Mucopolysaccharidosis (MPS) type VII, or Sly syndrome, is a lysosomal storage disease that develops when there is insufficient beta-glucuronidase (GUS) to aid in the breakdown of glycosaminoglycans. These undegraded glycosaminoglycans (or mucopolysaccharides) accumulate in lysosomes, where they would normally be degraded, to form storage granules that distort cells and eventually compromise their function. This genetic disease causes a variety of chronic and progressive disorders including mental retardation, abnormal bone development, organ malfunctions and premature death. Although Sly syndrome is very rare, it has served as a model for the study of lysosomal storage diseases in general. These studies have been greatly aided by animal models that closely mimic the human disease. Gene therapy, by which the ability to make the missing enzyme is restored, is the most promising type of treatment on the horizon for this and many other inherited metabolic diseases. One method to deliver viable genes to cells of an affected individual is to use recombinant viral vectors. Very encouraging preliminary results using an adeno-associated virus (AAV) vector to treat MPS VII in mice suggest that this mode of gene therapy is worth exploring. While the immediate focus of this proposal is to maximize the therapeutic potential of AAV vectors in treating MPS VII disease, the broader goal is to improve the tools, techniques and understanding of the gene therapy process in general. To do this four Specific Aims are proposed: (1) Develop protocols that successfully treat the brain, which has been a particularly difficult target organ for gene therapy. Already promising results employing intrathecal administration of AAV vector are being pursued. Experimentally, the elimination of storage granules in the brain and the restoration of normal learning ability will be monitored. (2) Increase the expression level of therapeutic protein by the vector. New vectors will be constructed using alternative promoters to drive the expression of the GUS cDNA. These new vectors will be tested in mice that have inherited MPS VII disease. (3) Make new vectors that express altered, more effective, therapeutic protein. Since AAV vectors do not transduce every cell within an organism, altered secretion signal sequences will be used to help distribute GUS from high- producing, transduced cells to non-producing cells. (4) Combine targeted treatments to effect a complete cure. Treatment with different AAV vectors and different modes of administration will be combined to maximize the benefit to the whole organism.
| Watson, G; Bastacky, J; Belichenko, P et al. (2006) Intrathecal administration of AAV vectors for the treatment of lysosomal storage in the brains of MPS I mice. Gene Ther 13:917-25 |
