A research roadmap for SCN8A-related disorders: addressing knowledge gaps and aligning research priorities across stakeholders.

Abstract

Background: Despite significant scientific progress since the 2012 discovery that variants in the SCN8A gene can cause human epilepsy, disease mechanisms and best practices for management of SCN8A-related disorders (SCN8A-RD) remain incompletely understood. To accelerate the rate of progress, the International SCN8A Alliance sponsored a conference in Boston, Massachusetts, on August 16-18, 2024. The goals were to identify core knowledge gaps and research priorities, and to establish a collaborative research strategy to improve quality of life. In addition to a number of family leaders representing caregiver priorities, the meeting included laboratory scientists, clinicians, and representatives from the biopharmaceutical industry.

Main body: The scientific literature and requests for proposals from epilepsy funding agencies were reviewed prior to the meeting. Stakeholder-specific surveys were conducted focusing on knowledge gaps, research priorities, and scientific roadblocks. Interviews with biotechnology leaders were conducted to identify their priorities. These data were analyzed to assess responsiveness to caregiver concerns and to identify top research priorities for advancing the field. The Caregiver survey (n = 175) revealed top challenges and identified novel therapeutics and management of non-seizure phenotypes/comorbidities as top priorities. Clinician (n = 46) and scientist (n = 23) surveys identified a number of common research priorities, partially overlapping with caregiver concerns. Five core areas emerged from integrated analysis of all four stakeholder surveys and became the focus areas of five Working Groups: (1) Transformative Therapeutics, (2) Non-Seizure Outcomes, (3) Current Therapeutics, (4) Biomarkers, and (5) Whole Brain/Whole Body.

Conclusions: Taking account of the concerns and priorities of the caregiver community, the five working groups identified research directions to address knowledge gaps that include both short- and long-term priorities to improve understanding of disease mechanisms and management for the spectrum of SCN8A-RD phenotypes. Challenges included identification of suitable funding mechanisms and the lack of expertise in certain methodologies and research areas. This Research Roadmap is expected to accelerate progress toward the goals of improved quality of life and transformative care for all those with SCN8A-RD.