Intrathecal AAV-CLN3 gene replacement for juvenile NCL: rationale and challenges for c.1054C>T (p.Gln352Ter)

AAV-mediated CLN3 gene replacement via intrathecal or intracerebroventricular delivery is the primary gene therapy strategy for CLN3 disease (juvenile neuronal ceroid lipofuscinosis, Batten disease). The c.1054C>T (p.Gln352Ter) nonsense variant truncates CLN3 near the C-terminus, eliminating the final transmembrane domain and cytoplasmic tail required for proper lysosomal membrane localization and function. As a complete loss-of-function allele, it is mechanistically appropriate for gene replacement.

CLN3 encodes battenin/CLN3 protein, a multipass transmembrane protein localized to lysosomes and late endosomes. Its exact biochemical function remains incompletely understood, but it participates in lysosomal homeostasis, autophagy regulation, and potentially lipid/glycosphingolipid metabolism. CLN3 disease is the most common NCL subtype, typically presenting at age 4-7 with progressive vision loss, followed by cognitive decline, seizures, and motor deterioration. Weill Cornell Medical College / Abeona Therapeutics initiated an intrathecal AAV9-CLN3 gene therapy trial. Preclinical studies in Cln3-knockout mice and the CLN3Δex7/8 knock-in model (which recapitulates the common ~1 kb deletion founder variant) showed reduced storage material accumulation and improved neuropathological markers after AAV-CLN3 delivery. The p.Gln352Ter variant produces a truncated protein missing the last ~30 residues including transmembrane domain 6 and the C-terminal cytoplasmic tail, which is critical for lysosomal targeting signals.

CLN3 disease is a diffuse neurodegenerative process affecting the entire CNS including the retina — achieving widespread transduction with intrathecal AAV is challenging, and retinal disease may require separate subretinal or intravitreal delivery. The slow progression of juvenile NCL (over decades) makes clinical trial design difficult: meaningful endpoints require years of follow-up. The function of CLN3 protein is still not fully elucidated, complicating biomarker development for target engagement. The common pathogenic variant in CLN3 disease is a ~1 kb genomic deletion (c.461-280_677+382del), not a point mutation — the c.1054C>T variant is less common, and trial populations may not include this specific genotype. No pivotal trial results have been published for CLN3 gene therapy as of the knowledge cutoff.