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

Seemin Seher Ahmed, Stefan A. Schattgen, Ashley E. Frakes, Elif M. Sikoglu, Qin Su, Jia Li, Thomas G. Hampton, Andrew R. Denninger, Daniel A. Kirschner, Brian Kaspar, Reuben Matalon, Guangping Gao

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.Molecular Therapy (2016); doi:10.1038/mt.2016.68.

Original languageEnglish (US)
JournalMolecular Therapy
DOIs
StateAccepted/In press - Apr 4 2016

Fingerprint

Canavan Disease
Dependovirus
Genetic Therapy
Central Nervous System
Pathology
Central Nervous System Diseases
Peripheral Nervous System
Aspartic Acid
Neurodegenerative Diseases
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

rAAV Gene Therapy in a Canavan’s Disease Mouse Model Reveals Immune Impairments and an Extended Pathology Beyond the Central Nervous System. / 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; Gao, Guangping.

In: Molecular Therapy, 04.04.2016.

Research output: Contribution to journalArticle

Ahmed, SS, Schattgen, SA, Frakes, AE, Sikoglu, EM, Su, Q, Li, J, Hampton, TG, Denninger, AR, Kirschner, DA, Kaspar, B, Matalon, R & Gao, G 2016, 'rAAV Gene Therapy in a Canavan’s Disease Mouse Model Reveals Immune Impairments and an Extended Pathology Beyond the Central Nervous System', Molecular Therapy. https://doi.org/10.1038/mt.2016.68
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 ; Gao, Guangping. / rAAV Gene Therapy in a Canavan’s Disease Mouse Model Reveals Immune Impairments and an Extended Pathology Beyond the Central Nervous System. In: Molecular Therapy. 2016.
@article{14e3f997a1cc4a1e91da5ba94cd5979b,
title = "rAAV Gene Therapy in a Canavan’s Disease Mouse Model Reveals Immune Impairments and an Extended Pathology Beyond the Central Nervous System",
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.Molecular Therapy (2016); doi:10.1038/mt.2016.68.",
author = "Ahmed, {Seemin Seher} and Schattgen, {Stefan A.} and Frakes, {Ashley E.} and Sikoglu, {Elif M.} and Qin Su and Jia Li and Hampton, {Thomas G.} and Denninger, {Andrew R.} and Kirschner, {Daniel A.} and Brian Kaspar and Reuben Matalon and Guangping Gao",
year = "2016",
month = "4",
day = "4",
doi = "10.1038/mt.2016.68",
language = "English (US)",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - rAAV Gene Therapy in a Canavan’s Disease Mouse Model Reveals Immune Impairments and an Extended Pathology Beyond the Central Nervous System

AU - Ahmed, Seemin Seher

AU - Schattgen, Stefan A.

AU - Frakes, Ashley E.

AU - Sikoglu, Elif M.

AU - Su, Qin

AU - Li, Jia

AU - Hampton, Thomas G.

AU - Denninger, Andrew R.

AU - Kirschner, Daniel A.

AU - Kaspar, Brian

AU - Matalon, Reuben

AU - Gao, Guangping

PY - 2016/4/4

Y1 - 2016/4/4

N2 - 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.Molecular Therapy (2016); doi:10.1038/mt.2016.68.

AB - 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.Molecular Therapy (2016); doi:10.1038/mt.2016.68.

UR - http://www.scopus.com/inward/record.url?scp=84965069984&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84965069984&partnerID=8YFLogxK

U2 - 10.1038/mt.2016.68

DO - 10.1038/mt.2016.68

M3 - Article

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

ER -