A “one size fits all” gene therapy for neurological disorders with mitochondrial dysfunction

Adeno-associated virus (AAV)-based gene therapy for genetic neurological disorders has attracted increasing attention over the last 7 years, since the publication of promising clinical trial data for spinal muscular atrophy using a single-dose AAV9 treatment. 1 Mendell J.R. Al-Zaidy S. Shell R. Arnold W.D. Rodino-Klapac L.R. Prior T.W. Lowes L. Alfano L. Berry K. Church K. et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N. Engl. J. Med. 2017; 377: 1713-1722 Crossref PubMed Scopus (1565) Google Scholar Hundreds of clinical trials to assess the safety and efficacy of AAV gene therapy have been conducted since then, and the majority of them are designed to target monogenetic rare diseases or a complex multigenetic disease with a single gene target. 2 Ling Q. Herstine J.A. Bradbury A. Gray S.J. AAV-based in vivo gene therapy for neurological disorders. Nat. Rev. Drug Discov. 2023; 22: 789-806 Crossref PubMed Scopus (22) Google Scholar However, with over 7,000 rare diseases and 20,000 protein-coding genes, developing a gene therapy for every disease individually becomes an overwhelming challenge. Further, it is even more challenging for mitochondrial diseases, as the mitochondrial genome can be involved, and current gene delivery technologies cannot deliver into mitochondria. Thus, a "one size fits all" strategy, aiming to use a single gene therapy product to attenuate the symptoms of multiple diseases with common manifestations, becomes attractive. In this issue of Molecular Therapy, Corral-Debrinski et al. attempted to address such a need by developing a gene therapy of neuroglobin to tackle ataxia caused by mitochondrial dysfunction. 3 Cwerman-Thibault H. Malko-Baverel V. Le Guilloux G. Ratcliffe E. Mouri D. Torres-Cuevas I. Millán I. Saubaméa B. Mignon V. Boespflug-Tanguy O. et al. Neuroglobin overexpression in cerebellar neurons of Harlequin mice improves mitochondrial homeostasis and reduces ataxic behavior. Mol. Ther. 2024; 32: 2150-2175https://doi.org/10.1016/j.ymthe.2024.05.030 Abstract Full Text Full Text PDF Scopus (0) Google Scholar The study used Harlequin (Hq) mice, a disease model in which the expression of apoptosis-inducing factor (AIF) protein is significantly reduced. The study reported that neuroglobin delivered by an AAV restored the biochemical and behavioral defects caused by cerebellar dysfunction in the Hq mice to a similar degree as delivering the root cause gene of the mouse model, the AIFM1 (AIF mitochondrion-associated 1) gene. Whether this gene therapy can be extended to other primary mitochondrial diseases or neurological disorders involving mitochondrial dysfunction still merits further investigation, especially efforts to understand the function of neuroglobin for its translational potential.