New genome editing technologies in the treatment of X-linked adrenoleukodystrophy

Abstract

X-linked adrenoleukodystrophy is a severe progressive neurological disease that is predominantly found in male patients and caused by mutations in the X-linked ABCD1 gene encoding peroxisome transport protein. The disease is clinically characterized by two main phenotypes: the most severe infant cerebral form and adrenomyeloneuropathy. The disease is treated by allogeneic transplantation of hematopoietic cells from a healthy donor to stop progression, and gene therapy with a self-activating lentiviral vector, the carrier of the functional gene ABCD1. Each method has its own limitations. The authors present and theoretically substantiate an alternative approach to the treatment of adrenoleukodystrophy; they propose to modify the autologous CD34+ cells from the patient using genomic editing, in order to replace the mutant DNA sequence of ABCD1 gene with a wild-type sequence, while replacing the mutant protein in the edited cells. The edited autologous CD34+ cells can be introduced by their transplantation into the bone marrow or by a series of repeated intravenous infusions. This method will allow avoiding both the search for a donor and the graft-versus-host reaction