polarization ExploreR (PIPER) balloon-borne instrument. PIPER is designed to map the polarization of the CMB on the largest angular scales and characterize dust foregrounds by observing a large fraction of the sky in four frequency bands in the range 200 to 600 GHz. The BUG TES arrays are read out by planar SQUID-based time division multiplexer chips (2dMUX) of matching form factor and hybridized directly with the detector arrays through indium bump bonding. Here, we discuss the performance of the 2dMUX and present measurements of the TES transition temperature, thermal conductance, saturation power, and preliminary noise performance. The detectors achieve saturation power below 1 pW and phonon noise equivalent power (NEP) on the order of a few aW/rtHz. Detector performance is further verified through pre-flight tests in the integrated PIPER receiver, performed in an environment simulating balloon float conditions., Comment: 11 pages, 11 figures

Published
2022

3. NOS1AP is a novel molecular target and critical factor in TDP-43 pathology

Author

Cappelli, Sara, Spalloni, Alida, Feiguin, Fabian, Visani, Giulia, Šušnjar, Urša, Brown, Anna-Leigh, Phatnani, Hemali, Kwan, Justin, Sareen, Dhruv, Broach, James R, Simmons, Zachary, Arcila-Londono, Ximena, Lee, Edward B, Van Deerlin, Vivianna M, Shneider, Neil A, Fraenkel, Ernest, Ostrow, Lyle W, Baas, Frank, Zaitlen, Noah, Berry, James D, Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A, Thompson, Leslie M, Finkbeiner, Steve, Dardiotis, Efthimios, Miller, Timothy M, Chandran, Siddharthan, Pal, Suvankar, Hornstein, Eran, MacGowan, Daniel J, Heiman-Patterson, Terry, Hammell, Molly G, Patsopoulos, Nikolaos A, Butovsky, Oleg, Dubnau, Joshua, Nath, Avindra, Bowser, Robert, Harms, Matt, Aronica, Eleonora, Poss, Mary, Phillips-Cremins, Jennifer, Crary, John, Atassi, Nazem, Lange, Dale J, Adams, Darius J, Stefanis, Leonidas, Gotkine, Marc, Baloh, Robert H, Babu, Suma, Raj, Towfique, Paganoni, Sabrina, Shalem, Ophir, Smith, Colin, Zhang, Bin, Harris, Brent, Broce, Iris, Drory, Vivian, Ravits, John, McMillan, Corey, Menon, Vilas, De Bardi, Marco, Borsellino, Giovanna, Secrier, Maria, Romano, Maurizio, Longone, Patrizia, and Buratti, Emanuele

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Biotechnology, Genetics, Aetiology, 2.1 Biological and endogenous factors, NYGC ALS Consortium, ALS, CAPON/NOS1AP, RNA stability, TDP-43, hnRNPs, Clinical sciences, Biological psychology
Abstract

Many lines of evidence have highlighted the role played by heterogeneous nuclear ribonucleoproteins in amyotrophic lateral sclerosis. In this study, we have aimed to identify transcripts co-regulated by TAR DNA-binding protein 43 kDa and highly conserved heterogeneous nuclear ribonucleoproteins which have been previously shown to regulate TAR DNA-binding protein 43 kDa toxicity (deleted in azoospermia-associated protein 1, heterogeneous nuclear ribonucleoprotein -Q, -D, -K and -U). Using the transcriptome analyses, we have uncovered that Nitric Oxide Synthase 1 Adaptor Protein mRNA is a direct TAR DNA-binding protein 43 kDa target, and in flies, its modulation alone can rescue TAR DNA-binding protein 43 kDa pathology. In primary mouse cortical neurons, we show that TAR DNA-binding protein 43 kDa mediated downregulation of Nitric Oxide Synthase 1 Adaptor Protein expression strongly affects the NMDA-receptor signalling pathway. In human patients, the downregulation of Nitric Oxide Synthase 1 Adaptor Protein mRNA strongly correlates with TAR DNA-binding protein 43 kDa proteinopathy as measured by cryptic Stathmin-2 and Unc-13 homolog A cryptic exon inclusion. Overall, our results demonstrate that Nitric Oxide Synthase 1 Adaptor Protein may represent a novel disease-relevant gene, potentially suitable for the development of new therapeutic strategies.

Published
2022

4. Effect of sodium phenylbutyrate/taurursodiol on tracheostomy/ventilation-free survival and hospitalisation in amyotrophic lateral sclerosis: long-term results from the CENTAUR trial

Author

Paganoni, Sabrina, Hendrix, Suzanne, Dickson, Samuel P, Knowlton, Newman, Berry, James D, Elliott, Michael A, Maiser, Samuel, Karam, Chafic, Caress, James B, Owegi, Margaret Ayo, Quick, Adam, Wymer, James, Goutman, Stephen A, Heitzman, Daragh, Heiman-Patterson, Terry D, Jackson, Carlayne, Quinn, Colin, Rothstein, Jeffrey D, Kasarskis, Edward J, Katz, Jonathan, Jenkins, Liberty, Ladha, Shafeeq S, Miller, Timothy M, Scelsa, Stephen N, Vu, Tuan H, Fournier, Christina, Johnson, Kristin M, Swenson, Andrea, Goyal, Namita, Pattee, Gary L, Babu, Suma, Chase, Marianne, Dagostino, Derek, Hall, Meghan, Kittle, Gale, Eydinov, Mathew, Ostrow, Joseph, Pothier, Lindsay, Randall, Rebecca, Shefner, Jeremy M, Sherman, Alexander V, Tustison, Eric, Vigneswaran, Prasha, Yu, Hong, Cohen, Joshua, Klee, Justin, Tanzi, Rudolph, Gilbert, Walter, Yeramian, Patrick, and Cudkowicz, Merit

Subjects
Rare Diseases, ALS, Neurosciences, Clinical Research, Clinical Trials and Supportive Activities, Neurodegenerative, Brain Disorders, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, MOTOR NEURON DISEASE, NEUROMUSCULAR, RANDOMISED TRIALS, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

BackgroundCoformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS).ObjectiveDetermine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial.MethodsAdults with El Escorial Definite ALS ≤18 months from symptom onset were randomised to PB/ TURSO or placebo for 6 months. Those completing randomised treatment could enrol in an open-label extension (OLE) phase and receive PB/TURSO for ≤30 months. Times to the following individual or combined key events were compared in the originally randomised treatment groups over a period spanning trial start through July 2020 (longest postrandomisation follow-up, 35 months): death, tracheostomy, permanent assisted ventilation (PAV) and first hospitalisation.ResultsRisk of any key event was 47% lower in those originally randomised to PB/TURSO (n=87) versus placebo (n=48, 71% of whom received delayed-start PB/TURSO in the OLE phase) (HR=0.53; 95% CI 0.35 to 0.81; p=0.003). Risks of death or tracheostomy/PAV (HR=0.51; 95% CI 0.32 to 0.84; p=0.007) and first hospitalisation (HR=0.56; 95% CI 0.34 to 0.95; p=0.03) were also decreased in those originally randomised to PB/TURSO.ConclusionsEarly PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS.Trial registration numberNCT03127514; NCT03488524.

Published
2022

8. TSC1 loss increases risk for tauopathy by inducing tau acetylation and preventing tau clearance via chaperone-mediated autophagy

Author

Alquezar, Carolina, Schoch, Kathleen M, Geier, Ethan G, Ramos, Eliana Marisa, Scrivo, Aurora, Li, Kathy H, Argouarch, Andrea R, Mlynarski, Elisabeth E, Dombroski, Beth, DeTure, Michael, Dickson, Dennis W, Yokoyama, Jennifer S, Cuervo, Ana M, Burlingame, Alma L, Schellenberg, Gerard D, Miller, Timothy M, Miller, Bruce L, and Kao, Aimee W

Subjects
Biochemistry and Cell Biology, Biological Sciences, Dementia, Alzheimer's Disease, Rare Diseases, Alzheimer's Disease Related Dementias (ADRD), Frontotemporal Dementia (FTD), Neurosciences, Neurodegenerative, Aging, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Genetics, Brain Disorders, 2.1 Biological and endogenous factors
Abstract

Age-associated neurodegenerative disorders demonstrating tau-laden intracellular inclusions are known as tauopathies. We previously linked a loss-of-function mutation in the TSC1 gene to tau accumulation and frontotemporal lobar degeneration. Now, we have identified genetic variants in TSC1 that decrease TSC1/hamartin levels and predispose to tauopathies such as Alzheimer’s disease and progressive supranuclear palsy. Cellular and murine models of TSC1 haploinsufficiency, as well as human brains carrying a TSC1 risk variant, accumulated tau protein that exhibited aberrant acetylation. This acetylation hindered tau degradation via chaperone-mediated autophagy, thereby leading to its accumulation. Aberrant tau acetylation in TSC1 haploinsufficiency resulted from the dysregulation of both p300 acetyltransferase and SIRT1 deacetylase. Pharmacological modulation of either enzyme restored tau levels. This study substantiates TSC1 as a novel tauopathy risk gene and includes TSC1 haploinsufficiency as a genetic model for tauopathies. In addition, these findings promote tau acetylation as a rational target for tauopathy therapeutics and diagnostic.

