NM_000059.4(BRCA2):c.8487G>C (p.Gln2829His)

Prime Editing (PE5max/PEmax) via RNP electroporation (ex vivo) delivery is a rationale-driven therapeutic strategy for Fanconi anemia complementation group D1 (BRCA2-related Fanconi anemia) targeting the BRCA2 c.8487G>C (p.Gln2829His) variant (Pathogenic, missense variant, non-coding transcript variant). The editing system (PEmax with engineered pegRNA) search-and-replace editing that directly rewrites the pathogenic transversion back to wild-type without requiring DSBs. Target tissue: Blood/HSC. Therapeutic goal: Correct BRCA2/FANCD1 loss-of-function variants in hematopoietic stem cells at the BRCA2 locus to restore homologous recombination DNA repair, prevent bone marrow failure, and reduce early-onset leukem. Risk profile: off-target Low (prime editing has inherently low off-target rate), delivery complexity Low, immunogenicity Low.

1. Molecular basis: BRCA2 NM_000059.4(BRCA2):c.8487G>C (p.Gln2829His) is classified as Pathogenic (ClinVar variation ID 4687466). Molecular consequence: missense variant, non-coding transcript variant. Protein change: Q1185H, Q2797H, Q2829H, Q690H. 2. Epidemiology: Fanconi anemia overall has an estimated prevalence between 1 in 100,000 and 1 in 350,000 live births, with higher incidences in certain founder populations (WEB-04). It is usually inherited in an autosomal recessive manner with more than 20 genes implicated including BRCA2/FANCD1 (WEB-04). BRCA2/FAN 3. Standard of care: Guidelines and Orphanet describe Fanconi anemia as a bone marrow failure and cancer predisposition syndrome characterized by growth deficiency, congenital malformations, progressive bone marrow failure typically presenting in the first decade, and markedly increased risk of myelodysplastic syndrome, 4. Pipeline: ClinicalTrials.gov and rare-disease foundations document multiple HSCT optimization studies and ex vivo gene therapy trials for Fanconi anemia, primarily focusing on FANCA but demonstrating platform feasibility. An early and subsequent Phase I/II lentiviral gene-therapy program (e.g., NCT04248439 an 5. Prime editing validation: PEmax (Chen et al. 2021, Cell) enables precise insertions, deletions, and all 12 point mutations without DSBs. Prime Medicine is advancing PE programs into clinical development. LNP and dual-AAV delivery of PE have been demonstrated in preclinical liver and CNS models.

1. No published data specifically correcting BRCA2 c.8487G>C (p.Gln2829His) with Prime Editing (PE5max/PEmax); strategy is based on general principles and must be validated preclinically. 3. Long-term durability, off-target genome-wide effects, and immunogenicity in the target patient population require thorough preclinical and clinical evaluation.