Base Editing (BE4max) for ZMPSTE24 c.794A>G (p.Asn265Ser) in Restrictive dermopathy 1 (ZMPSTE24-related)

Base Editing (BE4max) via AAV delivery is a rationale-driven therapeutic strategy for Restrictive dermopathy 1 (ZMPSTE24-related) targeting the ZMPSTE24 c.794A>G (p.Asn265Ser) 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: Lung. Therapeutic goal: Correct biallelic loss-of-function mutations in ZMPSTE24 at the RSDM1 locus to restore prelamin A processing and prevent the lethal restrictive dermopathy phenotype.. Risk profile: off-target Medium (bystander bases in editing window), delivery complexity Medium, immunogenicity High (AAV pre-existing immunity).

1. Molecular basis: ZMPSTE24 NM_005857.5(ZMPSTE24):c.794A>G (p.Asn265Ser) is classified as Pathogenic (ClinVar variation ID 140540). Molecular consequence: missense variant. Protein change: N265S. 2. Epidemiology: Extremely rare neonatal-lethal laminopathy with prevalence <1/1,000,000 and only a few dozen cases reported worldwide; cases are globally scattered and usually identified in tertiary perinatal centers (Orphanet ORPHA:1662 and clinical case series). 3. Standard of care: No disease-modifying therapy. Management consists of intensive neonatal supportive care (ventilation for respiratory failure due to pulmonary hypoplasia, nutritional support, and meticulous skin care) with predominantly palliative intent; survival is generally limited to days or weeks. 4. Pipeline: No interventional clinical trials directly target restrictive dermopathy or ZMPSTE24 deficiency. Related progeroid laminopathies (e.g., Hutchinson-Gilford progeria syndrome and LMNA cardiomyopathy) have small-molecule (statin/aminobisphosphonate) and genome-editing (CRISPR/AAV) programs at preclinic 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 ZMPSTE24 c.794A>G (p.Asn265Ser) 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.