Published
2021

9. An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients

Author

Consortium, The NeuroLINCS, Phatnani, Hemali, Kwan, Justin, Sareen, Dhruv, Broach, James R, Simmons, Zachary, Arcila-Londono, Ximena, Lee, Edward B, Van Deerlin, Vivianna M, Shneider, Neil A, Fraenkel, Ernest, Ostrow, Lyle W, Baas, Frank, Zaitlen, Noah, Berry, James D, Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A, Thompson, Leslie M, Finkbeiner, Steve, Dardiotis, Efthimios, Miller, Timothy M, Chandran, Siddharthan, Pal, Suvankar, Hornstein, Eran, MacGowan, Daniel J, Heiman-Patterson, Terry, Hammell, Molly G, Patsopoulos, Nikolaos A, Butovsky, Oleg, Dubnau, Joshua, Nath, Avindra, Bowser, Robert, Harms, Matt, Poss, Mary, Phillips-Cremins, Jennifer, Crary, John, Atassi, Nazem, Lange, Dale J, Adams, Darius J, Stefanis, Leonidas, Gotkine, Marc, Baloh, Robert H, Babu, Suma, Raj, Towfique, Paganoni, Sabrina, Shalem, Ophir, Smith, Colin, Zhang, Bin, Harris, Brent, Broce, Iris, Drory, Vivian, Ravits, John, McMillan, Corey, Menon, Vilas, Wu, Lani, Altschuler, Steven, Li, Jonathan, Lim, Ryan G, Kaye, Julia A, Dardov, Victoria, Coyne, Alyssa N, Wu, Jie, Milani, Pamela, Cheng, Andrew, Thompson, Terri G, Ornelas, Loren, Frank, Aaron, Adam, Miriam, Banuelos, Maria G, Casale, Malcolm, Cox, Veerle, Escalante-Chong, Renan, Daigle, J Gavin, Gomez, Emilda, Hayes, Lindsey, Holewenski, Ronald, Lei, Susan, Lenail, Alex, Lima, Leandro, Mandefro, Berhan, Matlock, Andrea, Panther, Lindsay, Patel-Murray, Natasha Leanna, Pham, Jacqueline, Ramamoorthy, Divya, Sachs, Karen, Shelley, Brandon, Stocksdale, Jennifer, Trost, Hannah, Wilhelm, Mark, Venkatraman, Vidya, Wassie, Brook T, Wyman, Stacia, Yang, Stephanie, Consortium, NYGC ALS, Van Eyk, Jennifer E, Lloyd, Thomas E, and Finkbeiner, Steven

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Neurodegenerative, Clinical Research, ALS, Stem Cell Research, Rare Diseases, Acquired Cognitive Impairment, Stem Cell Research - Induced Pluripotent Stem Cell, Brain Disorders, Neurosciences, Dementia, Stem Cell Research - Induced Pluripotent Stem Cell - Human, 2.1 Biological and endogenous factors, Aetiology, Neurological, Good Health and Well Being, NeuroLINCS Consortium, NYGC ALS Consortium, Biological sciences, Neuroscience, Omics, Systems biology, Systems neuroscience
Abstract

Neurodegenerative diseases are challenging for systems biology because of the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could address these challenges. We investigated DNA, RNA, epigenetics, and proteins in iPSC-derived motor neurons from patients with ALS carrying hexanucleotide expansions in C9ORF72. Using integrative computational methods combining all omics datasets, we identified novel and known dysregulated pathways. We used a C9ORF72 Drosophila model to distinguish pathways contributing to disease phenotypes from compensatory ones and confirmed alterations in some pathways in postmortem spinal cord tissue of patients with ALS. A different differentiation protocol was used to derive a separate set of C9ORF72 and control motor neurons. Many individual -omics differed by protocol, but some core dysregulated pathways were consistent. This strategy of analyzing patient-specific neurons provides disease-related outcomes with small numbers of heterogeneous lines and reduces variation from single-omics to elucidate network-based signatures.

Published
2021

10. Long‐term survival of participants in the CENTAUR trial of sodium phenylbutyrate‐taurursodiol in amyotrophic lateral sclerosis

Author

Paganoni, Sabrina, Hendrix, Suzanne, Dickson, Samuel P, Knowlton, Newman, Macklin, Eric A, Berry, James D, Elliott, Michael A, Maiser, Samuel, Karam, Chafic, Caress, James B, Owegi, Margaret Ayo, Quick, Adam, Wymer, James, Goutman, Stephen A, Heitzman, Daragh, Heiman‐Patterson, Terry D, Jackson, Carlayne E, Quinn, Colin, Rothstein, Jeffrey D, Kasarskis, Edward J, Katz, Jonathan, Jenkins, Liberty, Ladha, Shafeeq, Miller, Timothy M, Scelsa, Stephen N, Vu, Tuan H, Fournier, Christina N, Glass, Jonathan D, Johnson, Kristin M, Swenson, Andrea, Goyal, Namita A, Pattee, Gary L, Andres, Patricia L, Babu, Suma, Chase, Marianne, Dagostino, Derek, Hall, Meghan, Kittle, Gale, Eydinov, Matthew, McGovern, Michelle, Ostrow, Joseph, Pothier, Lindsay, Randall, Rebecca, Shefner, Jeremy M, Sherman, Alexander V, St Pierre, Maria E, Tustison, Eric, Vigneswaran, Prasha, Walker, Jason, Yu, Hong, Chan, James, Wittes, Janet, Yu, Zi‐Fan, Cohen, Joshua, Klee, Justin, Leslie, Kent, Tanzi, Rudolph E, Gilbert, Walter, Yeramian, Patrick D, Schoenfeld, David, and Cudkowicz, Merit E

Subjects
Brain Disorders, Rare Diseases, Neurodegenerative, Clinical Trials and Supportive Activities, Clinical Research, ALS, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adolescent, Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Double-Blind Method, Female, Humans, Male, Middle Aged, Neuroprotective Agents, Phenylbutyrates, Taurochenodeoxycholic Acid, Time, Young Adult, amyotrophic lateral sclerosis, CENTAUR, motor neuron disease, sodium phenylbutyrate&#8208, taurursodiol, survival analysis, sodium phenylbutyrate-taurursodiol, Medical and Health Sciences, Neurology & Neurosurgery
Abstract

An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P = .023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.

Published
2021

12. Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis

Author

Paganoni, Sabrina, Macklin, Eric A, Hendrix, Suzanne, Berry, James D, Elliott, Michael A, Maiser, Samuel, Karam, Chafic, Caress, James B, Owegi, Margaret A, Quick, Adam, Wymer, James, Goutman, Stephen A, Heitzman, Daragh, Heiman-Patterson, Terry, Jackson, Carlayne E, Quinn, Colin, Rothstein, Jeffrey D, Kasarskis, Edward J, Katz, Jonathan, Jenkins, Liberty, Ladha, Shafeeq, Miller, Timothy M, Scelsa, Stephen N, Vu, Tuan H, Fournier, Christina N, Glass, Jonathan D, Johnson, Kristin M, Swenson, Andrea, Goyal, Namita A, Pattee, Gary L, Andres, Patricia L, Babu, Suma, Chase, Marianne, Dagostino, Derek, Dickson, Samuel P, Ellison, Noel, Hall, Meghan, Hendrix, Kent, Kittle, Gale, McGovern, Michelle, Ostrow, Joseph, Pothier, Lindsay, Randall, Rebecca, Shefner, Jeremy M, Sherman, Alexander V, Tustison, Eric, Vigneswaran, Prasha, Walker, Jason, Yu, Hong, Chan, James, Wittes, Janet, Cohen, Joshua, Klee, Justin, Leslie, Kent, Tanzi, Rudolph E, Gilbert, Walter, Yeramian, Patrick D, Schoenfeld, David, and Cudkowicz, Merit E

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Neurodegenerative, Rare Diseases, Clinical Research, ALS, Brain Disorders, Neurosciences, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Aged, Amyotrophic Lateral Sclerosis, Disease Progression, Double-Blind Method, Drug Combinations, Female, Humans, Intention to Treat Analysis, Male, Middle Aged, Phenylbutyrates, Severity of Illness Index, Taurochenodeoxycholic Acid, Treatment Outcome, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundSodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known.MethodsIn this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization.ResultsA total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal.ConclusionsSodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).

