NM_170707.4(LMNA):c.317T>C (p.Leu106Pro)

Base Editing (BE4max) via LNP delivery is a rationale-driven therapeutic strategy for Hutchinson-Gilford progeria syndrome (LMNA-related progeroid laminopathy) targeting the LMNA c.317T>C (p.Leu106Pro) variant (Pathogenic, missense variant). The editing system (BE4max (cytosine base editor)) converts the pathogenic C to T (or G to A on the target strand), restoring the wild-type codon. Target tissue: Liver. Therapeutic goal: Correct the LMNA c.1824C>T (progerin) mutation in hepatocytes, vascular smooth muscle, and other affected tissues to reduce progerin production, normalize nuclear architecture, and extend survival. Risk profile: off-target Medium (bystander bases in editing window), delivery complexity Low, immunogenicity Low.

1. Molecular basis: LMNA NM_170707.4(LMNA):c.317T>C (p.Leu106Pro) is classified as Pathogenic (ClinVar variation ID 2098083). Molecular consequence: missense variant. Protein change: L106P. 2. Epidemiology: Extremely rare, with an estimated incidence of ~1 in 20 million births and global prevalent population on the order of 100–200 children alive at any time, with cases concentrated in countries with access to molecular diagnosis and registries (North America, Europe, selected other regions) [WEB-04, W 3. Standard of care: Supportive multidisciplinary care plus lonafarnib (ZOKINVY), an oral farnesyltransferase inhibitor approved to reduce risk of mortality in HGPS and certain processing-deficient progeroid laminopathies. Lonafarnib improves vascular pathology and survival but is not curative; additional off-label or i 4. Pipeline: For HGPS and progeroid laminopathies, one small-molecule (lonafarnib) has reached approval after Phase II/III studies. No gene-editing or ASO therapies have yet entered human trials; CRISPR adenine base editing of LMNA c.1824C>T using AAV9 has shown robust lifespan extension and vascular rescue in m 5. CBE clinical validation: BE4max (Koblan et al. 2018) is the gold-standard cytosine base editor. Multiple CBE programs are in clinical development for liver and hematologic targets.

1. No published data specifically correcting LMNA c.317T>C (p.Leu106Pro) with Base Editing (BE4max); 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. Long-term durability, off-target genome-wide effects, and immunogenicity in the target patient population require thorough preclinical and clinical evaluation.