Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders with defects in lysosomal function. They include approximately 46 genetic disorders that as a group have an incidence of one in 5,000-7,000 live births with 65 percent affecting the central nervous system (CNS). Mucopolysaccharidoses (MPS) disorders represent a subgroup of LSDs that consist of nearly 30 percent of all LSD patients. Each MPS disease results from a deficiency in lysosomal enzymes involved in the degradation of mucopolysaccharides, or more accurately glycosaminoglycans (GAG). In general, MPS diseases are associated with progressive systemic tissue pathology and, in severe forms, with neurological dysfunction and intellectual and other developmental disabilities. MPS type I, which is caused by the deficiency of alpha-L-iduronidase, is the most common MPS disease with variable clinical phenotypes ranging from Hurler syndrome to Scheie syndrome. The progression of disease includes visceral, cardiovascular, pulmonary, hematological and skeletal disease manifestations, as well as CNS abnormalities in severe patients. Many of these patients would die before age 10 if without treatment. MPS I is thus a model disease entity for therapeutic studies of many inherited and acquired diseases. Animal models (e.g., mouse and dog MPS I) are available to provide in vivo evaluation of potential therapeutic effects.
Early studies of Hurler syndrome (severe form of MPS I) have provided key insights into metabolic correction and cross-correction from intercellular lysosome enzyme transfer mediated by mannose-6-phosphate receptor (MPR) on cell surface in LSDs. This phenomenon of lysosomal enzyme release and reuptake among cells has provided the foundation for the development of the two main treatment options in MPS patients, namely allogeneic hematopoietic stem cell (HSC) transplantation and enzyme replacement therapy (ERT). Allogeneic bone marrow transplantation (BMT) has demonstrated a variable degree of clinical response in MPS patients, but is limited by the risk of significant mortality, high rate of engraftment failure and complications related to graft-versus-host disease. Enzyme replacement therapy, which was pioneered by Greg Grabowski at Cincinnati Children’s Hospital Medical Center, has led to clinical improvement in peripheral organs of some patients with non-neuronopathic forms of Gaucher disease, and is recently available for MPS I, II and VI. It is limited by likely poor penetration to the CNS and the need for frequent intravenous infusion for a lifetime. A therapeutic approach with the capacity to correct CNS deterioration is needed for MPS disorders with major CNS complications.
The extra challenges for neuropathic MPS treatment are presented by the fact that the progression of CNS manifestations may result in “irreversible” deficits; and that the blood-brain-barrier (BBB) is generally considered impermeable to lysosomal enzymes. We aim to study both in vivo and ex vivo stem cell gene transfer, with the hope of potentially providing a more efficient lifelong treatment of the CNS and visceral manifestations for LSD patients.