Gene Therapy for Xeroderma Pigmentosum - Cockayne Syndrome.

PROJECT SUMMARY The goal of this project is to refine our gene therapy strategy for Xeroderma Pigmentosum-Cockayne Syndrome (XP-CS), with the ultimate aim of improving the neurological outcomes and life expectancy for this disorder. XP- CS is a rare, inherited DNA repair disorder that is characterized by an accelerated aging phenotype and

prominent, severe neurodegenerative complications mirroring those seen in classic Cockayne syndrome (CS), including cognitive dysfunction, brain atrophy, neurodevelopmental delays, peripheral neuropathy, brain atrophy, and dementia. There are several genetic subtypes of XP-CS, including one associated with pathogenic variants

in the gene ERCC5 (XPG). We have found that the Xpg-/- mouse accurately recapitulates key features of the XP- CS phenotype, including neurological features. We have also developed a first generation adeno-associated virus (AAV) vector capable of delivering ERCC5 that shows great promise but requires further development prior

to translation into human clinical trials. Our preliminary studies using the first generation vector in the Xpg-/- mouse point to a clear path towards optimizing this approach, including capsid optimization, promoter optimization, delivery optimization, dose tuning, toxicity studies, and biomarker evaluations. We expect that our

proposed studies will lead to a gene therapy strategy that overcomes many of the obstacles to translation into a Phase 1 human clinical trial. The knowledge obtained from these studies will be generalizable, and will accelerate the development of gene therapies for other genetic subtypes of XP-CS.