Published
2020

13. SOFIA - HIRMES: Looking forward to the HIgh-Resolution Mid-infrarEd Spectrometer

Author

Richards, Samuel N., Moseley, Samuel H., Stacey, Gordon, Greenhouse, Matthew, Kutyrev, Alexander, Arendt, Richard, Atanasoff, Hristo, Banks, Stuart, Brekosky, Regis P., Brown, Ari-David, Bulcha, Berhanu, Cazeau, Tony, Choi, Michael, Colazo, Felipe, Engler, Chuck, Hadjimichael, Theodore, Hays-Wehle, James, Henderson, Chuck, Hsieh, Wen-Ting, Huang, Jeffrey, Jenstrom, Iver, Kellogg, Jim, Kimball, Mark, Kovacs, Attila, Leiter, Steve, Maher, Steve, McMurray, Robert, Melnick, Gary J., Mentzell, Eric, Mikula, Vilem, Miller, Timothy M., Nagler, Peter, Nikola, Thomas, Oxborrow, Joseph, Pontoppidan, Klaus M., Rangwala, Naseem, Rhodes, Alan, Roberge, Aki, Rosner, Stefan, Rostem, Karwan, Rustemeyer, Nancy, Sharp, Elmer, Sparr, Leroy, Stevanovic, Dejan, Taraschi, Peter, Temi, Pasquale, Vacca, William D., de Lorenzo, Jordi Vila Hernandez, Wohler, Bill, Wollack, Edward J., and Wilks, Shannon

Subjects
Astrophysics - Instrumentation and Methods for Astrophysics
Abstract

The HIgh-Resolution Mid-infrarEd Spectrometer (HIRMES) is the 3rd Generation Instrument for the Stratospheric Observatory For Infrared Astronomy (SOFIA), currently in development at the NASA Goddard Space Flight Center (GSFC), and due for commissioning in 2019. By combining direct-detection Transition Edge Sensor (TES) bolometer arrays, grating-dispersive spectroscopy, and a host of Fabry-Perot tunable filters, HIRMES will provide the ability for High Resolution (R~100,000), Mid-Resolution (R~10,000), and Low-Resolution (R~600) slit-spectroscopy, and 2D Spectral Imaging (R~2000 at selected wavelengths) over the 25 - 122 {\mu}m mid-far infrared waveband. The driving science application is the evolution of proto-planetary systems via measurements of water-vapor, water-ice, deuterated hydrogen (HD), and neutral oxygen lines. However, HIRMES has been designed to be as flexible as possible to cover a wide range of science cases that fall within its phase-space, all whilst reaching sensitivities and observing powers not yet seen thus far on SOFIA, providing unique observing capabilities which will remain unmatched for decades., Comment: Accepted to the Journal of Astronomical Instrumentation (SOFIA Special Edition) on 11th November 2018

Published
2018

18. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

Author

Nicolas, Aude, Kenna, Kevin P, Renton, Alan E, Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A, Kenna, Brendan J, Nalls, Mike A, Keagle, Pamela, Rivera, Alberto M, van Rheenen, Wouter, Murphy, Natalie A, van Vugt, Joke JFA, Geiger, Joshua T, Van der Spek, Rick A, Pliner, Hannah A, Shankaracharya, Smith, Bradley N, Marangi, Giuseppe, Topp, Simon D, Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D, Kenna, Aoife, ITALSGEN Consortium, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L, Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L, Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O, D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Genomic Translation for ALS Care (GTAC) Consortium, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Goldstein, David B, ALS Sequencing Consortium, Gitler, Aaron D, Harris, Tim, Myers, Richard M, NYGC ALS Consortium, Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C, Answer ALS Foundation, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K, LeNail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N, Thompson, Leslie M, Van Eyk, Jennifer E, Berry, James D, Miller, Timothy M, Kolb, Stephen J, Cudkowicz, Merit, Baxi, Emily, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Benatar, Michael, Taylor, J Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, SLAGEN Consortium, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P, Sorarù, Gianni, Cereda, Cristina, French ALS Consortium, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, and Orrell, Richard W

Subjects
ITALSGEN Consortium, Genomic Translation for ALS Care (GTAC) Consortium, ALS Sequencing Consortium, NYGC ALS Consortium, Answer ALS Foundation, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, SLAGEN Consortium, French ALS Consortium, Project MinE ALS Sequencing Consortium, Humans, Amyotrophic Lateral Sclerosis, Cohort Studies, Amino Acid Sequence, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Genome-Wide Association Study, Young Adult, Loss of Function Mutation, Kinesins, ALS, GWAS, KIF5A, WES, WGS, axonal transport, cargo, Brain Disorders, Genetics, Human Genome, Rare Diseases, Neurosciences, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Neurological, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Published
2018

19. An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients

Author

Phatnani, Hemali, Kwan, Justin, Sareen, Dhruv, Broach, James R., Simmons, Zachary, Arcila-Londono, Ximena, Lee, Edward B., Van Deerlin, Vivianna M., Shneider, Neil A., Fraenkel, Ernest, Ostrow, Lyle W., Baas, Frank, Zaitlen, Noah, Berry, James D., Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steve, Dardiotis, Efthimios, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos.A., Butovsky, Oleg, Dubnau, Joshua, Nath, Avindra, Bowser, Robert, Harms, Matt, Poss, Mary, Phillips-Cremins, Jennifer, Crary, John, Atassi, Nazem, Lange, Dale J., Adams, Darius J., Stefanis, Leonidas, Gotkine, Marc, Baloh, Robert H., Babu, Suma, Raj, Towfique, Paganoni, Sabrina, Shalem, Ophir, Smith, Colin, Zhang, Bin, Harris, Brent, Broce, Iris, Drory, Vivian, Ravits, John, McMillan, Corey, Menon, Vilas, Wu, Lani, Altschuler, Steven, Li, Jonathan, Lim, Ryan G., Kaye, Julia A., Dardov, Victoria, Coyne, Alyssa N., Wu, Jie, Milani, Pamela, Cheng, Andrew, Thompson, Terri G., Ornelas, Loren, Frank, Aaron, Adam, Miriam, Banuelos, Maria G., Casale, Malcolm, Cox, Veerle, Escalante-Chong, Renan, Daigle, J. Gavin, Gomez, Emilda, Hayes, Lindsey, Holewenski, Ronald, Lei, Susan, Lenail, Alex, Lima, Leandro, Mandefro, Berhan, Matlock, Andrea, Panther, Lindsay, Patel-Murray, Natasha Leanna, Pham, Jacqueline, Ramamoorthy, Divya, Sachs, Karen, Shelley, Brandon, Stocksdale, Jennifer, Trost, Hannah, Wilhelm, Mark, Venkatraman, Vidya, Wassie, Brook T., Wyman, Stacia, Yang, Stephanie, Van Eyk, Jennifer E., Lloyd, Thomas E., Finkbeiner, Steven, Rothstein, Jeffrey D., and Svendsen, Clive N.

Published
2021
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21. The Primordial Inflation Polarization Explorer (PIPER)

Author

Gandilo, Natalie N., Ade, Peter A. R., Benford, Dominic, Bennett, Charles L., Chuss, David T., Dotson, Jessie L., Eimer, Joseph R., Fixsen, Dale J., Halpern, Mark, Hilton, Gene, Hinshaw, Gary F., Irwin, Kent, Jhabvala, Christine, Kimball, Mark, Kogut, Alan, Lowe, Luke, McMahon, Jeff J., Miller, Timothy M., Mirel, Paul, Moseley, S. Harvey, Pawlyk, Samuel, Rodriguez, Samelys, Sharp III, Elmer, Shirron, Peter, Staguhn, Johannes G., Sullivan, Dan F., Switzer, Eric R., Taraschi, Peter, Tucker, Carole E., and Wollack, Edward J.

Subjects
Astrophysics - Instrumentation and Methods for Astrophysics
Abstract

The Primordial Inflation Polarization ExploreR (PIPER) is a balloon-borne telescope designed to measure the polarization of the Cosmic Microwave Background on large angular scales. PIPER will map 85% of the sky at 200, 270, 350, and 600 GHz over a series of 8 conventional balloon flights from the northern and southern hemispheres. The first science flight will use two 32x40 arrays of backshort-under-grid transition edge sensors, multiplexed in the time domain, and maintained at 100 mK by a Continuous Adiabatic Demagnetization Refrigerator. Front-end cryogenic Variable-delay Polarization Modulators provide systematic control by rotating linear to circular polarization at 3 Hz. Twin telescopes allow PIPER to measure Stokes I, Q, U, and V simultaneously. The telescope is maintained at 1.5 K in an LHe bucket dewar. Cold optics and the lack of a warm window permit sensitivity at the sky-background limit. The ultimate science target is a limit on the tensor-to-scalar ratio of r ~ 0.007, from the reionization bump to l ~ 300. PIPER's first flight will be from the Northern hemisphere, and overlap with the CLASS survey at lower frequencies. We describe the current status of the PIPER instrument., Comment: 8 pages, 6 figures. To be published in Proceedings of SPIE Volume 9914. Presented at SPIE Astronomical Telescopes + Instrumentation 2016, conference 9914

Published
2016
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22. Phosphorylated neurofilament heavy chain: A biomarker of survival for C9ORF72‐associated amyotrophic lateral sclerosis

Author

Gendron, Tania F, Daughrity, Lillian M, Heckman, Michael G, Diehl, Nancy N, Wuu, Joanne, Miller, Timothy M, Pastor, Pau, Trojanowski, John Q, Grossman, Murray, Berry, James D, Hu, William T, Ratti, Antonia, Benatar, Michael, Silani, Vincenzo, Glass, Jonathan D, Floeter, Mary Kay, Jeromin, Andreas, Boylan, Kevin B, Petrucelli, Leonard, and Group, the C9ORF72 Neurofilament Study

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, ALS, Brain Disorders, Rare Diseases, Neurodegenerative, Clinical Research, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Neurological, Good Health and Well Being, Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Biomarkers, C9orf72 Protein, Case-Control Studies, Disease Progression, Female, Humans, Male, Middle Aged, Neurofilament Proteins, Phosphorylation, Proteins, Survival Analysis, Young Adult, C9ORF72 Neurofilament Study Group, Neurology & Neurosurgery, Clinical sciences
Abstract

As potential treatments for C9ORF72-associated amyotrophic lateral sclerosis (c9ALS) approach clinical trials, the identification of prognostic biomarkers for c9ALS becomes a priority. We show that levels of phosphorylated neurofilament heavy chain (pNFH) in cerebrospinal fluid (CSF) predict disease status and survival in c9ALS patients, and are largely stable over time. Moreover, c9ALS patients exhibit higher pNFH levels, more rapid disease progression, and shorter survival after disease onset than ALS patients without C9ORF72 expansions. These data support the use of CSF pNFH as a prognostic biomarker for clinical trials, which will increase the likelihood of successfully developing a treatment for c9ALS. Ann Neurol 2017;82:139-146.

