Congenital / Infantile Neuronal Ceroid Lipofuscinosis (CLN1/CLN2 spectrum)

Base Editing (ABE8e) via AAV9 delivery is a rationale-driven therapeutic strategy for Congenital / Infantile Neuronal Ceroid Lipofuscinosis (CLN1/CLN2 spectrum) targeting the TPP1 c.1094G>A (p.Cys365Tyr) 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 the recurrent TPP1 nonsense variant (c.622C>T, p.Arg208Ter) at the CLN2 locus to restore functional tripeptidyl peptidase 1 activity in CNS neurons and glia, aiming to durably halt or reverse . Risk profile: off-target Medium (bystander bases in editing window), delivery complexity Medium, immunogenicity High (AAV pre-existing immunity).

1. Molecular basis: TPP1 NM_000391.4(TPP1):c.1094G>A (p.Cys365Tyr) is classified as Pathogenic (ClinVar variation ID 2642). Molecular consequence: missense variant. Protein change: C365Y. 2. Epidemiology: Neuronal ceroid lipofuscinoses (NCLs) are ultra-rare, autosomal recessive, fatal pediatric neurodegenerative lysosomal storage disorders with an overall prevalence around 1 in 100,000 live births, with higher incidence in founder populations such as Finland (CLN1 about 1 in 20,000) [WEB-01, WEB-11, 3. Standard of care: Before disease-modifying therapy, management of CLN1/CLN2 and related early-onset NCLs was purely symptomatic and palliative (seizure control, spasticity management, feeding support, respiratory care), with no approved treatments to alter the neurodegenerative course [WEB-05, WEB-06, PAPER-02]. For 4. Pipeline: For CLN2, AAV2 and AAVrh.10 CNS gene-transfer approaches have progressed through phase 1/2 trials, showing slowed functional decline and markedly prolonged survival compared with natural history, with follow-up to ~20 years indicating durable benefit and acceptable safety [WEB-04, PAPER-03, PAPER-04 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 TPP1 c.1094G>A (p.Cys365Tyr) 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. 4. 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.

For TPP1 c.622C>T (p.Arg208Ter), cerliponase alfa is a rational therapeutic option because the variant creates a loss-of-function stop codon and the approved treatment bypasses allele-specific repair by replacing TPP1 enzyme directly within the CNS. That makes this a strong disease-level fit for enzyme replacement, even though the drug does not correct the underlying DNA lesion.

ClinVar classifies c.622C>T (p.Arg208Ter) as pathogenic for CLN2/TPP1 deficiency. The current FDA label for Brineura, updated through 2026-04-03 in openFDA, indicates cerliponase alfa to slow the loss of ambulation in pediatric patients with CLN2 disease, also known as TPP1 deficiency. Clinical pharmacokinetic and pharmacodynamic data published in 2021 support intracerebroventricular enzyme replacement as a viable delivery route, and the first French cohort reported that cerliponase alfa changed the natural history of children with CLN2 compared with expected progression.

This is not curative therapy. Brineura requires chronic intracerebroventricular infusions and device management, and it primarily addresses CNS enzyme deficiency rather than restoring endogenous TPP1 production everywhere it is needed. The evidence is disease-level rather than specific to p.Arg208Ter, and treatment burden, infusion reactions, seizures, shunt complications, and incomplete control of extra-CNS manifestations remain important constraints.