A Prospective Natural History Study Protocol for Clinical Trial Readiness in Synaptic Disorders.
Overview
abstract
OBJECTIVE: STXBP1- Related Disorders ( STXBP1 -RD) and SYNGAP1 -Related Disorder ( SYNGAP1 -RD) are two common genetic synaptopathies, leading to epilepsy, developmental delay, and intellectual disability. Both STXBP1 -RD and SYNGAP1 -RD are potential targets for disease-modifying therapies, but there is limited information in the literature describing the natural history of either disorder, which impedes outcome selection for future clinical trials. The objective of this study is to develop a framework to better define and outline the clinical spectrum and longitudinal trajectories of STXBP1 -RD and SYNGAP1 -RD natural history, including development, behavior, seizure histories, and electrophysiology. METHODS: Here, we describe a protocol, regulatory structure, and supportive preliminary data for multi-center, prospective natural history studies of STXBP1 -RD (STARR) and SYNGAP1 -RD (ProMMiS). The protocols incorporate gold-standard clinician-assessed outcome measures including the Bayley Scales of Infant and Toddler Development 4 th edition, Gross Motor Function Measure-66, and fine motor domains of the Peabody Developmental Motor Scales 3 rd Edition, parent reported outcome measures (PROMs), epilepsy histories, and biomarker exploration. To date, the study has enrolled 164 individuals with STXBP1 -RD and 159 with SYNGAP1 -RD, with ongoing longitudinal assessments every 6 months in a subset of approximately 200 total individuals across both disorders. RESULTS: Our data support that existing developmental measures are feasible, informative, and show minimal floor or ceiling effects. Furthermore, we demonstrate that medical record-based seizure history reconstruction reveals unique epilepsy trajectories while minimizing burden to families. We observe disease-specific patterns of developmental performance and distinct longitudinal seizure dynamics, highlighting the need for data generation in a gene/disorder-specific manner for clinical trial readiness. SIGNIFICANCE: In summary, we present a feasible natural history protocol with prospective data for two complex neurodevelopmental disorders with natural histories that have previously been incompletely characterized, within a regulatory framework that will support the use of these data to expedite clinical trial development. KEY POINTS: STXBP1 -Related Disorder ( STXBP1 -RD) and SYNGAP1 -Related Disorder ( SYNGAP1 -RD) are two common genetic causes of epilepsy, developmental delay, and intellectual disability. STXBP1 -RD and SYNGAP1 -RD are potential targets for drug and gene therapy, but there is limited information in the literature describing the natural history of either disorder which impedes the development of possible therapeutics. The current paper is a description of a prospective natural history study of STXBP1 -RD and SYNGAP1 -RD which will assess the clinical spectrum of each disorder through detailed developmental assessments, seizure histories, behavioral assessments, and electronic medical record reconstruction. By studying STXBP1 -RD and SYNGAP1-RD with both cross sectional and longitudinal assessments, we aim to improve clinical trial readiness so that potential treatments can be assessed expeditiously.