Published
2017

23. Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis

Author

Gendron, Tania F, Chew, Jeannie, Stankowski, Jeannette N, Hayes, Lindsey R, Zhang, Yong-Jie, Prudencio, Mercedes, Carlomagno, Yari, Daughrity, Lillian M, Jansen-West, Karen, Perkerson, Emilie A, O'Raw, Aliesha, Cook, Casey, Pregent, Luc, Belzil, Veronique, van Blitterswijk, Marka, Tabassian, Lilia J, Lee, Chris W, Yue, Mei, Tong, Jimei, Song, Yuping, Castanedes-Casey, Monica, Rousseau, Linda, Phillips, Virginia, Dickson, Dennis W, Rademakers, Rosa, Fryer, John D, Rush, Beth K, Pedraza, Otto, Caputo, Ana M, Desaro, Pamela, Palmucci, Carla, Robertson, Amelia, Heckman, Michael G, Diehl, Nancy N, Wiggs, Edythe, Tierney, Michael, Braun, Laura, Farren, Jennifer, Lacomis, David, Ladha, Shafeeq, Fournier, Christina N, McCluskey, Leo F, Elman, Lauren B, Toledo, Jon B, McBride, Jennifer D, Tiloca, Cinzia, Morelli, Claudia, Poletti, Barbara, Solca, Federica, Prelle, Alessandro, Wuu, Joanne, Jockel-Balsarotti, Jennifer, Rigo, Frank, Ambrose, Christine, Datta, Abhishek, Yang, Weixing, Raitcheva, Denitza, Antognetti, Giovanna, McCampbell, Alexander, Van Swieten, John C, Miller, Bruce L, Boxer, Adam L, Brown, Robert H, Bowser, Robert, Miller, Timothy M, Trojanowski, John Q, Grossman, Murray, Berry, James D, Hu, William T, Ratti, Antonia, Traynor, Bryan J, Disney, Matthew D, Benatar, Michael, Silani, Vincenzo, Glass, Jonathan D, Floeter, Mary Kay, Rothstein, Jeffrey D, Boylan, Kevin B, and Petrucelli, Leonard

Subjects
Clinical Research, Neurodegenerative, Brain Disorders, Acquired Cognitive Impairment, Dementia, Neurosciences, ALS, Rare Diseases, Clinical Trials and Supportive Activities, Genetics, Neurological, Adult, Aged, Amyotrophic Lateral Sclerosis, Animals, Biomarkers, Brain, C9orf72 Protein, Cell Line, Dinucleotide Repeats, Humans, Induced Pluripotent Stem Cells, Leukocytes, Mononuclear, Longitudinal Studies, Mice, Middle Aged, Neurons, Oligonucleotides, Antisense, Prognosis, RNA, Biological Sciences, Medical and Health Sciences
Abstract

There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.

Published
2017

24. Defining SOD1 ALS natural history to guide therapeutic clinical trial design

Author

Bali, Taha, Self, Wade, Liu, Jingxia, Siddique, Teepu, Wang, Leo H, Bird, Thomas D, Ratti, Elena, Atassi, Nazem, Boylan, Kevin B, Glass, Jonathan D, Maragakis, Nicholas J, Caress, James B, McCluskey, Leo F, Appel, Stanley H, Wymer, James P, Gibson, Summer, Zinman, Lorne, Mozaffar, Tahseen, Callaghan, Brian, McVey, April L, Jockel-Balsarotti, Jennifer, Allred, Peggy, Fisher, Elena R, Lopate, Glenn, Pestronk, Alan, Cudkowicz, Merit E, and Miller, Timothy M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Brain Disorders, Neurosciences, ALS, Rare Diseases, Clinical Research, Neurodegenerative, Clinical Trials and Supportive Activities, Adult, Age of Onset, Amyotrophic Lateral Sclerosis, Clinical Trials as Topic, Disease Progression, Humans, Middle Aged, Mutation, Research Design, Retrospective Studies, Superoxide Dismutase, Vital Capacity, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ImportanceUnderstanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALSSOD1) will provide key information for optimising clinical trials in this patient population.ObjectiveTo establish an updated natural history of ALSSOD1.Design, setting and participantsRetrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000.Main outcomes and measuresAge of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1A4V), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1non-A4V) for analysis.ResultsMean age of disease onset was 49.7±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1A4V and SOD1non-A4V (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1A4V. SOD1A4V survival probability (median survival 1.2 years) was significantly decreased compared with SOD1non-A4V (median survival 6.8 years; p

Published
2017

25. Body mass index is lower in asymptomatic C9orf72 expansion carriers but not in SOD1 pathogenic variant carriers compared to gene negatives.

Author

Lee, Ikjae, Garret, Mark A., Wuu, Joanne, Harrington, Elizabeth A., Berry, James D., Miller, Timothy M., Harms, Matthew, Benatar, Michael, and Shneider, Neil

Subjects
AMYOTROPHIC lateral sclerosis, BODY mass index, GRADUATE education, HIGHER education, REGRESSION analysis
Abstract

Objective: To examine the relationship between body mass index (BMI) and genotype among pre-symptomatic carriers of different pathogenic variants associated with amyotrophic lateral sclerosis. Methods: C9orf72+ carriers, SOD1+ carriers, and pathogenic variant negative controls (Gene-Negatives) were included from 3 largely independent cohorts: ALS Families Project (ALS-Families); Dominantly inherited ALS (DIALS); and Pre-symptomatic Familial ALS (Pre-fALS). First reported (ALS-Families) or measured (DIALS and Pre-fALS) weight and height were used to calculate BMI. Age at weight measurement, self-reported sex (male vs. female), and highest education (high school or below vs. college education vs. graduate school or above) were extracted. The associations between BMI and genotype in each cohort were examined with multivariable linear regression models, adjusted for age, sex, and education. Results: A total of 223 C9orf72+ carriers, 135 SOD1+ carriers, and 191 Gene-Negatives were included, deriving from ALS-Families (n = 114, median age 46, 37% male), DIALS (n = 221, median age 46, 30% male), and Pre-fALS (n = 214, median age 44, 39% male). Adjusting for age, sex, and education, the mean BMI of C9orf72+ carriers was lower than Gene-Negatives by 2.4 units (95% confidence interval [CI] = 0.3–4.6, p = 0.02) in ALS-Families; 2.7 units (95% CI = 0.9–4.4, p = 0.003) in DIALS; and 1.9 units (95% CI = 0.5–4.2, p = 0.12) in Pre-fALS. There were no significant differences in BMI between SOD1+ carriers and Gene-Negatives in any of the 3 cohorts. Conclusions: Compared to Gene-Negatives, average BMI is lower in asymptomatic C9orf72+ carriers across 3 cohorts while no significant difference was found between Gene-Negatives and SOD1+ carriers. [ABSTRACT FROM AUTHOR]

Published
2024
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29. The Primordial Inflation Polarization Explorer (PIPER)

Author

Lazear, Justin, Ade, Peter A. R., Benford, Dominic, Bennett, Charles L., Chuss, David T., Dotson, Jessie L., Eimer, Joseph R., Fixsen, Dale J., Halpern, Mark, Hilton, Gene, Hinderks, James, Hinshaw, Gary F., Irwin, Kent, Jhabvala, Christine, Johnson, Bradley, Kogut, Alan, Lowe, Luke, McMahon, Jeff J., Miller, Timothy M., Mirel, Paul, Moseley, S. Harvey, Rodriguez, Samelys, Sharp, Elmer, Staguhn, Johannes G., Switzer, Eric R., Tucker, Carole E., Weston, Amy, and Wollack, Edward J.

