Gene therapy for Batten disease: A systemic review of preclinical and clinical studies

Abstract

Background: Batten disease (BD), or neuronal ceroid lipofuscinosis (NCL), is a group of rare, fatal neurodegenerative disorders caused by mutations in CLN genes, leading to lysosomal dysfunction and progressive neuronal loss. Gene therapy, particularly using adeno-associated virus (AAV) vectors, has emerged as a promising strategy to address the genetic basis of BD across various subtypes, including CLN2, CLN5, and CLN6. This systematic review evaluates the efficacy and challenges of gene therapy in preclinical and clinical settings.

Methods: Following PRISMA guidelines, we reviewed studies from January 2000 to January 2025, sourced from PubMed, Embase, Scopus, and other databases. Included studies assessed viral and non-viral vector-mediated gene therapies for BD in preclinical (animal, in vitro) and clinical contexts. Primary outcomes were restoration of enzymatic function, reduction in neurodegeneration, improvements in motor and cognitive function, safety, and survival.

Results: Preclinical studies demonstrated that AAV-based gene therapy effectively restored enzyme activity, reduced neuronal degeneration, and extended survival in models of CLN5, CLN6, and other subtypes. Clinical trials, particularly for CLN2, showed slower disease progression with intracerebroventricular AAV-TPP1 delivery. However, challenges include genetic heterogeneity, immune responses to vectors, limited central nervous system (CNS) transduction due to the blood-brain barrier, and uncertainties about long-term safety and optimal treatment timing.

Conclusion: Gene therapy holds significant potential for treating BD by targeting its genetic roots, with AAV-mediated approaches showing promise in both preclinical and early clinical studies. Nonetheless, optimizing vector design, delivery methods, and immune management, alongside improving early diagnosis, remains critical to realising its therapeutic potential.