Future Prospects of Gene Therapy for Friedreich's Ataxia

Abstract

Friedreich's ataxia is an autosomal recessive neurogenetic disease that is mainly associated with atrophy of the spinal cord and progressive neurodegeneration in the cerebellum. The disease is caused by a GAA-expansion in the first intron of the frataxin gene leading to a decreased level of frataxin protein, which results in mitochondrial dysfunction. Currently, there is no effective treatment to delay neurodegeneration in Friedreich's ataxia. A plausible therapeutic approach is gene therapy. Indeed, Friedreich's ataxia mouse models have been treated with viral vectors en-coding for either FXN or neurotrophins, such as brain-derived neurotrophic factor showing promising results. Thus, gene therapy is increasingly consolidating as one of the most promising therapies. However, several hurdles have to be overcome, including immunotoxicity and pheno-toxicity. We review the state of the art of gene therapy in Friedreich's ataxia, addressing the main challenges and the most feasible solutions for them.

Keywords: AAV; Friedreich’s Ataxia; clinical trials; gene therapy; mouse models; neurodegeneration; preclinical studies.

Figure 1

Different routes of administration used in gene therapy for CNS delivery. (a) Routes of delivery implemented clinically (IV, IT, ICV) or in the progress of being implemented (ICM). (b) Preclinical routes of gene delivery used in mice. IV: intravenous. IT: Intrathecal. ICV: Intracerebroventricular. ICM: Intra-cisterna magna.