Subjects
Astrophysics - Instrumentation and Methods for Astrophysics
Abstract

The Primordial Inflation Polarization Explorer (PIPER) is a balloon-borne cosmic microwave background (CMB) polarimeter designed to search for evidence of inflation by measuring the large-angular scale CMB polarization signal. BICEP2 recently reported a detection of B-mode power corresponding to the tensor-to-scalar ratio r = 0.2 on ~2 degree scales. If the BICEP2 signal is caused by inflationary gravitational waves (IGWs), then there should be a corresponding increase in B-mode power on angular scales larger than 18 degrees. PIPER is currently the only suborbital instrument capable of fully testing and extending the BICEP2 results by measuring the B-mode power spectrum on angular scales $\theta$ = ~0.6 deg to 90 deg, covering both the reionization bump and recombination peak, with sensitivity to measure the tensor-to-scalar ratio down to r = 0.007, and four frequency bands to distinguish foregrounds. PIPER will accomplish this by mapping 85% of the sky in four frequency bands (200, 270, 350, 600 GHz) over a series of 8 conventional balloon flights from the northern and southern hemispheres. The instrument has background-limited sensitivity provided by fully cryogenic (1.5 K) optics focusing the sky signal onto four 32x40-pixel arrays of time-domain multiplexed Transition-Edge Sensor (TES) bolometers held at 140 mK. Polarization sensitivity and systematic control are provided by front-end Variable-delay Polarization Modulators (VPMs), which rapidly modulate only the polarized sky signal at 3 Hz and allow PIPER to instantaneously measure the full Stokes vector (I, Q, U, V) for each pointing. We describe the PIPER instrument and progress towards its first flight., Comment: 11 pages, 7 figures. To be published in Proceedings of SPIE Volume 9153. Presented at SPIE Astronomical Telescopes + Instrumentation 2014, conference 9153

Published
2014
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30. The GISMO 2-millimeter Deep Field in GOODS-N

Author

Staguhn, Johannes G., Kovacs, Attila, Arendt, Richard G., Benford, Dominic J., Decarli, Roberto, Dwek, Eli, Fixsen, Dale J., Hilton, Gene C., Irwin, Kent D., Jhabvala, Christine A., Karim, Alexander, Leclercq, Samuel, Maher, Stephen F., Miller, Timothy M., Moseley, S. Harvey, Sharp, Elmer H., Walter, Fabian, and Wollack, Edward J.

Subjects
Astrophysics - Cosmology and Nongalactic Astrophysics
Abstract

We present deep continuum observations using the GISMO camera at a wavelength of 2 mm centered on the Hubble Deep Field (HDF) in the GOODS-N field. These are the first deep field observations ever obtained at this wavelength. The 1 sigma sensitivity in the innermost approx. 4 arcminutes of the 7 utes map is approx. 135 uJy/beam, a factor of three higher in flux/beam sensitivity than the deepest available SCUBA 850 um observations, and almost a factor of four higher in flux / beam sensitivity than the combined MAMBO/AzTEC 1.2 mm observations of this region. Our source extraction algorithm identifies 12 sources directly, and another 3 through correlation with known sources at 1.2 mm and 850 um. Five of the directly detected GISMO sources have counterparts in the MAMBO/AzTEC catalog, and four of those also have SCUBA counterparts. HDF850.1, one of the first blank-field detected submillimeter galaxies, is now detected at 2 mm. The median redshift of all sources with counterparts of known redshifts is med(z) = 2.91 +/- 0.94. Statistically, the detections are most likely real for 5 of the seven 2 mm sources without shorter wavelength counterparts, while the probability for none of them being real is negligible., Comment: Accepted for publication in ApJ

Published
2013
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31. Distinct Tau Prion Strains Propagate in Cells and Mice and Define Different Tauopathies

Author

Sanders, David W, Kaufman, Sarah K, DeVos, Sarah L, Sharma, Apurwa M, Mirbaha, Hilda, Li, Aimin, Barker, Scarlett J, Foley, Alex C, Thorpe, Julian R, Serpell, Louise C, Miller, Timothy M, Grinberg, Lea T, Seeley, William W, and Diamond, Marc I

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Pick's Disease, Frontotemporal Dementia (FTD), Transmissible Spongiform Encephalopathy (TSE), Brain Disorders, Rare Diseases, Alzheimer's Disease, Aging, Infectious Diseases, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Emerging Infectious Diseases, Dementia, Neurodegenerative, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Aetiology, Neurological, Animals, Disease Progression, HEK293 Cells, Hippocampus, Humans, Mice, Mice, Transgenic, Neurodegenerative Diseases, Plaque, Amyloid, Prions, Tauopathies, tau Proteins, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Prion-like propagation of tau aggregation might underlie the stereotyped progression of neurodegenerative tauopathies. True prions stably maintain unique conformations ("strains") in vivo that link structure to patterns of pathology. We now find that tau meets this criterion. Stably expressed tau repeat domain indefinitely propagates distinct amyloid conformations in a clonal fashion in culture. Reintroduction of tau from these lines into naive cells reestablishes identical clones. We produced two strains in vitro that induce distinct pathologies in vivo as determined by successive inoculations into three generations of transgenic mice. Immunopurified tau from these mice recreates the original strains in culture. We used the cell system to isolate tau strains from 29 patients with 5 different tauopathies, finding that different diseases are associated with different sets of strains. Tau thus demonstrates essential characteristics of a prion. This might explain the phenotypic diversity of tauopathies and could enable more effective diagnosis and therapy.

