Mucopolysaccharidosis type I (MPS I) is an autosomal recessive storage disease caused by absence of a-L- iduronidase (IDUA), resulting in systemic accumulation of glycosaminoglycan storage materials, hepatosplenomegaly, skeletal dysplasias, cardiopulmonary obstruction, progressive neurologic impairment and death by age 15. MPS I is currently treated by enzyme replacement therapy (ERT) and by allogeneic hematopoietic stem cell transplantation (HSCT), but the neurologic effectiveness of these treatments is limited by the amount IDUA enzyme provided to the brain. In this proposal, we present preliminary data demonstrating extraordinarily high levels of IDUA enzyme expression (2- to 40-fold normal) in all areas ofthe brain 10 months after intracerebroventricular infusion of neonatal (4-6 day old) MPS I mice with an AAV8 vector transducing the human IDUA gene, completely preventing neurocognitive deficits exhibited by untreated animals in a Morris water maze test of spatial navigation and memory. These unprecedented results demonstrate that AAV-mediated IDUA gene transfer directly to the CNS has the potential to overcome the current limitations of ERT and HSCT in the treatment of MPS I. However, there are several challenges that must be faced in the development of this approach for treatment of MPS I in humans: (1) We will evaluate the effectiveness of intrathecal, intranasal, and endovascular (with blood brain barrier disruption) routes of AAV vector infusion to identify a less invasive means of administration for human IDUA gene delivery and expression in the CNS. (ii) We will evaluate /VW-mediated IDUA gene transfer to the CNS in iduronidase-deficient dogs as a large animal model of MPS I. We will also pilot a new neurocognitive testing regimen in these animals to evaluate the effectiveness of vector treatment in preventing neurologic decline in the animals, (iii) We will compare the effectiveness of several different AAV serotypes for gene transfer efficiency in human neuronal primary cultures and brain tissue slices. Results from these studies will directly impact the development of AAV-mediated IDUA gene transfer as an approach for improved therapy of MPS I, with implications for application of AAV mediated gene transfer for related neurologic diseases.
Lysosomal storage disorders are a rare group of inherited diseases in which patients suffer from skeletal abnormalities, heart and breathing problems, mental retardation and death. It is envisioned in this grant application that one way to treat these diseases would be to restore the missing gene in patients'central nervous system (in the brain) to prevent neurodegeneration.
|Ou, Li; Przybilla, Michael J; Whitley, Chester B (2017) Proteomic analysis of mucopolysaccharidosis I mouse brain with two-dimensional polyacrylamide gel electrophoresis. Mol Genet Metab 120:101-110|
|Ou, Li; Przybilla, Michael J; Koniar, Brenda L et al. (2016) Elements of lentiviral vector design toward gene therapy for treating mucopolysaccharidosis I. Mol Genet Metab Rep 8:87-93|
|Aronovich, Elena L; Hackett, Perry B (2015) Lysosomal storage disease: gene therapy on both sides of the blood-brain barrier. Mol Genet Metab 114:83-93|
|Satzer, David; DiBartolomeo, Christina; Ritchie, Michael M et al. (2015) Assessment of dysmyelination with RAFFn MRI: application to murine MPS I. PLoS One 10:e0116788|
|Wolf, Daniel A; Banerjee, Sharbani; Hackett, Perry B et al. (2015) Gene therapy for neurologic manifestations of mucopolysaccharidoses. Expert Opin Drug Deliv 12:283-96|
|Hackett, Perry; Carroll, Dana (2015) Regulatory hurdles for agriculture GMOs. Science 347:1324|
|Ou, Li; Herzog, Tyler L; Wilmot, Carrie M et al. (2014) Standardization of ?-L-iduronidase enzyme assay with Michaelis-Menten kinetics. Mol Genet Metab 111:113-5|
|Carpentier, Claire E; Schreifels, Jeffrey M; Aronovich, Elena L et al. (2014) NMR structural analysis of Sleeping Beauty transposase binding to DNA. Protein Sci 23:23-33|
|Hackett, Perry B; Aronovich, Elena L (2014) Rational design for enhanced gene therapy with DNA transposons. Mol Ther 22:1575-7|
|Janson, Christopher G; Romanova, Liudmila G; Leone, Paola et al. (2014) Comparison of Endovascular and Intraventricular Gene Therapy With Adeno-Associated Virus-?-L-Iduronidase for Hurler Disease. Neurosurgery 74:99-111|
Showing the most recent 10 out of 84 publications