Gene therapy strategies for rare monogenic disorders with nuclear or mitochondrial gene mutations

Abstract

Rare monogenic disorders are a group of single-gene-mutated diseases that have a low incidence rate (less than 0.5%o) and eventually lead to patient disability and even death. Due to the relatively low number of people affected, these diseases typically fail to attract a great deal of commercial investment and research interest, and the affected patients thus have unmet medical needs. Advances in genomics biology, gene editing, and gene delivery can now offer potentially effective options for treating rare monogenic diseases. Herein, we review the application of gene therapy strategies (traditional gene therapy and gene editing) against various rare monogenic diseases with nuclear or mitochondrial gene mutations, including eye, central nervous system, pulmonary, systemic, and blood cell diseases. We summarize their pathologic features, address the barriers to gene delivery for these diseases, discuss available therapies in the clinic and in clinical trials, and sum up in-development gene delivery systems for various rare monogenic disorders. Finally, we elaborate the possible directions and outlook of gene therapy for rare monogenic disorders.