Published
2014

33. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author

Logullo, Francesco O., Simone, Isabella, Logroscino, Giancarlo, Salvi, Fabrizio, Bartolomei, Ilaria, Borghero, Giuseppe, Murru, Maria Rita, Costantino, Emanuela, Pani, Carla, Puddu, Roberta, Caredda, Carla, Piras, Valeria, Tranquilli, Stefania, Cuccu, Stefania, Corongiu, Daniela, Melis, Maurizio, Milia, Antonio, Marrosu, Francesco, Marrosu, Maria Giovanna, Floris, Gianluca, Cannas, Antonino, Capasso, Margherita, Caponnetto, Claudia, Mancardi, Gianluigi, Origone, Paola, Mandich, Paola, Conforti, Francesca L., Cavallaro, Sebastiano, Mora, Gabriele, Marinou, Kalliopi, Sideri, Riccardo, Penco, Silvana, Mosca, Lorena, Lunetta, Christian, Pinter, Giuseppe Lauria, Corbo, Massimo, Riva, Nilo, Carrera, Paola, Volanti, Paolo, Mandrioli, Jessica, Fini, Nicola, Fasano, Antonio, Tremolizzo, Lucio, Arosio, Alessandro, Ferrarese, Carlo, Trojsi, Francesca, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Piccirillo, Giovanni, Femiano, Cinzia, Ticca, Anna, Ortu, Enzo, La Bella, Vincenzo, Spataro, Rossella, Colletti, Tiziana, Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Santarelli, Marialuisa, Petrucci, Antonio, Pugliatti, Maura, Pirisi, Angelo, Parish, Leslie D., Occhineri, Patrizia, Giannini, Fabio, Battistini, Stefania, Ricci, Claudia, Benigni, Michele, Cau, Tea B., Loi, Daniela, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Barberis, Marco, Restagno, Gabriella, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Ossola, Irene, Cammarosano, Stefania, Canosa, Antonio, Ilardi, Antonio, Manera, Umberto, Grassano, Maurizio, Tanel, Raffaella, Pisano, Fabrizio, Harms, Matthew B., Goldstein, David B., Shneider, Neil A., Goutman, Stephen, Simmons, Zachary, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Manousakis, Georgios, Appel, Stanley H., Simpson, Ericka, Wang, Leo, Baloh, Robert H., Gibson, Summer, Bedlack, Richard, Lacomis, David, Sareen, Dhruv, Sherman, Alexander, Bruijn, Lucie, Penny, Michelle, Allen, Andrew S., Appel, Stanley, Bedlack, Richard S., Boone, Braden E., Brown, Robert, Carulli, John P., Chesi, Alessandra, Chung, Wendy K., Cirulli, Elizabeth T., Cooper, Gregory M., Couthouis, Julien, Day-Williams, Aaron G., Dion, Patrick A., Gitler, Aaron D., Glass, Jonathan D., Han, Yujun, Harris, Tim, Hayes, Sebastian D., Jones, Angela L., Keebler, Jonathan, Krueger, Brian J., Lasseigne, Brittany N., Levy, Shawn E., Lu, Yi-Fan, Maniatis, Tom, McKenna-Yasek, Diane, Myers, Richard M., Petrovski, Slavé, Pulst, Stefan M., Raphael, Alya R., Ravits, John M., Ren, Zhong, Rouleau, Guy A., Sapp, Peter C., Sims, Katherine B., Staropoli, John F., Waite, Lindsay L., Wang, Quanli, Wimbish, Jack R., Xin, Winnie W., Phatnani, Hemali, Kwan, Justin, Broach, James R., Arcila-Londono, Ximena, Lee, Edward B., Van Deerlin, Vivianna M., Fraenkel, Ernest, Ostrow, Lyle W., Baas, Frank, Zaitlen, Noah, Berry, James D., Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steve, Dardiotis, Efthimios, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos A., Dubnau, Joshua, Nath, Avindra, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia, LeNail, Alexander, Lima, Leandro, Rothstein, Jeffrey D., Svendsen, Clive N., Van Eyk, Jenny, Maragakis, Nicholas J., Kolb, Stephen J., Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J. Paul, Wu, Gang, Rampersaud, Evadnie, Wuu, Joanne, Rademakers, Rosa, Züchner, Stephan, Schule, Rebecca, McCauley, Jacob, Hussain, Sumaira, Cooley, Anne, Wallace, Marielle, Clayman, Christine, Barohn, Richard, Statland, Jeffrey, Ravits, John, Swenson, Andrea, Jackson, Carlayne, Trivedi, Jaya, Khan, Shaida, Katz, Jonathan, Jenkins, Liberty, Burns, Ted, Gwathmey, Kelly, Caress, James, McMillan, Corey, Elman, Lauren, Pioro, Erik, Heckmann, Jeannine, So, Yuen, Walk, David, Maiser, Samuel, Zhang, Jinghui, Silani, Vincenzo, Ticozzi, Nicola, Gellera, Cinzia, Ratti, Antonia, Taroni, Franco, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P., Sorarù, Gianni, Cereda, Cristina, D’Alfonso, Sandra, Corrado, Lucia, De Marchi, Fabiola, Corti, Stefania, Ceroni, Mauro, Mazzini, Letizia, Siciliano, Gabriele, Filosto, Massimiliano, Inghilleri, Maurizio, Peverelli, Silvia, Colombrita, Claudia, Poletti, Barbara, Maderna, Luca, Del Bo, Roberto, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, Pensato, Viviana, Castellotti, Barbara, Camu, William, Mouzat, Kevin, Lumbroso, Serge, Corcia, Philippe, Meininger, Vincent, Besson, Gérard, Lagrange, Emmeline, Clavelou, Pierre, Guy, Nathalie, Couratier, Philippe, Vourch, Patrick, Danel, Véronique, Bernard, Emilien, Lemasson, Gwendal, Al Kheifat, Ahmad, Al-Chalabi, Ammar, Andersen, Peter, Basak, A. Nazli, Blair, Ian P., Chio, Adriano, Cooper-Knock, Jonathan, de Carvalho, Mamede, Dekker, Annelot, Drory, Vivian, Redondo, Alberto Garcia, Gotkine, Marc, Hardiman, Orla, Hide, Winston, Iacoangeli, Alfredo, Glass, Jonathan, Kenna, Kevin, Kiernan, Matthew, Kooyman, Maarten, Landers, John, McLaughlin, Russell, Middelkoop, Bas, Mill, Jonathan, Neto, Miguel Mitne, Moisse, Mattieu, Pardina, Jesus Mora, Morrison, Karen, Newhouse, Stephen, Pinto, Susana, Pulit, Sara, Robberecht, Wim, Shatunov, Aleksey, Shaw, Pamela, Shaw, Chris, Sproviero, William, Tazelaar, Gijs, van Damme, Philip, van den Berg, Leonard, van der Spek, Rick, van Eijk, Kristel, van Es, Michael, van Rheenen, Wouter, van Vugt, Joke, Veldink, Jan, Weber, Markus, Williams, Kelly L., Zatz, Mayana, Bauer, Denis C., Twine, Natalie A., Nicolas, Aude, Kenna, Kevin P., Renton, Alan E., Faghri, Faraz, Chia, Ruth, Dominov, Janice A., Kenna, Brendan J., Nalls, Mike A., Keagle, Pamela, Rivera, Alberto M., Murphy, Natalie A., van Vugt, Joke J.F.A., Geiger, Joshua T., Van der Spek, Rick A., Pliner, Hannah A., Shankaracharya, Smith, Bradley N., Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Messina, Sonia, Simone, Isabella L., Ferrucci, Luigi, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Wyman, Stacia K., LeNail, Alex, Van Eyk, Jennifer E., Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W., Sidle, Katie C., Hardy, John, Singleton, Andrew B., Johnson, Janel O., Arepalli, Sampath, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, ten Asbroek, Anneloor L.M.A., Muñoz-Blanco, José Luis, Hernandez, Dena G., Ding, Jinhui, Gibbs, J. Raphael, Scholz, Sonja W., Floeter, Mary Kay, Campbell, Roy H., Landi, Francesco, Bowser, Robert, MacGowan, Daniel J.L., Kirby, Janine, Pioro, Erik P., Pamphlett, Roger, Broach, James, Gerhard, Glenn, Dunckley, Travis L., Brady, Christopher B., Kowall, Neil W., Troncoso, Juan C., Le Ber, Isabelle, Heiman-Patterson, Terry D., Kamel, Freya, Van Den Bosch, Ludo, Strom, Tim M., Meitinger, Thomas, Van Eijk, Kristel R., Moisse, Matthieu, McLaughlin, Russell L., Van Es, Michael A., Boylan, Kevin B., Van Blitterswijk, Marka, Morrison, Karen E., Mora, Jesús S., Drory, Vivian E., Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Fifita, Jennifer A., Nicholson, Garth A., Esteban-Pérez, Jesús, García-Redondo, Alberto, Rogaeva, Ekaterina, Zinman, Lorne, Cooper-Knock, Johnathan, Brice, Alexis, Goutman, Stephen A., Feldman, Eva L., Gibson, Summer B., Van Damme, Philip, Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Trojanowski, John Q., Brown, Robert H., Jr., van den Berg, Leonard H., Veldink, Jan H., Stone, David J., Tienari, Pentti, Chiò, Adriano, Shaw, Christopher E., Traynor, Bryan J., and Landers, John E.

Published
2018
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34. Tau Kinetics in Neurons and the Human Central Nervous System

Author

Sato, Chihiro, Barthélemy, Nicolas R., Mawuenyega, Kwasi G., Patterson, Bruce W., Gordon, Brian A., Jockel-Balsarotti, Jennifer, Sullivan, Melissa, Crisp, Matthew J., Kasten, Tom, Kirmess, Kristopher M., Kanaan, Nicholas M., Yarasheski, Kevin E., Baker-Nigh, Alaina, Benzinger, Tammie L.S., Miller, Timothy M., Karch, Celeste M., and Bateman, Randall J.

Published
2018
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35. SILK studies — capturing the turnover of proteins linked to neurodegenerative diseases

Author

Paterson, Ross W., Gabelle, Audrey, Lucey, Brendan P., Barthélemy, Nicolas R., Leckey, Claire A., Hirtz, Christophe, Lehmann, Sylvain, Sato, Chihiro, Patterson, Bruce W., West, Tim, Yarasheski, Kevin, Rohrer, Jonathan D., Wildburger, Norelle C., Schott, Jonathan M., Karch, Celeste M., Wray, Selina, Miller, Timothy M., Elbert, Donald L., Zetterberg, Henrik, Fox, Nick C., and Bateman, Randall J.

Published
2019
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37. COURAGE-ALS: a randomized, double-blind phase 3 study designed to improve participant experience and increase the probability of success

Author

Shefner, Jeremy M., primary, Al-Chalabi, Ammar, additional, Andrews, Jinsy A., additional, Chio, Adriano, additional, De Carvalho, Mamede, additional, Cockroft, Bettina M., additional, Corcia, Philippe, additional, Couratier, Philippe, additional, Cudkowicz, Merit E., additional, Genge, Angela, additional, Hardiman, Orla, additional, Heiman-Patterson, Terry, additional, Henderson, Robert D., additional, Ingre, Caroline, additional, Jackson, Carlayne E., additional, Johnston, Wendy, additional, Lechtzin, Noah, additional, Ludolph, Albert, additional, Maragakis, Nicholas J., additional, Miller, Timothy M., additional, Mora Pardina, Jesus S., additional, Petri, Susanne, additional, Simmons, Zachary, additional, Van Den Berg, Leonard H., additional, Zinman, Lorne, additional, Kupfer, Stuart, additional, Malik, Fady I., additional, Meng, Lisa, additional, Simkins, Tyrell J., additional, Wei, Jenny, additional, Wolff, Andrew A., additional, and Rudnicki, Stacy A., additional

Published
2023
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38. TREM2 inhibition triggers antitumor cell activity of myeloid cells in glioblastoma

Author

Sun, Rui, primary, Han, Rowland, additional, McCornack, Colin, additional, Khan, Saad, additional, Tabor, G. Travis, additional, Chen, Yun, additional, Hou, Jinchao, additional, Jiang, Haowu, additional, Schoch, Kathleen M., additional, Mao, Diane D., additional, Cleary, Ryan, additional, Yang, Alicia, additional, Liu, Qin, additional, Luo, Jingqin, additional, Petti, Allegra, additional, Miller, Timothy M., additional, Ulrich, Jason D., additional, Holtzman, David M., additional, and Kim, Albert H., additional

Published
2023
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41. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS

