TY - JOUR
T1 - Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy
T2 - Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping
AU - Ndayisaba, Alain
AU - Pitaro, Ariana T.
AU - Willett, Andrew S.
AU - Jones, Kristie A.
AU - de Gusmao, Claudio Melo
AU - Olsen, Abby L.
AU - Kim, Jisoo
AU - Rissanen, Eero
AU - Woods, Jared K.
AU - Srinivasan, Sharan R.
AU - Nagy, Anna
AU - Nagy, Amanda
AU - Mesidor, Merlyne
AU - Cicero, Steven
AU - Patel, Viharkumar
AU - Oakley, Derek H.
AU - Tuncali, Idil
AU - Taglieri-Noble, Katherine
AU - Clark, Emily C.
AU - Paulson, Jordan
AU - Krolewski, Richard C.
AU - Ho, Gary P.
AU - Hung, Albert Y.
AU - Wills, Anne Marie
AU - Hayes, Michael T.
AU - Macmore, Jason P.
AU - Warren, Luigi
AU - Bower, Pamela G.
AU - Langer, Carol B.
AU - Kellerman, Lawrence R.
AU - Humphreys, Christopher W.
AU - Glanz, Bonnie I.
AU - Dielubanza, Elodi J.
AU - Frosch, Matthew P.
AU - Freeman, Roy L.
AU - Gibbons, Christopher H.
AU - Stefanova, Nadia
AU - Chitnis, Tanuja
AU - Weiner, Howard L.
AU - Scherzer, Clemens R.
AU - Scholz, Sonja W.
AU - Vuzman, Dana
AU - Cox, Laura M.
AU - Wenning, Gregor
AU - Schmahmann, Jeremy D.
AU - Gupta, Anoopum S.
AU - Novak, Peter
AU - Young, Geoffrey S.
AU - Feany, Mel B.
AU - Singhal, Tarun
AU - Khurana, Vikram
N1 - Publisher Copyright:
© The Author(s) 2022. corrected publication 2022.
PY - 2024/2
Y1 - 2024/2
N2 - 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.
AB - 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.
KW - Clinical trials
KW - Induced pluripotent stem cells
KW - Multiple system atrophy
KW - N-of-1 clinical trials
KW - Stratification
UR - https://www.scopus.com/pages/publications/85139624754
U2 - 10.1007/s12311-022-01471-8
DO - 10.1007/s12311-022-01471-8
M3 - Article
C2 - 36190676
AN - SCOPUS:85139624754
SN - 1473-4222
VL - 23
SP - 31
EP - 51
JO - Cerebellum
JF - Cerebellum
IS - 1
ER -