Therapeutic impact of CRISPR-corrected patient fibroblasts on CADASIL phenotype

Ascertain whether genetically corrected patient-derived fibroblasts produced via CRISPR-Cas9 base editing and reprogramming can modify the disease presentation of CADASIL, given that NOTCH3 mutations predominantly affect vascular smooth muscle cells.

Background

A reported ex vivo approach corrects a common CADASIL-associated NOTCH3 single-nucleotide mutation in patient fibroblasts using adenine base editors during reprogramming. However, CADASIL pathophysiology primarily involves vascular smooth muscle cells, raising questions about the relevance and efficacy of fibroblast-based corrections for altering disease expression.

Determining whether corrected fibroblasts can impact CADASIL phenotypes is important for assessing the translational potential of fibroblast-targeted or fibroblast-derived therapeutic strategies.

References

It is also unclear whether the modified fibroblasts would change the disease presentation, as the NOTCH3 mutation typically most strongly affects VSMCs.

— Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL): Immunotherapy and Cell Therapy approaches  (2506.09293 - Haile et al., 10 Jun 2025) in CADASIL as a Candidate for Cell and Gene Therapy