Work

346. AAV9 Delivery into Cerebrospinal Fluid Corrects CNS Disease in a Murine Model of Mucopolysaccharidosis Type II

Year: 2016

Type: article

Abstract: Mucopolysaccharidosis type II (MPS II) is an X-linked lysosomal storage disorder typically manifesting in early childhood with bone and joint deformities, cardiac and respiratory disease, and developmental delay. Systemic delivery of the deficient enzyme, iduronate-2-sulfatase (IDS), improves many symptoms of MPS II, but because the enzyme does not cross the blood-brain barrier, there is currently no effective method to prevent the progression of central nervous system (CNS) disease. Using a mouse model of MPS II, we evaluated AAV serotype 9 vector-mediated delivery of the IDS gene as a means of achieving continuous IDS expression in the CNS. IDS knockout mice received a single injection into the lateral ventricle of one of three vector doses (3 × 108, 3 × 109 or 3 × 1010 genome copies) and were sacrificed either three weeks after vector administration for assessment of vector biodistribution and IDS expression (n = 7-8 mice per group), or 3 months after vector administration to evaluate the impact of gene transfer on disease progression (n = 7-8 mice per group). IDS activity was detectable in cerebrospinal fluid, reaching 15% of wild-type levels in the low-dose cohort and 268% of normal at the highest dose. Brain enzyme activity ranged from 2.7% of normal in the low-dose cohort to 32% in the high-dose cohort. Quantification of brain storage lesions by staining for the ganglioside GM3 indicated dose-dependent correction, with 35%, 46%, and 86% reductions in the low-, mid-, and high-dose cohorts, respectively. Treated mice also demonstrated improved cognitive function in a novel object recognition test. These findings indicate that intrathecal AAV-mediated gene transfer could serve as a platform for sustained enzyme delivery to the CNS, potentially addressing this critical unmet need for patients with MPS II.

Source: Molecular Therapy

DOI: 10.1016/s1525-0016(16)33155-0