Mucopolysaccharidosis (MPS) I and VII are lysosomal storage disorders caused by deficient activity of alpha- L-iduronidase and beta-glucuronidase, respectively, which are enzymes required for the degradation of glycosaminoglycans. Current enzyme replacement therapy in patients with MPS disorders does not effectively treat the brain. It is also expensive ($300,000 a year for life) and inconvenient (weekly intravenous injections). In ongoing studies, our laboratories have investigated therapeutic regimens that can ameliorate disease in the canine models of MPS I and VII, which are naturally occurring diseases that faithfully recapitulate the human disorders. Dogs and children have central nervous system (CNS) disease, as well as corneal clouding, cardiac valve disease, aortic dilatation, and progressive gait abnormalities due to skeletal dysostosis. Although our current neonatal intravenous gamma retroviral gene therapy strategy provided constant, very high levels (to 65-fold normal) of circulating enzyme and somewhat reduced lysosomal storage in the brain at 1 year after transduction, there are concerns for insertional mutagenesis limiting clinical trials. The central feature of this grant proposal, which merges R01-funded studies in MPS VII dogs (DK54481) with those in MPS I dogs (DK66448), is to administer four viral vectors (AAV9, AAVrh10, and two lentiviral vectors) into the cerebral spinal fluid (CSF) and determine if these can reduce evidence of lysosomal storage disease in MPS dogs. These vectors have produced significant transduction in the CNS in mice, but none have been tested therapeutically via injection into the CSF in a large animal model for any of the more than 50 lysosomal storage diseases known in children. This hypothesis will be tested in dogs because such experiments will determine the scale-up feasibility and be able to evaluate the persistence of the therapeutic effect and long-term safety in a long-lived species prior to translation to human patients. The ability to target the CNS without injecting vector directly into the brain parenchyma would be a significant and important advancement for treating the 60% of lysosomal storage diseases that are neurotropic. Finally, this proposal will test the hypothesis that a combination of a neonatal intravenous and intra-CSF injection of the best of these 4 vectors will provide an effective therapy for the CNS and somatic tissue lesions. Importantly, these treatments can serve as a paradigm for the other MPS syndromes and the entire class of lysosomal storage diseases. The development of effective and safe therapy will have a dramatic and positive impact on the lives of patients and the families that care for them.

Public Health Relevance

This grant will investigate strategies to achieve widespread gene delivery to the brain using viral vectors. The strategies will be tested in two dog models of human genetic disease that are representative of a large class of human diseases, the lysosomal disorders, none of which have adequate therapies for the central nervous system.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Therapeutic Approaches to Genetic Diseases (TAG)
Program Officer
Leschek, Ellen W
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University of Pennsylvania
Schools of Veterinary Medicine
United States
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Swain, G P; Prociuk, M; Bagel, J H et al. (2014) Adeno-associated virus serotypes 9 and rh10 mediate strong neuronal transduction of the dog brain. Gene Ther 21:28-36
Cubizolle, Aurelie; Serratrice, Nicolas; Skander, Nadia et al. (2014) Corrective GUSB transfer to the canine mucopolysaccharidosis VII brain. Mol Ther 22:762-73
Serratrice, Nicolas; Cubizolle, Aurelie; Ibanes, Sandy et al. (2014) Corrective GUSB transfer to the canine mucopolysaccharidosis VII cornea using a helper-dependent canine adenovirus vector. J Control Release 181:22-31

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