Title

rAAV Gene Therapy in a Canavan's Disease Mouse Model Reveals Immune Impairments and an Extended Pathology Beyond the Central Nervous System

UMMS Affiliation

Horae Gene Therapy Center; Department of Microbiology and Physiological Systems; Department of Medicine; Center for Comparative Neuroimaging, Department of Psychiatry

Publication Date

6-1-2016

Document Type

Article

Disciplines

Genetics | Neurology | Psychiatry

Abstract

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

10.1038/mt.2016.68

Source

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

Journal/Book/Conference Title

Molecular therapy : the journal of the American Society of Gene Therapy

Related Resources

Link to Article in PubMed

PubMed ID

27039844

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