Induced Pluripotent Stem Cells for the Development of Novel Drug Therapies for Hepatic and Neurological Morquio Disease

The mucopolysaccharidoses are a group of inherited lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain carbohydrates and fats. In individuals with MPS disorders, deficiency or malfunction of specific lysosomal enzymes lead to an abnormal accumulation of certain complex carbohydrates (mucopolysaccharides or glycosaminoglycans) in the arteries, skeleton, eyes, joints, ears, skin and/or teeth. These accumulations may also be found in the respiratory system, liver, spleen, central nervous system, blood, and bone marrow. This accumulation eventually causes progressive damage to cells, tissues, and various organ systems of the body. There are several different types and subtypes of mucopolysaccharidosis. These disorders, with one exception, are inherited as autosomal recessive traits and all vary in their clinical phenotype. Within our clinical trial we focus on MPS type IV.

Morquio syndrome (mucopolysaccharidosis type IV; MPS IV) is a mucopolysaccharide storage disease that exists in two forms (Morquio syndromes A and B) and occurs because of a deficiency of the enzymes N-acetyl-galactosamine-6-sulfatase and beta-galactosidase, respectively. A deficiency of either enzyme leads to the accumulation of mucopolysaccharides in the body, abnormal skeletal development, and additional symptoms. In most cases, individuals with Morquio syndrome have normal intelligence. The clinical features of MPS IV-B are less severe than those associated with MPS IV-A. Symptoms may include growth retardation, a prominent lower face, an abnormally short neck, knees that are abnormally close together (knock knees or genu valgum), flat feet, abnormal sideways and front-to-back or side-to-side curvature of the spine (kyphoscoliosis), abnormal development of the growing ends of the long bones (epiphyses) resulting in dwarfism, and/or a prominent breast bone (pectus carinatum) as well as bell shaped chest. Though the CNS and peripheral nerves are primarily not affected the bone defects may result in neurological symptoms such as spinal cord compression. Hearing loss, weakness of the legs, and/or additional abnormalities may also occur.

The goal of the study is to prepare a cell culture from patients affected with Morquio disease in order to identify novel pathways and proteins involved in disease progression that allow for an earlier diagnosis (i.e. before symptom onset) and that are suitable targets for an individualized therapeutic approach able to address not only the hepatic form, but also the neurologic form of the disease, which is less responsive to the current therapeutic approaches.