Molecular therapy for mucopolysaccharidosis Type I

Abstract

Mucopolysaccharidosis type I (MPS I) is caused by deficiency of the lysosomal hydrolase alpha-L-iduronidase (IDUA). IDUA is a required component of the step-wise degradative pathway responsible for the catabolism of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate. As a result, these GAGs accumulate within lysosomes causing the development of multisystemic disease. Patients with MPS I present with clinical manifestations of disease within the first two years of life including corneal clouding, hepatoslenomegaly, skeletal dysplasias, cardiopulmonary disease, and obstructive airway disease. Additionally, patients with severe MPS I, also known as Hurler syndrome, develop hydrocephalus and severe neurocognitive decline. The current standard of care for Hurler patients included intravenous administration of recombinant enzyme upon diagnosis followed by hematopoeitic stem cell transplantation (HSCT) once a proper donor cell source is identified. Following HSCT, many patients exhibit a reduced rate of neurological deterioration. However, the potential of HSCT to ameliorate central nervous system manifestations of disease is limited by the inability of IDUA to efficiently cross the blood brain barrier. The results of my experiments demonstrate that GAG storage materials were partially reduced in the brains of MPS I mice following bone marrow transplantation with wild-type donor marrow (Chapter 2). However, pathogenic accumulation of GM3 ganglioside, not normally expressed in the brain, remained present in treated animals. This highlights the necessity to achieve more efficient delivery of IDUA to the central nervous system in order to normalize brain biochemistry. Thus, I propose the application of intracerebroventricular (ICV) infusion of adeno-associated viral vectors in order to mediate gene transfer and expression of IDUA in the brain. Infusion of an AAV serotype 8 vector into neonatal MPS I mice resulted in widespread long-term expression of high levels of IDUA throughout the brain consistent with normalization of GAG storage material and complete prevention of a neurocognitive deficit in a Morris water maze test (Chapter 3). Infusion of the same vector into adult MPS I animals resulted in low levels of IDUA expression and partial reduction of storage material in the brain consistent with partial improvement in the Morris water maze test (Chapter 4). The results of these experiments support the adoption of ICV infusion of AAV vectors as a supplement to enzyme replacement therapy and HSCT for the treatment of Hurler syndrome.