Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy: Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Ndayisaba Alain, Pitaro Ariana T, Willett Andrew S, Jones Kristie A, de Gusmao Claudio Melo, Olsen Abby L, Kim Jisoo, Rissanen Eero, Woods Jared K, Srinivasan Sharan R, Nagy Anna, Nagy Amanda, Mesidor Merlyne, Cicero Steven, Patel Viharkumar, Oakley Derek H, Tuncali Idil, Taglieri-Noble Katherine, Clark Emily C, Paulson Jordan, Krolewski Richard C, Ho Gary P, Hung Albert Y, Wills Anne-Marie, Hayes Michael T, Macmore Jason P, Warren Luigi, Bower Pamela G, Langer Carol B, Kellerman Lawrence R, Humphreys Christopher W, Glanz Bonnie I, Dielubanza Elodi J, Frosch Matthew P, Freeman Roy L, Gibbons Christopher H, Stefanova Nadia, Chitnis Tanuja, Weiner Howard L, Scherzer Clemens R, Scholz Sonja W, Vuzman Dana, Cox Laura M, Wenning Gregor, Schmahmann Jeremy D, Gupta Anoopum S, Novak Peter, Young Geoffrey S, Feany Mel B, Singhal Tarun, Khurana Vikram
Аннотация
Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation of the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson's disease (PD), and rapid progression have sparked interest in drug development. One significant obstacle to therapeutics is disease heterogeneity. Here, we share our process of developing a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal "n-of-few" clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including volumetric MRI, FDG-PET, MIBG scan, polysomnography, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham SCiN study (stem cells in neurodegeneration), we generate induced pluripotent stem cell (iPSC) models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including alpha-synuclein triplication cases), 22 matched to whole-genome sequenced postmortem brain. iPSC models may facilitate matching patients to appropriate therapies, particularly in heterogeneous diseases for which patient-specific biology may elude animal models. We anticipate that deeply phenotyped and genotyped patient cohorts matched to cellular models will increase the likelihood of success in clinical trials for MSA.