Author

Miller, Timothy M, Cudkowicz, Merit E, Andrews, Jinsy A, Hesters, Adele, Kermorvant, Hugo, Lacomblez, Lucette, Forestier, Nadine Le, Lenglet, Thimotée, Retail, Maryvonne, Ruiz Del Mar Amador, Maria, Salachas, François, Shotar, Eimad, Sourour, Nader, Babu, Suma, Dorst, Johannes, Froehlich, Elke, Fromm, Andrea, Kandler, Katharina, Langer, Eva, Leichtle, Sarah, Ludolph, Albert, Mayer, Kristina, Michels, Sebastian, Raubold, Sabine, Benatar, Michael, Schuster, Joachim, Weiland, Ulrike, Wiesenfarth, Maximilian, Witzel, Simon, Calvo, Andrea, Canosa, Antonio, Casale, Federico, Chiò, Adriano, Fuda, Giuseppe, Grassano, Maurizio, McDermott, Christopher J, Marchese, Giulia, Moglia, Cristina, Palumbo, Francesca, Salamone, Paolina, Ajiki, Takahiro, Akasaka, Aya, Ando, Masahiro, Arata, Hitoshi, Asuka, Kitamura, Baba, Kosuke, Cochrane, Thos, Bekku, Goichi, Chiba, Tomoya, Date, Yugaku, Eriko, Takeuchi, Hashiguchi, Akihiro, Hatatori, Ritsuko, Hayano, Eri, Hayashi, Yuto, Higashi, Keiko, Higuchi, Eriko, Chary, Sowmya, Hiramatsu, Yu, Horikawa, Rui, Ikenaka, Kensuke, Ishiura, Hiroyuki, Ito, Daisuke, Kawai, Sachiko, Kikuchi, Junko, Kuzuyama, Haruko, Li, Xuehong, Matsumoto, Chika, Chew, Sheena, Matsuura, Eiji, Michizono, Kumiko, Mitsui, Jun, Mitsutake, Akihiko, Mochizuki, Hideki, Nagamatsu, Akemi, Nagano, Seiichi, Nakamura, Tomonori, Naruse, Hiroya, Ogasawara, Asuka, Zhu, Han, Okada, Kensuke, Okamoto, Yuji, Okuno, Tatsusada, Oyama, Satoshi, Ozono, Tatsuhiko, Sakiyama, Yusuke, Sakuishi, Kaori, Seki, Morinobu, Shibata, Shota, Shimizu, Mikito, Wu, Fan, Takahata, Katsunori, Takahito, Yoshizaki, Takashima, Hiroshi, Takeichi, Hiroko, Tashiro, Yuichi, Toda, Tatsushi, Tomizu, Yuki, Tomoya, Wadayama, Ujiakira, Nishiike, Yashita, Daiki, Nestorov, Ivan, Al-Chalabi, Ammar, Alix, James, Bangalore, Priyadarshini, Blackburn, Daniel, Chiwera, Theresa, Clegg, Rosie, Collins, Alexis, Cooper-Knock, Jonathan, Emery, Anna, Franklin, John, Genge, Angela, Graham, Danielle, Green, Louisa, Harvey, Callum, Hobson, Esther, Islam, Mahjabim, Jenkins, Thomas Michael, Kazoka, Mbombe, Kelly, Gillian, Korley, Mercy, Madarshahaian, Daniel, Mayl, Keith, Sun, Peng, McDermott, Christopher John, Radford, Alex, Shaw, Christopher, Shaw, Pamela J, Sidebottom, Joe, Smart, Lynne, Sreedharan, Jemeen, Stone, Ben, Tsironis, Theocharis, Tuddenham, Lee, McNeill, Manjit, Verber, Nick, Wollff, Helen, Young, Stacy, Zis, Panagiotis, Adamo, Ashley, Ahmed, Arubah, Ajroud-Driss, Senda, Alameda, Gustave, Arcila-Londono, Ximena, Fanning, Laura, Baird, Candy, Bazan, Tracy, Berry, James, Bordeau, Jane, Bradford, Wendy, Brook, Nyda, Brown, Lauren, Bucelli, Robert C, Ferguson, Toby A, Buckner, Katherine, Budler, Michael W, Burba, Lindita, Burke, Katherine, Calhoun, Ashley D, Campbell, Sarah, Carey, Judith, Caristo, Irys B, Carty, Simon, Chan, Emmanuel, Fradette, Stephanie, Chaudhry, Vinay, Chen, Ricky, Chow, Saephanh, Clawson, Lora L, Clemens, Mitchell, Cloninger, Suzann E, Coleman-Wood, Krista, Cooper, Thomas N, Cummings, Arlena, Daniels, Jacquelyn, VALOR, DeSaro, Pamela, DeWitt, Michelle, Dedi, Brixhilda, Dempsey, Debbie, Denny, Carol, Doherty, Jenna, Doherty, Leana, Donahue, Megan, Doyle, Michael, Duncan, Jessie, Group, OLE Working, Elman, Lauren, Eloge, Christine M, Echiti, Desirae R, Ferrey, Dominic, Fournier, Christina, Fukumura, Yuriko, Gallagher, Katherine, Garaycoa, Jessica, Garrett, Mark, Gibson, Richard L, Beullens, Lien, Gifford, Ryan, Glass, Jonathan D, Gogol, Danuta, Golden, Shea, Gonzalez, Alexa, Goodman, Ira, Goolsby, Christopher, Goslin, Kimberly, Goulbourne, Michael, Granit, Volkan, Claeys, Kristl, Grignon, Anne-Laure, GuhaRay, Adreeja, Guide, Debra, Gundogdu, Melek Betul, Gutierrez, Gil, Hastings, Debbie, Hayzen, Colleen, Herzog, Hilary, Holloway, Raegan, Jacobs, Gabriel, Claeys, Thomas, Jacobsen, Bill, James, Virginia, Jenkins, Liberty, Jockel-Balsarotti, Jennifer, Johnson, Linda Carol, Jose, Sunil, Joslin, Benjamin, Karanja, Elizabeth, Katz, Jonathan, Keener, Anthony, Couwelier, Goedele, Kittle, Gale, Klein, Sara, Kreple, Collin, Rebecca, Rebecca, Kuenzler, Kuenzler, Kusnir, Jorge, Labbe, Kristen, Lachica-Encinas, Nicolet, Ladha, Shafeeq, Leimer, Lesli, D'Hondt, Ann, Levy, Michael, Levy, Wendy, Li, Yingji, Likanje, Marie-France, Livigni, Rebecca, Locatelli, Eduardo, Luppino, Sarah, Malcolm, Amber, Maragakis, Nicholas, Marin, Horia, Debien, Elisa, Markowitz, Clyde, Markway, Jesse, McCaffrey, Alexandra, McCoy, Arita, McCoy Gross, Kelly, Mehta, Kush, Meyer, Robert, Milan, Jennifer, Miller, Timothy, Miller, Robert G, de Keersmaecker, Sebastiaan, Morales, Francisco, Mosmiller, Elizabeth, Mott, Donovan, Moulton, Kelsey, Murphy, Christine A, Negron, Tirso, Nelson, Cassandra, Newman, Daniel S, Nissinen, Janne Kristoffer, Norman, Andrew, Della Faille, Laetitia, Ohkubo, Takuya, Olney, Nicholas, Ortiz, Natasha, Oskarsson, Bjorn, Pace, Mitchell, Packard, Kathleen, Padgett, Denny, Paganoni, Sabrina, Paredes, Maria E, Parker, Elizabeth, Delmotte, Koen, Partlow, Ann, Pattee, Gary L, Paulett, Jany, Pelot, Antoinette, Pfeifer, Kyle M, Pijanowski, Olivia, Pioro, Erik, Polak, Meraida, Prakash, Ahalya, Previte, Rosemarie, Depoortere, Sofie, Pukenas, Bryan, Quinn, Colin, Ravits, John, Razavi, Ryan, Regan, Tyler, Riley, Kristen M, Roth, Heather, Sanders, Danica, Scalia, Jennifer, Schmidt, Emma, de Velder, Laura, Schwen, Edward, Shah, Jaimin, Shah, Stuti, Shefner, Jeremy, Sheldon, Danielle, Simmons, Karon, Singh, Navneet K, Singleton, Jessica, Smiley, Richard, Smith, William B, Dobbels, Laurens, Smith, Sean, Sotirchos, Elias, Sorenson, Eric, Staff, Nathan, Steele, Julie, Steijlen, Kara, Stirrat, Taylor, Stoica, George S, Strong, Stephanie, Sufit, Robert, Sobue, Gen, Gijs, Jeroen, Sultze, Jane, Swartz, Amy, Szymanski, April, Tay, Anna, Thakore, Nimish, Thiessen, Diana, Thotala, Sukrutha, Trudell, Randall G, Turcotte, Nicole, Turner, Michelle, Horckmans, Simon, Uchil, Alpa, Upadhyay, Vihar, Usman, Uzma, Vallis, Anne, Vaporean-Bussey, Danielle, Vladimirova, Valentine, Weber, Harli, Winbigler, Jennifer, Wojanowski, Heather, Wulf, Charlie, Lamaire, Nikita, Yasek, Julia, Yoo, Stephanie, Zivalic, Hannah, Cole, Alexandra, File, Greta, Foate, Jeremy, Mason, Deborah, Newton, Susan, Roberts, Stephen, Sellwood, Cory Dean, Liessens, Hannelore, Swan, James, Werno, Anja, Zhong, Cathy, Masrori, Pegah, Nysten, Celine, Schotte, Caroline, Serrien, Anouk, Swinnen, Bart, Tilkin, Petra, van Daele, Sien, Van Damme, Philip, Vynckier, Jan, Wouters, Anke, Abrahao, Agessandro, Angle, Mark, Badawy, Mohamed, Berube, Maxime, Bertone, Vanessa, Cooper, Sarah Marie, Dobrowolski, Peter, Fong, Helen, Hannouche, Matthew, Hartley, Denise, Hogan, Michael, Johnston, Wendy, Khalfallah, Yousra, Korngut, Lawrence, Kroetsch, Gina, Letourneau, Justin, Magnussen, Claire, Martinez, Jose, Massie, Rami, Mobach, Theodore, Mookshah, Jahan, Ozelsel, Timur, Parks, Andrea, Petrillo, Janet, Pfeffer, Gerald, Ludolph, Albert C, Pham, Shirley, Phung, Liane, Shiungsun, Rodney, Pi-Shan, Li, Santos, Denizart, Salmon, Kristiana, Saunders, Natalie, Sembinelli, Dylan, Tymkow, Kelsey, Wong, Berchman, Zinman, Lorne, Karlsborg, Merete, Pedersen Lomholt, Therese, Nilsson, Sigrid, Salvesen, Lisette, Skov, Pernille, Svenstrup, Kristen, Bruneteau, Gaelle, Calerencon, Frederic, and Guimaraes Costa, Raquel

