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Comparison of Endovascular and Intraventricular Gene Therapy With Adeno-Associated Virus-L-Iduronidase for Hurler Disease

Janson, Christopher G. MD*,‡,§; Romanova, Liudmila G. PhD; Leone, Paola PhD§; Nan, Zhenhong PhD*; Belur, Lalitha PhD; McIvor, R. Scott PhD; Low, Walter C. PhD*

doi: 10.1227/NEU.0000000000000157
Research-Animal:Editor' Choice
Editor's Choice

BACKGROUND: Hurler disease (mucopolysaccharidosis type I [MPS-I]) is an inherited metabolic disorder characterized by deficiency of the lysosomal enzyme α-L-iduronidase (IDUA). Currently, the only therapies for MPS-I, enzyme replacement and hematopoietic stem cell transplantation, are generally ineffective for central nervous system manifestations.

OBJECTIVE: To test whether brain-targeted gene therapy with recombinant adeno-associated virus (rAAV5)-IDUA vectors in an MPS-I transgenic mouse model would reverse the pathological hallmarks.

METHODS: Gene therapy approaches were compared using intraventricular or endovascular delivery with a marker (rAAV5-green fluorescent protein) or therapeutic (rAAV5-IDUA) vector. To improve the efficiency of brain delivery, we tested different applications of hyperosmolar mannitol to disrupt the blood-brain barrier or ependymal-brain interface.

RESULTS: Intraventricular delivery of 1 × 1011 viral particles of rAAV5-IDUA with systemic 5 g/kg mannitol co-administration resulted in IDUA expression throughout the brain, with global enzyme activity >200% of the baseline level in age-matched, wild-type mice. Endovascular delivery of 1 × 1012 viral particles of rAAV5-IDUA to the carotid artery with 29.1% mannitol blood-brain barrier disruption resulted in mainly ipsilateral brain IDUA expression and ipsilateral brain enzyme activity 42% of that in wild-type mice. Quantitative assays for glycosaminoglycans showed a significant decrease in both hemispheres after intraventricular delivery and in the ipsilateral hemisphere after endovascular delivery compared with untreated MPS-I mice. Immunohistochemistry for ganglioside GM3, another disease marker, showed reversal of neuronal inclusions in areas with IDUA co-expression in both delivery methods.

CONCLUSION: Physiologically relevant biochemical correction is possible with neurosurgical or endovascular gene therapy approaches for MPS-I. Intraventricular or endovascular delivery of rAAV5-IDUA was effective in reversing brain pathology, but in the latter method, effects were limited to the ipsilateral hemisphere.

ABBREVIATIONS: ECA, external carotid artery

GAG, glycosaminoglycans

GFP, green fluorescent protein

g.p., genomic particles

IA, intra-arterial

ICA, internal carotid artery

ICV, intracerebral ventricular

IDUA, α-L-iduronidase

MPS-I, mucopolysaccharidosis type I

rAAV, recombinant adeno-associated virus

scAAV, self-complimentary adeno-associated virus

*Department of Neurosurgery,

Department of Neurology,

Department of Medicine, and

Genetics and Cell Biology, University of Minnesota, School of Medicine

§Cell & Gene Therapy Center, University of Medicine and Dentistry of New Jersey School of Medicine

Correspondence: Christopher G. Janson, MD, 500 Harvard St, Minneapolis, MN 55455. E-mail:

Received February 03, 2013

Accepted September 03, 2013

Copyright © by the Congress of Neurological Surgeons