Gene and epigenetic editing in the treatment of primary ciliopathies

Abstract

Primary ciliopathies are inherited human disorders that arise from mutations in ciliary genes. They represent a spectrum of severe, incurable phenotypes, differentially involving several organs, including the kidney and the eye. The development of gene-based therapies is opening up new avenues for the treatment of ciliopathies. Particularly attractive is the possibility of correcting in situ the causative genetic mutation, or pathological epigenetic changes, through the use of gene editing tools. Due to their versatility and efficacy, CRISPR/Cas-based systems represent the most promising gene editing toolkit for clinical applications. However, delivery and specificity issues have so far held back the translatability of CRISPR/Cas-based therapies into clinical practice, especially where systemic administration is required. The eye, with its characteristics of high accessibility and compartmentalization, represents an ideal target for in situ gene correction. Indeed, studies for the evaluation of a CRISPR/Cas-based therapy for in vivo gene correction to treat a retinal ciliopathy have reached the clinical stage. Further technological advances may be required for the development of in vivo CRISPR-based treatments for the kidney. We discuss here the possibilities and the challenges associated to the implementation of CRISPR/Cas-based therapies for the treatment of primary ciliopathies with renal and retinal phenotypes.

Keywords: CRISPR; Ciliopathies; Cystic kidney disease; Epigenetic; Gene editing; Gene therapy; Retinal degeneration.