Gene Therapy for Mitochondrial Diseases: Current Status and Future Perspective

Abstract

Mitochondrial diseases (MDs) are a group of severe genetic disorders caused by mutations in the nuclear or mitochondrial genome encoding proteins involved in the oxidative phosphorylation (OXPHOS) system. MDs have a wide range of symptoms, ranging from organ-specific to multisystemic dysfunctions, with different clinical outcomes. The lack of natural history information, the limits of currently available preclinical models, and the wide range of phenotypic presentations seen in MD patients have all hampered the development of effective therapies. The growing number of pre-clinical and clinical trials over the last decade has shown that gene therapy is a viable precision medicine option for treating MD. However, several obstacles must be overcome, including vector design, targeted tissue tropism and efficient delivery, transgene expression, and immunotoxicity. This manuscript offers a comprehensive overview of the state of the art of gene therapy in MD, addressing the main challenges, the most feasible solutions, and the future perspectives of the field.

Keywords: gene therapy; mitochondria; mitochondrial DNA; mitochondrial disease; precision medicine.

Figure 1

Clinical features of mitochondrial disorder: MDs are caused by oxidative phosphorylation (OXPHOS) failure and display high biochemical, genetic, and clinical complexity, which complicate the prognosis and the development of therapeutic solutions. Adapted from “Adult male” by BioRender.com (accessed on 5 April 2022). Retrieved from https://app.biorender.com/biorender-templates (accessed on 3 June 2022).

Figure 2

Schematic representation of “Adeno-Associated Virus (AAV) Genome”. Retrieved from https://app.biorender.com/biorender-templates (accessed on 16 April 2022).

Figure 3

Representation of the different AAV serotypes and their target tissues. Adapted from AAV Tissue Specificity by BioRender.com (accessed on 16 April 2022) (2022). Retrieved from https://app.biorender.com/biorender-templates (accessed on 16 April 2022).

Figure 4

Schematic representation of IUFGT to restore correct neurodevelopment in Surf1 LS-affected fetus. The therapeutic gene can be delivered to the fetus through transabdominal intrauterine ultrasound-guided injection of AAV9-Surf1 in the fetal umbilical cord vessels. Figure 4 was modified from SMART (Servier Medical Art) and licensed under a Creative Common Attribution 3.0 Generic License. http://smart.servier.com/ (accessed on 16 April 2022 ).