Bilateral renal agenesis (dominant type)

Base Editing (BE4max) via AAV delivery is a rationale-driven therapeutic strategy for Bilateral renal agenesis (dominant type) targeting the GREB1L c.4607A>G (p.His1536Arg) 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: Kidney. Therapeutic goal: Correct the GREB1L c.4796G>A (p.Arg1599His) variant at chr18:21513881 to wild-type to restore normal GREB1L function and prevent dominant bilateral renal agenesis within the renal hypodysplasia/aplasi. Risk profile: off-target Medium (bystander bases in editing window), delivery complexity Medium, immunogenicity High (AAV pre-existing immunity).

1. Molecular basis: GREB1L NM_001142966.3(GREB1L):c.4607A>G (p.His1536Arg) is classified as Pathogenic (ClinVar variation ID 453283). Molecular consequence: missense variant. Protein change: H1536R. 2. Epidemiology: Bilateral renal agenesis is a rare, typically lethal congenital anomaly with reported birth prevalence around 1 in 8,000-10,000 births, including live births, fetal deaths, and terminations (EUROCAT BRAHD data and Orphanet registry). Most cases present with oligohydramnios/anhydramnios and Potter se 3. Standard of care: Current management is largely prenatal counseling and palliative care. Prenatal diagnosis is usually made by mid-trimester ultrasound (often supplemented by MRI). Families are counseled about the almost uniformly fatal prognosis. Experimental serial amnioinfusion programs aim to restore amniotic flu 4. Pipeline: For bilateral renal agenesis itself, there are no registered gene therapy or gene-editing clinical trials. Fetal serial amnioinfusion has been studied in small non-randomized interventional series and feasibility studies (pre-phase I). Gene therapy for other kidney diseases (e.g., Fabry disease) is 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 GREB1L c.4607A>G (p.His1536Arg) 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.