CRISPR/Cas9-mediated gene correction of Wilson disease H1069Q point mutation in patient-specific induced pluripotent stem cells

Résumé fourni par la source

The innovative clustered regularly interspaced short palindromic repeats (CRISPR) associated nuclease 9 (Cas9) gene editing technique may represent a suitable therapeutic opportunity for the treatment of inherited diseases such as Wilson disease (WD). This monogenetic liver disease is based on a mutation of the ATP7B gene and leads to a functional deterioration in copper (Cu) excretion. Excess Cu accumulations in organs such as the liver and brain lead to severe cytotoxicity, followed by acute or chronic liver failure and/or neurological symptoms, and even death, which makes cellular Cu excretion indispensable for any potential WD therapy, e.g., gene therapy. A life-long treatment with zinc or chelators such as D-penicillamine may improve the course of the disease, but serious side effects have been observed in a significant portion of patients. In this study, isolated urinary epithelial cells from a WD patient carrying the ATP7B H1069Q mutation were reprogrammed into induced pluripotent stem cells (iPSCs). Using the CRISPR/Cas9 technology, ATP7B H1069Q was corrected by the additional use of single-stranded oligo DNA nucleotides (ssODNs). After differentiation into hepatocyte-like cells (HLCs), a high resistance to Cu was observed, plus a recovery of ATP7B trafficking. This is the first study to confirm that CRISPR/Cas9-mediated correction of the ATP7B point mutation H1069Q is possible and could open new possibilities for future applications.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.