Subjects
Adult, drug effects [Recovery of Function], Spinal, Oligonucleotides, blood [Neurofilament Proteins], administration & dosage [Oligonucleotides, Antisense], tofersen, Injections, blood [Amyotrophic Lateral Sclerosis], pharmacology [Oligonucleotides, Antisense], Superoxide Dismutase-1, Double-Blind Method, Neurofilament Proteins, Humans, ddc:610, Antisense, Injections, Spinal, Biomarkers, Recovery of Function, Amyotrophic Lateral Sclerosis, Oligonucleotides, Antisense, blood [Biomarkers], drug therapy [Amyotrophic Lateral Sclerosis], therapeutic use [Oligonucleotides, Antisense], SOD1 protein, human, General Medicine, genetics [Superoxide Dismutase-1], genetics [Amyotrophic Lateral Sclerosis], cerebrospinal fluid [Biomarkers], cerebrospinal fluid [Superoxide Dismutase-1], cerebrospinal fluid [Amyotrophic Lateral Sclerosis]
Abstract

The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 ALS).In this phase 3 trial, we randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort).A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients.In persons with SOD1 ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.).

Published
2022

43. Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models

Author

McCampbell, Alex, Cole, Tracy, Wegener, Amy J., Tomassy, Giulio S., Setnicka, Amy, Farley, Brandon J., Schoch, Kathleen M., Hoye, Mariah L., Shabsovich, Mark, Sun, Linhong, Luo, Yi, Zhang, Mingdi, Thankamony, Sai, Salzman, David W., Cudkowicz, Merit, Graham, Danielle L., Bennett, C. Frank, Kordasiewicz, Holly B., Swayze, Eric E., and Miller, Timothy M.

Subjects
Antisense drugs -- Research -- Health aspects -- Dosage and administration, Amyotrophic lateral sclerosis -- Genetic aspects -- Research -- Care and treatment, Gene mutation -- Research, Health care industry
Abstract

Mutations in superoxide dismutase 1 (SOD1) are responsible for 20% of familial ALS. Given the gain of toxic function in this dominantly inherited disease, lowering SOD1 mRNA and protein is predicted to provide therapeutic benefit. An early generation antisense oligonucleotide (ASO) targeting SOD1 was identified and tested in a phase I human clinical trial, based on modest protection in animal models of SOD1 ALS. Although the clinical trial provided encouraging safety data, the drug was not advanced because there was progress in designing other, more potent ASOs for CNS application. We have developed next- generation SOD1 ASOs that more potently reduce SOD1 mRNA and protein and extend survival by more than 50 days in [SOD1.sup.G93A] rats and by almost 40 days in [SOD1.sup.G93A] mice. We demonstrated that the initial loss of compound muscle action potential in [SOD1.sup.G93A] mice is reversed after a single dose of SOD1 ASO. Furthermore, increases in serum phospho-neurofilament heavy chain levels, a promising biomarker for ALS, are stopped by SOD1 ASO therapy. These results define a highly potent, new SOD1 ASO ready for human clinical trial and suggest that at least some components of muscle response can be reversed by therapy., Introduction Amyotrophic lateral sclerosis (ALS) is caused by the loss and dysfunction of neurons in motor pathways and leads to severe weakness, stiffness, and ultimately death in 3-5 years. Approximately [...]

Published
2018
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45. Protein kinetics of superoxide dismutase‐1 in familial and sporadic amyotrophic lateral sclerosis

Author

Ly, Cindy V., primary, Ireland, Margaret D., additional, Self, Wade K., additional, Bollinger, James, additional, Jockel‐Balsarotti, Jennifer, additional, Herzog, Hillary, additional, Allred, Peggy, additional, Miller, Leah, additional, Doyle, Michael, additional, Anez‐Bruzual, Isabel, additional, Trikamji, Bhavesh, additional, Hyman, Ted, additional, Kung, Tyler, additional, Nicholson, Katherine, additional, Bucelli, Robert C., additional, Patterson, Bruce W., additional, Bateman, Randall J., additional, and Miller, Timothy M., additional

Published
2023
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46. Health utilities and quality-adjusted life years for patients with amyotrophic lateral sclerosis receiving reldesemtiv or placebo in FORTITUDE-ALS

Author

Gebrehiwet, Paulos, primary, Meng, Lisa, additional, Rudnicki, Stacy A., additional, Sarocco, Phil, additional, Wei, Jenny, additional, Wolff, Andrew A., additional, Butzner, Michael, additional, Chiò, Adriano, additional, Andrews, Jinsy A., additional, Genge, Angela, additional, Hughes, Dyfrig A., additional, Jackson, Carlayne E., additional, Lechtzin, Noah, additional, Miller, Timothy M., additional, and Shefner, Jeremy M., additional

Published
2023
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47. Courage-als: a randomized, double-blind phase 3 study designed to improve participant experience and increase the probability of success

Author

Neurologen, Projectafdeling ALS, Brain, Regenerative Medicine and Stem Cells, Shefner, Jeremy M, Al-Chalabi, Ammar, Andrews, Jinsy A, Chio, Adriano, De Carvalho, Mamede, Cockroft, Bettina M, Corcia, Philippe, Couratier, Philippe, Cudkowicz, Merit E, Genge, Angela, Hardiman, Orla, Heiman-Patterson, Terry, Henderson, Robert D, Ingre, Caroline, Jackson, Carlayne E, Johnston, Wendy, Lechtzin, Noah, Ludolph, Albert, Maragakis, Nicholas J, Miller, Timothy M, Mora Pardina, Jesus S, Petri, Susanne, Simmons, Zachary, Van Den Berg, Leonard H, Zinman, Lorne, Kupfer, Stuart, Malik, Fady I, Meng, Lisa, Simkins, Tyrell J, Wei, Jenny, Wolff, Andrew A, Rudnicki, Stacy A, Neurologen, Projectafdeling ALS, Brain, Regenerative Medicine and Stem Cells, Shefner, Jeremy M, Al-Chalabi, Ammar, Andrews, Jinsy A, Chio, Adriano, De Carvalho, Mamede, Cockroft, Bettina M, Corcia, Philippe, Couratier, Philippe, Cudkowicz, Merit E, Genge, Angela, Hardiman, Orla, Heiman-Patterson, Terry, Henderson, Robert D, Ingre, Caroline, Jackson, Carlayne E, Johnston, Wendy, Lechtzin, Noah, Ludolph, Albert, Maragakis, Nicholas J, Miller, Timothy M, Mora Pardina, Jesus S, Petri, Susanne, Simmons, Zachary, Van Den Berg, Leonard H, Zinman, Lorne, Kupfer, Stuart, Malik, Fady I, Meng, Lisa, Simkins, Tyrell J, Wei, Jenny, Wolff, Andrew A, and Rudnicki, Stacy A

Published
2023

48. Prospective natural history study of C9orf72 ALS clinical characteristics and biomarkers

Author

Cammack, Alexander J., Atassi, Nazem, Hyman, Theodore, van den Berg, Leonard H., Harms, Matthew, Baloh, Robert H., Brown, Robert H., van Es, Michael A., Veldink, Jan H., de Vries, Balint S., Rothstein, Jeffrey D., Drain, Caroline, Jockel-Balsarotti, Jennifer, Malcolm, Amber, Boodram, Sonia, Salter, Amber, Wightman, Nicholas, Yu, Hong, Sherman, Alexander V., Esparza, Thomas J., McKenna-Yasek, Diane, Owegi, Margaret A., Douthwright, Catherine, McCampbell, Alexander, Ferguson, Toby, Cruchaga, Carlos, Cudkowicz, Merit, and Miller, Timothy M.

Published
2019
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50. A dual MTOR/NAD+ acting gerotherapy

Author

Li, Jinmei, primary, Kumar, Sandeep, additional, Miachin, Kirill, additional, Bean, Nicholas L., additional, Halawi, Ornella, additional, Lee, Scott, additional, Park, JiWoong, additional, Pierre, Tanya H., additional, Hor, Jin-Hui, additional, Ng, Shi-Yan, additional, Wallace, Kelvin J., additional, Rindtorff, Niklas, additional, Miller, Timothy M., additional, Niehoff, Michael L., additional, Farr, Susan A., additional, Kletzien, Rolf F., additional, Colca, Jerry, additional, Tanis, Steven P., additional, Chen, Yana, additional, Griffett, Kristine, additional, McCommis, Kyle S., additional, Finck, Brian N., additional, and Peterson, Tim R., additional

Published
2023
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