Base Editing (ABE8e) for CLN3 c.883G>A (p.Glu295Lys) in Juvenile neuronal ceroid lipofuscinosis (CLN3 disease)

Base Editing (ABE8e) via AAV9 delivery is a rationale-driven therapeutic strategy for Juvenile neuronal ceroid lipofuscinosis (CLN3 disease) targeting the CLN3 c.883G>A (p.Glu295Lys) variant (Pathogenic, missense variant). The editing system (ABE8e-nSpCas9 (adenine base editor)) converts the pathogenic A back to G on the target strand, restoring the wild-type codon. Target tissue: CNS. Therapeutic goal: Correct loss-of-function CLN3 variants (e.g., common 1.02-kb deletion) in CNS neurons to restore lysosomal/endolysosomal CLN3 function and slow or halt neurodegeneration in juvenile neuronal ceroid li. Risk profile: off-target Medium (bystander bases in editing window), delivery complexity Medium, immunogenicity High (AAV pre-existing immunity).

1. Molecular basis: CLN3 NM_001042432.2(CLN3):c.883G>A (p.Glu295Lys) is classified as Pathogenic (ClinVar variation ID 3556). Molecular consequence: missense variant. Protein change: E295K, E195K, E217K, E271K, E241K. 2. Epidemiology: JNCL/CLN3 disease is the most common form of neuronal ceroid lipofuscinosis, with incidence estimates ranging from ~0.02 to 4.8 per 100,000 worldwide and overall Batten disease prevalence around 1 in 100,000 live births (PAPER-01, WEB-01). Onset typically occurs at 5-7 years with rapid progression a 3. Standard of care: There is no approved disease-modifying therapy specific for CLN3 disease; management is symptomatic and supportive, including seizure control, management of behavioral issues, visual impairment support, mobility aids, nutritional and respiratory support, and palliative care in a multidisciplinary se 4. Pipeline: For CLN3, an intrathecal AAV9-based gene therapy (AT-GTX-502) is in Phase I/II clinical trials (NCT03770572), with early data indicating good tolerability and possible slowing of motor decline compared with natural history (WEB-06, WEB-07, PAPER-04, PAPER-05, PAPER-06). Preclinical CNS AAV gene repl 5. ABE clinical validation: ABE8e (Richter et al. 2020, Nat Biotechnol) achieves ~1.7x higher editing efficiency than ABE7.10. VERVE-101 demonstrated first-in-human LNP-ABE liver editing with 55-66% PCSK9 reduction (Raal et al. 2025, NEJM). Beam Therapeutics is advancing multiple ABE programs.

1. No published data specifically correcting CLN3 c.883G>A (p.Glu295Lys) with Base Editing (ABE8e); strategy is based on general principles and must be validated preclinically.
2. PAM availability and bystander base analysis for the specific genomic context have not been performed. If no canonical NGG PAM positions the target within the editing window, PAM-flexible variants (SpRY) may be needed.
3. Delivery to CNS tissue remains a major translational bottleneck. Current vectors have limited transduction efficiency in these compartments.
4. Long-term durability, off-target genome-wide effects, and immunogenicity in the target patient population require thorough preclinical and clinical evaluation.