Functional Recovery in a Friedreich's Ataxia Mouse Model by Frataxin Gene Transfer Using an HSV-1 Amplicon Vector.

Lim, Filip; Palomo, Gloria M.; Mauritz, Christina; Giménez-Cassina, Alfredo; Illana, Belen; Wandosell, Francisco; Díaz-Nido, Javier

There is currently no effective treatment for Friedreich's ataxia (FA), the most common of the hereditary ataxias. The disease is caused by mutations in FRDA that drastically reduce expression levels of the mitochondrial protein frataxin. In FA animal models, a key difficulty is obtaining the precise levels of frataxin expression in the appropriate tissues to provoke pathology without early lethality. To develop strategies to circumvent these problems, conditional frataxin transgenic mice have been generated. We now show that frataxin expression can be eliminated in neurons from these loxP[frda] mice by infection with CRE-expressing herpes simplex virus type 1 (HSV-1) amplicon vectors. We have also achieved in vivo delivery by stereotaxic injection of these CRE-expressing vectors into the brainstem of loxP[frda] mice to generate a localized gene knockout model. These mice develop a behavioral deficit in the rotarod assay detectable after 4 weeks, and when re-injected with HSV-1 amplicon vectors expressing human frataxin complementary DNA (cDNA) exhibit behavioral recovery as early as 4 weeks after the second injection. To the best of our knowledge, this is the first proof of principle of recovery of neurological function by a therapeutic agent aimed at correcting frataxin deficiency.Molecular Therapy (2007) 15 6, 1072–1078. doi:10.1038/sj.mt.6300143

MEDICAL research; GENETIC transformation; HERPES simplex virus; FRIEDREICH'S ataxia; MITOCHONDRIAL membranes; TRANSGENIC mice

Molecular Therapy, 2007, Vol 15, Issue 6, p1072

1525-0016

Academic Journal

10.1038/sj.mt.6300143