Gene therapy of the brain in the dog model of Hurler's syndrome

Institut National de la Sante et de la Recherche Médicale U649, CHU Hôtel Dieu, Nantes, France.
Annals of Neurology (Impact Factor: 11.91). 08/2006; 60(2):204-13. DOI: 10.1002/ana.20870
Source: PubMed

ABSTRACT A defect of the lysosomal enzyme alpha-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.
Because deficient dogs raise antibodies against IDUA in response to infusion, intracerebral vector injections were combined with an immunosuppressive regimen.
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.
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.

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    • "This could provide sustained therapy if a sufficient level of enzyme was secreted in the brain. We and others have demonstrated the potential of different vectors in correcting neuronal pathologies in MPS II (Cardone et al., 2006), MPS IIIA and B (Cressant et al., 2004; Langford- Smith et al., 2012), and MPS VII mice (Bosch et al., 2000a,b; Liu et al., 2007) as well as in larger animal models for the disease (Ciron et al., 2006; Ellinwood et al., 2011). However, clinically relevant gene therapy using common human pathogens as vectors may be complicated by the high incidence of preexisting humoral and cellular immunity (Chirmule et al., 1999; Perreau et al., 2007a). "
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    Human gene therapy 12/2013; 25(3). DOI:10.1089/hum.2013.152 · 3.62 Impact Factor
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    • "Transgene expression in the pig brain can be induced using rAAV vectors This is the first study to explore transgene expression after injection of viral vectors into the pig brain, and here we present proof of principle that, using the same technique as used in rodents, an efficient and widespread gene transduction can be achieved in a larger brain. Three other non-rodent species (cat, dog, and monkey) have been evaluated for rAAV vector transduction in the brain (Kirik et al., 2003; Vite et al., 2003; Ciron et al., 2006, 2009; Dodiya et al., 2009), and it is evident from these studies that each rAAV serotype displays different species-specific transduction efficiency and pattern. Based on the above data, however, direct comparison between species is not possible, since different brain regions, transgenes, or promoters have been used in the various studies. "
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    • "The vector genome was widely distributed in the brain of immunosuppressed dogs and prevented glycosaminoglycan and secondary ganglioside accumulations. However, in dogs with only partial immunosuppression, vector injection was associated with subacute encephalitis (Ciron et al. 2006). An alternative approach to somatic gene therapy is to deliver a therapeutic protein by implanting " universal " recombinant cells in alginate microcapsules that provide immunological protection from graft rejection. "
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