Methods to treat mucopolysaccharidosis type II or deficiency in iduronate-2-sulfatase using a recombinant adeno-associated virus (AAV) vector encoding iduronate-2-sulfatase

Inventors

McIvor, R. Scott • Belur, Lalitha R. • Low, Walter • Fairbanks, Carolyn • Kozarsky, Karen

Assignees

Regenxbio Rs LLC • University of Minnesota System

Abstract

A method to prevent, inhibit or treat one or more symptoms associated with a disease of the central nervous system by intrathecally, intracerebroventricularly or endovascularly administering a rAAV encoding a gene product associated with the disease, e.g., a mammal in which the gene product is absent or present at a reduced level relative to a mammal without the disease.

Core Innovation

The invention relates to methods for preventing, inhibiting, or treating mucopolysaccharidosis type II (MPSII) symptoms in a mammal by administering a recombinant adeno-associated virus (rAAV) vector to the central nervous system. The disclosed approach addresses mucopolysaccharidosis type II (MPSII) and iduronate-2-sulfatase deficiency, and uses a composition comprising an rAAV vector including an open reading frame encoding iduronate-2-sulfatase to provide therapeutic enzyme expression within the CNS.

A key feature of the disclosed method is direct CNS administration, including intrathecal administration, intracerebroventricular administration, endovascular administration, and cisterna magna administration. The disclosed rationale is that the blood-brain barrier (BBB) limits enzyme therapy, and that direct CNS AAV transduction enables therapeutic enzyme expression to treat CNS symptoms.

The disclosed vectors include rAAV9 and rAAVrh10 comprising an open reading frame encoding iduronate-2-sulfatase. The document further includes use of immunosuppression and immunotolerization, including immunotolerization to iduronate-2-sulfatase, and reports functional outcomes such as restored enzyme activity and reduced glycosaminoglycans (GAG) in preclinical mouse examples.

Claims Coverage

The document includes multiple independent claims covering treatment of mucopolysaccharidosis type II (MPSII) symptoms and symptoms associated with an iduronate-2-sulfatase deficiency using cisterna magna administration of rAAV9 or rAAVrh10 vectors encoding iduronate-2-sulfatase, optionally combining the rAAV vector with immunosuppression or immunotolerization. Across the independent claims, the inventive subject matter centers on cisterna magna CNS delivery and immune modulation.

Across the independent claims, the coverage centers on cisterna magna administration of rAAV9 or rAAVrh10 vectors encoding iduronate-2-sulfatase for treating MPSII symptoms, including neurological symptoms, and symptoms associated with iduronate-2-sulfatase deficiency, optionally in combination with immunosuppression or an immunotolerized condition to iduronate-2-sulfatase.

Stated Advantages

Documented Applications