Format

Send to

Choose Destination
Mol Ther. 2016 Jun;24(6):1030-1041. doi: 10.1038/mt.2016.68. Epub 2016 Apr 4.

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

Author information

1
Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
2
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
3
Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
4
The Center for Comparative Neuroimaging, University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
5
Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
6
Mouse Specifics, Inc., Framingham, Massachusetts, USA.
7
Biology Department, Boston College, Chestnut Hill, Massachusetts, USA.
8
Department of Pediatrics, Biochemical and Molecular Genetics, University of Texas Medical Branch, Galveston, Texas, USA.
9
Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA. Electronic address: Guangping.Gao@umassmed.edu.

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.

PMID:
27039844
PMCID:
PMC4923332
DOI:
10.1038/mt.2016.68
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center