Efficacy of gene therapy in a CLN5 sheep model using a dual route of administration supports a first-in-human clinical trial

Abstract

CLN5 Batten disease is a rare, fatal neurodegenerative disease characterized by loss of vision, decline in intellectual and motor capabilities and seizures, with typical disease onset in early childhood. Pathogenic variants in the CLN5 gene are responsible for disease, therefore gene therapy represents a promising treatment approach. To establish efficacy and safety, an adeno-associated virus serotype 9 (AAV9) gene therapy containing ovine CLN5 (AAV9/ oCLN5) was evaluated in an early and advanced symptomatic ovine model (CLN5−/−) recapitulating multiple facets of human CLN5 disease. Combined intraventricular (ICV) and intravitreal (IVT) routes of administration were used to maximize treatment outcomes. Animals were treated with a dose of either AAV9/oCLN5 of 2.9E11vg or 3.2E12vg ICV and 6.5E10vg IVT into a single eye. Disease progression was significantly slowed or halted as measured by clinical scoring. 6- and 9-month animals receiving the higher ICV dose had the most robust response. MRI results confirmed reduced brain atrophy. Disease-associated pathology (neuroinflammation and storage body accumulation) was improved. Vision was preserved in most treated sheep to 24months of age, with improvements in retinal pathology and function. On the basis of these data, we designed a first-in-human, open-label Phase 1/2 study, which aims to assess safety, tolerability and efficacy of NGN101, an AAV9 investigational product containing the human CLN5 transgene. 3 symptomatic individuals, ages 3–8 years, with confirmed biallelic pathogenic or likely pathogenic CLN5 variants, with disease onset age of ≤4 years will receive a single dose of NGN101 via ICV and IVT administration. Assessments will include physical and neurological examinations, Hamburg Scale, the Unified Batten Disease Rating Scale, visual acuity, Spectral Domain Optical Coherence Tomography, and the Caregiver Global Impression of Severity Scale. Biomarker assessments will also be collected. Data from this study has the potential to advance development of a disease-modifying treatment for CLN5 Batten disease.