Cross-sectional and Longitudinal Natural History of CLN3 Disease Progression

Objective: To quantify the relationship between symptom severity and age in CLN3 disease using both cross-sectional and longitudinal analyses. Background: CLN3 disease (Juvenile Batten Disease) is a neurodegenerative disease beginning in early childhood and progressing until death in the third decade of life. Design/Methods: Participants were evaluated using the Unified Batten Disease Rating Scale (UBDRS), a disease-specific rating scale with four subscales: physical, seizure, behavioral, and functional capability. The most recent evaluation for each participant, including those with only a single time point, was used to perform cross-sectional analyses. For individuals with multiple time points, longitudinal analyses were performed accounting for the effect of multiple within-subject evaluations. Results: We analyzed data from 126 unique individuals with a total of 380 evaluations. 47 individuals were evaluated at a single time point; 79 individuals had serial evaluations with up to 15 assessments per individual. In both cross-sectional and longitudinal analyses, the physical, seizure, and functional capability scores correlated with age. The behavior score did not correlate with age. The annual rate of physical progression was 3.02 ± 0.24 (slope ± SE) points (cross-sectional) and 3.11 ± 0.28 points (longitudinal). The annual rate of seizure progression was 0.53 ± 0.10 points (cross-sectional) and 0.59 ± 0.08 points (longitudinal). The annual rate of functional capability change was 0.53 ± 0.06 points (cross-sectional) and 0.60 ± 0.04 points (longitudinal). Conclusions: Our data provide a global assessment of CLN3 disease severity and show a nearly linear rate of relentless progression after onset. Cross-sectional and longitudinal analyses yielded similar results, supporting the combination of cross-sectional with longitudinal approaches to increase sample size in this rare disease. They also suggest the potential for combining such data as a baseline for future clinical trials in CLN3 disease. Used in combination with symptom age-at-onset, these data provide a comprehensive picture of CLN3 disease natural history. Disclosure: Dr. Masten has nothing to disclose. Dr. Vermilion has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Neurogene, Inc.. Dr. Adams has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biomarin Pharnmaceuticals; Neurogene Inc; Regenxbio; Signangt Health. Dr. Adams has received research support from Abeona Inc.. Dr. Vierhile has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory board for the Cannabinoid Education Working Group. Dr. Vierhile has received research support from Research support from NIH, Teva Pharmaceuticals, Abeona Therapeutics, Biohaven Pharmaceuticals. Dr. Marshall has nothing to disclose. Dr. Beck has received research support from Boston Scientific; Boehringer Ingelheim; Auspex Pharmaceuticals; Abeona Therapeutics. Dr. Mink has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Neurogene Inc; Amicus Inc; Abide Therapeutics; Censa Inc;. Dr. Mink has received personal compensation in an editorial capacity for American Academy of Neurology. Dr. Mink has received research support from Abeona Therapeutics. Dr. Augustine has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with BioMarin Pharmaceutical and RegenxBio. Dr. Augustine has received research support from Abeona Therapeutics and Biohaven Pharmaceutical.