Comparison of Endovascular and Intraventricular Gene Therapy With Adeno-Associated Virus–α-L-Iduronidase for Hurler Disease. Issue 1 (30th September 2013)

• Record Type: Journal Article
• Authors: Janson, Christopher G.; Romanova, Liudmila G.; Leone, Paola; Nan, Zhenhong; Belur, Lalitha; McIvor, R. Scott; Low, Walter C.
• Is Part Of: Neurosurgery. Volume 74:Issue 1(2014)
• Page Start: 99
• Page End: 111
• Publication Date: 2013-09-30
• Subjects: AAV -- Blood-brain barrier -- Gene therapy -- Hurler disease -- Mannitol -- Mucopolysaccharidosis; Nervous system -- Surgery -- Periodicals; 617.48005
• DOI: 10.1227/NEU.0000000000000157
• Languages: English
• ISSNs: 0148-396X

Abstract

Abstract: 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 11 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 12 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.