Lentiviral gene therapy for mucopolysaccharidosis

DESCRIPTION (provided by applicant): Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-linked recessive inherited disorder caused by absence of iduronate-2-sulfatase, resulting in systemic accumulation of glycosaminoglycans heparan sulphate and dermatan sulphate. Affected individuals suffer from skeletal abnormalities, organomegaly, life- threatening obstructive airway disease, and, in the severely enzyme deficient form, neurologic degeneration and death by age 15. While transplantation and engraftment of hematopoietic stem cells has shown efficacy in the treatment of some MPS diseases, allografted MPSII patients have thus far not exhibited improved neurologic outcomes. In this project, we hypothesize that allotransplant for MPSII is ineffective due to insufficient generation of IDS enzyme from engrafted cells, and that genetic engineering of donor cells to express high levels of IDS will overcome this insufficiency and provide effective metabolic cross- correction that includes neurologic manifestations of the disease. Lentigen is a leading company in the development of lentiviral vectors for treatment of human disease. In this Phase I STTR project, we propose to combine Lentigen's lentiviral vector technology with the University of Minnesota's experience in cellular therapies for lysosomal storage diseases by developing an ex vivo transduction approach for the treatment of Hunter syndrome, MPS II. The Specific Aims of the proposal are: (i) To construct and test lentiviral vectors for transduction of the human IDS gene along with green fluorescent protein as a cellular marker. Vector constructs will be generated based on dual promoter, bicistronic and fusion protein strategies, and packaged using Lentigen's proprietary LentiMax platform. (ii) Correction of metabolic and neurologic disease by ex vivo lentiviral transduction of the human IDS gene into hematopoietic stem cells of MSPII mice. Marrow from IDS deficient mice will be transduced with lentiviral vector carrying the IDS gene and transplanted into IDS deficient recipients as a model for ex vivo gene therapy of Hunter syndrome targeting hematopoietic stem cells. Treated animals will be tested for engraftment and transduction of donor cells, IDS enzyme expression in plasma and tissues, clearing of storage materials in urine and in tissues, and improved performance in neurobehavioral tests of learning and motor function. The overall goal of the proposed studies is to provide preclinical data to support the most straightforward and feasible approach for implementation of gene therapy for MPS II, with implications for the development of lentiviral gene therapies for other lysosomal storage diseases in the future.