Generating new Friedreich's Ataxia animal models for validating HSV-1 FXN gene therapy in Dorsal Root Ganglia
Ataxia UK
Autonomous University of Madrid
In a previous Ataxia UK-funded project, this group generated a novel HSV-1 vector, very similar to one already found to be safe in clinical trials for pain therapy (David Fink, Uni Michigan). They used the natural neurotropism of the vector to deliver a frataxin (FXN) transgene to deeply buried dorsal root ganglion (DRG) neurons after footpad injection.   To translate this non-invasive gene therapy to the clinic, biodistribution, and efficacy studies in Friedreich's ataxia (FA) animal models are of high priority. However, current mouse models pose several obstacles: avoiding cardiac lethality, masking of localised vector effects by severe phenotypes, and the costly and labour-intensive process of crossing different transgenic mice and screening for desired genotypes.   During this project, this group will aim to construct HSV-1 vectors to knock down frataxin in wild-type animals, or knock out frataxin in floxed FXN mice, to rapidly generate cell and animal FA models. This approach will complement whole animal models, eg by circumventing lethal cardiomyopathy, or by restricting pathology to localised tissues. Although primarily to advance translation of their gene therapy to the clinic, these tools will also facilitate the work of other groups needing FA models.
5.2 Cellular and gene therapies