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rAAV Gene Therapy in a Canavan's Disease Mouse Model Reveals Immune Impairments and an Extended Pathology Beyond the
Seemin Seher Ahmed1, Stefan A Schattgen2, Ashley E Frakes3
1Horae 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.
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.
Insights
Gene therapy for Canavan disease (CD) using adeno-associated viruses shows promise. Peripheral tissue involvement in CD pathology was revealed, impacting treatment strategies for this neurodegenerative disorder.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Canavan disease (CD) is a fatal pediatric neurodegenerative disorder caused by Aspartoacylase (AspA) gene mutations.
- Gene therapy using recombinant adeno-associated viruses (rAAVs) offers potential therapeutic avenues for CD.
Purpose of the Study:
- To investigate the efficacy of a reduced-dose, intracerebroventricularly delivered AspA gene therapy in a mouse model of CD.
- To explore the role of peripheral tissues in CD pathology and immune response.
Main Methods:
- Administration of three rAAV serotypes via intracerebroventricular injection in AspA(-/-) mice at a reduced dose.
- Histological and functional assessments of CNS and peripheral tissues.
- Evaluation of immune responses in treated and untreated CD mice.
Main Results:
- Central nervous system-restricted gene therapy prolonged survival but did not sustain motor function compared to systemic therapy.
- AspA deficiency in peripheral tissues was found to cause morphological and functional abnormalities.
- AspA deficiency triggers both peripheral and CNS immune responses, potentially due to N-acetyl aspartic acid accumulation.
Conclusions:
- Peripheral tissues play a significant role in Canavan disease pathology, challenging the notion of it being solely a CNS-defined disorder.
- Understanding peripheral involvement is crucial for developing more effective and sustained gene therapies for CD.
- This study provides foundational data for advancing therapeutic strategies for Canavan disease.
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