Functional recovery in a Friedreich's ataxia mouse model by frataxin gene transfer using an HSV-1 amplicon vector.
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.
Lim
Filip
F
Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de, Madrid, Madrid, Spain. flim@cbm.uam.es
Palomo
Gloria M
GM
Mauritz
Christina
C
Giménez-Cassina
Alfredo
A
Illana
Belen
B
Wandosell
Francisco
F
Díaz-Nido
Javier
J
D000818:Animals; D015153:Blotting, Western; D001933:Brain Stem / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005621:Friedreich Ataxia / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D005784:Gene Amplification; D015723:Gene Library; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D045442:Rotarod Performance Test; D000096923:Frataxin
D033862:Iron-Binding Proteins; D000096923:Frataxin