Research Home

Medical College of Georgia – Augusta, GA, Dr. Robert K. Yu

Mucopolysaccharidoses (MPS) are a group of inheritable genetic disorders. Owing to the defective degradation of naturally occurring substances, collectively called glycosaminoglycans (GAGs), these materials will accumulate in tissues causing disturbances in the normal physical and mental development of the body. The disease proceeds with severe neurological symptoms initiated in early childhood.

Among the various forms, MPS III (Sanfilippo Syndrome) is caused by deficiency in one of four degradative enzymes, leading to an accumulation of GAGs, such as heparan sulfate, to give rise to four different variants of the disease (A, B, C, and D). The accumulation of heparan sulfate is frequently accompanied by the accretion of gangliosides. These substances are important constituents of the nervous system and are known to play a crucial rose in normal brain development and function. The accumulation of abnormal amounts of these substances is known to contribute to the disease process. Recent studies from our laboratory have shown that the accumulation of ganglioside in Sanfilippo Syndrome is very likely the result of an impairment of enzymes involved in ganglioside metabolism as a result of the accumulation of heparan sulfate.

In recent years, enzyme replacement, bone marrow transplantation, and gene therapy have been proposed as therapeutic strategies for MPS and related lysosomal storage disorders. However, there are difficulties associated with these strategies for correcting the genetic defects in the brain because the brain is a well-protected organ. Most of the strategies mentioned above cannot be easily applied to the brain.

Since in a variety of gangliosidoes, the stored gangliosides are known to contribute to the development of mental retardation, it has been suggested that a reduction of the ganglioside content by enzyme replacement therapy, gene therapy, or metabolic control, may alleviate the mental symptoms of the disease. We already have tested the strategy of inhibiting ganglioside production under conditions of low toxicity to cells. This approach will be attempted in an animal model of Sanfilippo Syndrome established by Dr. Elizabeth Neufeld at UCLA. Several drugs that are active as inhibitors of ganglioside production are commercially available and will be orally or intravenously administered to the mouse. The efficacy of this therapeutic approach will be monitored by analysis of the ganglioside content in the nervous system, structural examination of the affected tissue, and behavioral testing of the treated mice.

In addition, the Sanfilippo mouse model also will be used for experimental analysis of two novel approaches for the treatment of the disease. In the first approach, cell replacement therapy, we will investigate the possibility of grafting normal glial cells (essential elements of nervous tissue) into the brain of Sanfilippo mice. We hope the grafted normal glial cells can correct the metabolic defects in abnormal nerve cells in these mice. This strategy has been successfully applied to the treatment of a number of neurodegenerative diseases, such as Multiple Sclerosis and Parkinson’s Disease. After we have tested the efficacy of this strategy in animals, we will test the possibility of using cell replacement therapy for the treatment of Sanfilippo Syndrome.

Another approach using the Sanfilippo mouse model is direct inhibition of enzymes involved in GAG production. Inhibitors of GAG production have been described in studies with cultivated cells. However, nothing is known about the potency of these inhibitors in animal models. We will initiate a detailed investigation using specific inhibitors of GAG production as well as other potential drugs for the effective treatment of Sanfilippo Syndrome.

In summary, we plan to employ the Sanfilippo mouse model for the development of a treatment strategy using three different approaches: 1. inhibition of ganglioside biosynthesis by application of commercially available enzyme inhibitors; 2. cell replacement therapy by transplantation of normal brain cells, and 3. inhibition of GAG biosynthesis by application of existing or chemically modified drugs.

It is anticipated that following the animal studies, we will proceed with clinical trails for patients with Sanfilippo Syndrome. The development of rational and effective therapeutic approaches should be of great interest to patients who are suffering from this debilitating disorder. Additionally, these strategies should prove applicable to other similar neurodegenerative diseases which affect many more children.

During the past year, we have completed a detailed study of the ganglioside compositional analysis of goat brain with Sanfilippo disease (MPS IIID). In addition, we also have finished a study to characterize the ganglioside composition of a mouse stem cell line, with the goal of using stem cells as a potential source for cell therapy. In addition to the testing of a drug therapy, which is on-going, we plan to develop this as an effective strategy for cell therapy, which promises to be more permanent. We also have established in our laboratory a Sanfilippo mouse colony provided by Dr. Elizabeth Neufeld, UCLA. These animals will be used for testing our proposed treatment plans using drugs and cell transplantation.