Premium
Gene therapy of the brain in the dog model of Hurler's syndrome
Author(s) -
Ciron Carine,
Desmaris Nathalie,
Colle MarieAnne,
Raoul Sylvie,
Joussemet Béatrice,
Vérot Lucie,
Ausseil Jérôme,
Froissart Roseline,
Roux Françoise,
Chérel Yan,
Ferry Nicolas,
Lajat Yaouen,
Schwartz Bertrand,
Vanier MarieThérèse,
Maire Irène,
Tardieu Marc,
Moullier Philippe,
Heard JeanMichel
Publication year - 2006
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.20870
Subject(s) - hurler syndrome , mucopolysaccharidosis type i , mucopolysaccharidosis i , medicine , genetic enhancement , immunosuppression , immunology , microglia , neuropathology , venezuelan equine encephalitis virus , immune system , enzyme replacement therapy , encephalitis , pathology , virus , biology , gene , disease , biochemistry , inflammation
Abstract Objective A defect of the lysosomal enzyme α‐ L ‐iduronidase (IDUA) interrupts the degradation of glycosaminoglycans in mucopolysaccharidosis type I, causing severe neurological manifestations in children with Hurler's syndrome. Delivery of the missing enzyme through stereotactic injection of adeno‐associated virus vectors coding for IDUA prevents neuropathology in affected mice. We examined the efficacy and the safety of this approach in enzyme‐deficient dogs. Methods Because deficient dogs raise antibodies against IDUA in response to infusion, intracerebral vector injections were combined with an immunosuppressive regimen. Results Treatment was tolerated well. We observed broad dispersion of vector genomes in the brain of efficiently immunosuppressed dogs. The delivery of IDUA to large areas, which could encompass the entire brain, prevented glycosaminoglycan and secondary ganglioside accumulations. This condition was associated with drastic reduction of neuropathology throughout the encephalon. In contrast, vector injection combined with partial immunosuppression was associated with subacute encephalitis, production of antibodies against IDUA in brain tissues, and elimination of genetically modified cells. Interpretation Gene therapy directed to the entire brain is feasible and may be beneficial to children with Hurler's syndrome. The possibility of subacute encephalitis emphasizes the importance of preventing immune response against IDUA, a problem that needs to be considered in similar therapies for other genetic defects. Ann Neurol 2006;