Natural history of multisystem proteinopathy-1

University Of Miami School Of Medicine, Coral Gables FL

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Abstract

PROJECT SUMMARY (Project 4: Natural History of MSP1) This proposal’s primary objective is to validate a promising measure of motor function as a future efficacy out- come in a large cohort of patients with multisystem proteinopathy 1 (MSP1) due to a pathogenic missense vari- ant in the valosin-containing protein (VCP) gene. Secondarily, we will establish the temporal course with which different phenotypic manifestations of MSP1 emerge and explore how these impact performance of clinical out- come assessments (COA), including our primary outcome the North Star Assessment for limb girdle-type Dys- trophies (NSAD). We hypothesize that this multicenter study will define an expected trajectory of disease pro- gression, quantify the impact of covariates on progression, and establish thresholds for meaningful change in MSP1. The VCP protein has been viewed as a tractable therapeutic target by industry. Small molecule inhibi- tors and activators exist, and some are in clinical trials for other diseases (i.e. blood cancers and solid tissue tumors). These compounds have shown promise by correcting disease phenotypes in pre-clinical models that include human derived motor neurons and mouse models. Other therapeutic approaches include allele spe- cific knockdown and gene editing platforms both of which have been performed in pre-clinical studies. While all these advances are promising, the current understanding of the underlying causes of disease heterogene- ity, including the genotype/phenotype relationships, impact of phenoconversion on trajectory of progression, and incomplete penetrance of other body system involvement even among sibling pairs add to the complexity of clinical trial planning in this ultra-rare disease. Thus, the need to prospectively characterize a large cohort of patients with MSP1 across a multisite consortium with sites distributed across the United States, United King- dom, and South Africa. The specific aims of our proposal are to (1) Validate the NSAD as a primary efficacy outcome to characterize the progression of motor dysfunction in MSP1, (2) Evaluate the emergence and im- pact of other system involvement on performance of motor COA, and (3) Establish a biorepository of longitudi- nal specimens from deeply-phenotyped MSP1 patients for future biomarker discovery. To achieve these aims, we propose to prospectively follow 80 patients with MSP1 over at least 2 years. Detailed training of at least two clinical evaluators from each collaborating site will take place at the lead institution, Nationwide Children’s Hos- pital, before enrollment with annual refresher trainings. MSP1 is ultra-rare, and travel is burdensome. There- fore, we also selected geographically diverse locations to minimize travel and burden of trial participation. Re- mote assessments have been validated as a testing method, which further reduces burden of participation with fewer onsite visits required. Our partnerships with advocacy groups, including Cure VCP Disease and the Mus- cular Dystrophy Association, will allow us to successfully recruit patients. Completion of our aims will result in a validated measure of meaningful change in motor function, an understanding of the impact of phenotypic pene- trance and changes in biomarkers on measurement of disease progression to achieve clinical trial readiness in this cohort.