Project 1

Boston Children'S Hospital, Boston MA

Investigators

Abstract

ABSTRACT/SUMMARY: Hereditary spastic paraplegias (HSPs) are a diverse group of over 80 rare neurogenetic disorders, representing the most common cause of inherited spasticity and related disabilities worldwide. Clinical Research Project 1 aims to create a clinical trial readiness platform by developing comprehensive natural history studies for both pediatric and adult populations, following FDA guidance. The platform will focus on common forms like SPG4 and SPG3A, as well as six rare, rapidly progressive forms: SPG47, SPG49, SPG50, SPG56, SPG83, and GPT2 deficiency. HSPs cause significant motor impairment, including lower limb weakness and spasticity. Currently, no therapies halt disease progression. Several targeted therapies are in preclinical or clinical stages, necessitating high-quality natural history data to support clinical trials. This project will establish a longitudinal natural history dataset, incorporating clinician-reported outcome measures (CROMs), patient-reported outcome measures (PROMs), and biomarkers like neurofilament light chain (NfL). By integrating disease-specific measures and biospecimen collection, it will provide a robust foundation for future clinical trials, ensuring comprehensive knowledge of disease progression and validated clinical tools. The project will enroll 200 individuals with SPG4 and 100 with SPG3A, along with additional cohorts for the six rare HSP forms. Participants will undergo yearly assessments using established and new CROMs and PROMs. Blood samples will be analyzed for NfL levels, correlating with clinical outcomes. This systematic approach will facilitate the design of efficient clinical trials by providing critical data on disease progression, therapeutic windows, and biomarkers. The project aims to establish minimal clinically important differences (MCID) for key outcome measures and validate NfL as a biomarker of axonal degeneration. By generating high-quality natural history data, the project will de-risk and incentivize the development of targeted therapies, supporting the transition from preclinical studies to human trials. A Working Group for Gene-Based Therapies (WGGT) featuring leading experts in gene therapy, antisense oligonucleotides, and other precision medicine approaches will be formed and will provide a strategic framework for therapy development for HSPs. Combined with the creation of a robust clinical trial readiness platform, this will expedite the evaluation of new treatments, ultimately improving clinical outcomes and quality of life for individuals affected by HSP.