369. AAV9 Mediated Correction of Iduronate-2-Sulfatase Deficiency in the Central Nervous System of Mucopolysaccharidosis Type II Mice

Abstract

Mucopolysaccharidosis type II (MPS II; Hunter Syndrome) is an X-linked inherited lysosomal storage disease caused by deficiency of iduronate-2-sulfatase (IDS) and subsequent accumulation of glycosaminoglycans (GAGs) dermatan and heparan sulphate. Affected individuals exhibit a range in severity of manifestations such as organomegaly, skeletal dysplasias, cardiopulmonary obstruction, neurocognitive deficit, and shortened life expectancy. There is no cure for MPS II at the moment. Current standard of care is enzyme therapy (ELAPSRASE; idursulfase), which is used to manage disease progression. As hematopoetic stem cell transplantation (HSCT) has not shown neurologic benefit for MPS II, there is currently no clinical recourse for patients exhibiting neurologic manifestations of this disease, and new therapies are desperately needed.We have been developing the use of AAV9 vectors for delivery of the human IDS gene into the central nervous system of MPS II mice to restore IDS levels in the brain and prevent the emergence of neurocognitive deficits in the treated animals. A series of CBA-regulated vectors were generated that encode human IDS with or without the human sulfatase modifying factor-1 (SUMF-1), required for activation of the sulfatase active site. Intrathecal (IT) administration of these vectors into IDS positive mice (NOD.SCID and C57BL/6) did not result in a significant increase in IDS levels in the brains or in the organs of treated mice when compared to untreated animals. However, plasma showed higher enzyme levels in the intrathecally treated C57BL/6 mice than in untreated animals that persisted for at least 6 weeks post injection. There was no evidence for diminished activity that would be associated with immune response against human IDS protein. In contrast to the IT administered mice, MPS II mice administered AAV9-IDS vector intracerebroventricularly exhibited two- to four-fold higher levels of IDS enzyme activity in all portions of the brain in comparison with untreated, unaffected littermates. The ICV treated animals also showed lower levels of tissue GAG in the brain than untreated MPS II animals and similar levels as their wild-type littermates. IDS activity in the plasma of ICV treated mice was also significantly higher than that of wild type mice with no sign of immune response at least 6 weeks post administration. These results show the potential therapeutic benefit of AAV9-mediated IDS gene delivery to the CNS through the cerebrospinal fluid to address neurological manifestations of MPS II, Hunter syndrome.