rAAV Gene Therapy in a Canavan's Disease Mouse Model Reveals Immune Impairments and an Extended Pathology Beyond the Central Nervous System
Horae Gene Therapy Center; Department of Microbiology and Physiological Systems; Department of Medicine; Center for Comparative Neuroimaging, Department of Psychiatry
Genetics | Neurology | Psychiatry
Aspartoacylase (AspA) gene mutations cause the pediatric lethal neurodegenerative Canavan disease (CD). There is emerging promise of successful gene therapy for CD using recombinant adeno-associated viruses (rAAVs). Here, we report an intracerebroventricularly delivered AspA gene therapy regime using three serotypes of rAAVs at a 20-fold reduced dose than previously described in AspA(-/-) mice, a bona-fide mouse model of CD. Interestingly, central nervous system (CNS)-restricted therapy prolonged survival over systemic therapy in CD mice but failed to sustain motor functions seen in systemically treated mice. Importantly, we reveal through histological and functional examination of untreated CD mice that AspA deficiency in peripheral tissues causes morphological and functional abnormalities in this heretofore CNS-defined disorder. We demonstrate for the first time that AspA deficiency, possibly through excessive N-acetyl aspartic acid accumulation, elicits both a peripheral and CNS immune response in CD mice. Our data establish a role for peripheral tissues in CD pathology and serve to aid the development of more efficacious and sustained gene therapy for this disease.
DOI of Published Version
Mol Ther. 2016 Jun;24(6):1030-41. doi: 10.1038/mt.2016.68. Epub 2016 Apr 4. Link to article on publisher's site
Molecular therapy : the journal of the American Society of Gene Therapy
Ahmed, Seemin Seher; Schattgen, Stefan A.; Frakes, Ashley E.; Sikoglu, Elif M.; Su, Qin; Li, Jia; Hampton, Thomas G.; Denninger, Andrew R.; Kirschner, Daniel A.; Kaspar, Brian; Matalon, Reuben; and Gao, Guangping, "rAAV Gene Therapy in a Canavan's Disease Mouse Model Reveals Immune Impairments and an Extended Pathology Beyond the Central Nervous System" (2016). Psychiatry Publications and Presentations. 795.