Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy: Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping

Abstract

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.

Combining alpha-synuclein PET and seeded-amplification to improve diagnostic accuracy of Multiple System Atrophy

“…The Brigham and Women's Hospital (BWH) P + A + MSA clinic and MSA-MyTrial Program work in close coordination to recruit MSA patients for accurate diagnosis, longitudinal biometric and biomarker assessment, with a view to pivoting from natural history to target-engagement studies for a variety of potential investigator-or industry-sponsored therapies. Fourteen participants with a clinically probable or clinically established MSA diagnosis were evaluated for participation in this study 29 . Three subjects were deemed ineligible due to insu cient diagnostic certainty or an alternative diagnosis under consideration.…”

“…In the current observational cohort study, we sought to exploit exciting advances in αSyn biomarkers to improve upon current clinical consensus criteria for MSA. We recruited patients who met the consensus criteria for probable or established MSA and were eligible for the ongoing clinical trials for MSA within the Brigham and Women's Hospital MSA Center of Excellence and Harvard Biomarkers Study MyTrial-MSA Program 29 . We combined brain imaging with the αSyn [18F]ACI-12589 PET tracer with a skin-based αSyn-SAA to simultaneously acquire conformational and spatial information about αSyn pathology.…”

Preparing for Disease‐Modification Trials in Degenerative Cerebellar Ataxias: Which Endpoints to Choose?

“…An early (biomarker-assisted) diagnosis and accurate distinction from other late-onset ataxias will be crucial for MSA-C trials. 4,32 In SCAs, several recent studies have shown nonlinear progression patterns of SARA score, depending on disease stage, and inclusion of mildly affected patients was suggested to be beneficial in terms of sample size requirements. 9,11,12 Finally, large interindividual differences in disease evolution have also been described in FRDA, which were mainly related to age of onset.…”

“…A second key question for all types of degenerative ataxia that is closely related to the choice of outcome measures concerns the selection of participants. An early (biomarker‐assisted) diagnosis and accurate distinction from other late‐onset ataxias will be crucial for MSA‐C trials 4,32 . In SCAs, several recent studies have shown nonlinear progression patterns of SARA score, depending on disease stage, and inclusion of mildly affected patients was suggested to be beneficial in terms of sample size requirements 9,11,12 .…”

Neuro-Urology and Biobanking: An Integrated Approach for Advancing Research and Improving Patient Care

“…Achieving protocol standardization in neuro-urological research is challenging due to variations in clinical practices, diagnostic criteria, and treatment approaches among different centers. This problem can be solved by creating unified guidelines [ 49 ] and standardizing treatment protocols, as well as through extensive disease group stratification strategies prior to clinical trial enrollment, involving deep clinical phenotyping, imaging, and biobanking [ 50 ].…”