Comparison of Endovascular and Intraventricular Gene Therapy With Adeno-Associated Virus-α-L-Iduronidase for Hurler Disease.
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 × 10 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 × 10 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.


CONCLUSIONS
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.
*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.
Christopher G
CG
Janson
Liudmila G
LG
Romanova
Paola
P
Leone
Zhenhong
Z
Nan
Lalitha
L
Belur
R Scott
RS
McIvor
Walter C
WC
Low
D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007068:Iduronidase / Q000008:administration & dosage* / Q000235:genetics; D007269:Injections, Intra-Arterial; D007276:Injections, Intraventricular; D051379:Mice; D008822:Mice, Transgenic; D008059:Mucopolysaccharidosis I / Q000473:pathology*
D007068:Iduronidase