Maple Syrup Urine Disease (MSUD) is a genetic disorder of branched-chain amino acid metabolism. The incidence of MSUD in general population is 1:185,000 and in certain population groups, such as the Mennonites of Pennsylvania, the incidence is as high as 1:176. Children with MSUD suffer from profound metabolic complications that culminate in mental retardation and early death. At the present time, no satisfactory treatment for MSUD is available. Our long-term goal is to develop gene therapy for MSUD. A major impediment for progress in this area had been the lack of a suitable animal model to perform preclinical studies. Fortunately, this impediment has now been overcome. We have recently made a gene knockout murine model of MSUD, which mimics the pathology of the human disease. Now the limiting factor for gene therapy In vivo is an appropriate gene delivery system. Since MSUD is a liver-based metabolic disease, a gene delivery system specific for liver is required. Recently, adeno-associated virus (AAV) has emerged as the vector of choice to deliver genes to the liver.
The specific aims of this SBIR Phase-I projects are: (1) to make an AAV vector for gene delivery to the liver, and (2) to test this vector in tissue culture system In vitro using primary hepatocytes. The successful completion of the above studies will poise us to move into phase Il of the project, in which gene therapy for MSUD will be performed In vivo. The information and experience gained from animal studies will pave the way to subsequently perform gene therapy for MSUD in humans.
Testing of novel therapies using the MSUD knockout mouse will lead to development of new products. These include diagnostic tools and technologies, gene therapy,vectors, candidate drugs, and novel dietary formulas. The potential use of these products and technologies in a clinical setting is expected to be of significant commercial interest and application.
| Skvorak, Kristen J; Paul, Harbhajan S; Dorko, Kenneth et al. (2009) Hepatocyte transplantation improves phenotype and extends survival in a murine model of intermediate maple syrup urine disease. Mol Ther 17:1266-73 |
| Skvorak, K J (2009) Animal models of maple syrup urine disease. J Inherit Metab Dis 32:229-46 |
| Homanics, Gregg E; Skvorak, Kristen; Ferguson, Carolyn et al. (2006) Production and characterization of murine models of classic and intermediate maple syrup urine disease. BMC Med Genet 7:33 |
