The goal of this project is to develop and characterize a murine model of Maple Syrup Urine Disease (MSUD), 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, and there is an urgent need to develop new treatments. Unfortunately, progress in this area has been hampered by the lack of a suitable animal model to perform preclinical studies. Therefore, the goal is to produce a murine model of MSUD that accurately mimics the pathophysiology of the human disease. The approach to developing such a model is to utilize the gene targeting technique in mouse embryonic stem (ES) cells. The Specific Aims of the Phase I project were to make and introduce a targeting construct into ES cells and screen and characterize the correctly targeted ES cells. The PI has now completed Phase I and now has several correctly targeted heterozygous ES cell clones. With the availability of these clones, the PI is now ready to move into Phase II of this project. The Specific Aims of Phase II are: (1) injection of correctly targeted ES cells into recipient blastocysts; (2) surgical transfer of blastocysts into the uterus of pseudopregnant female mice; (3) breeding chimeric offspring to establish heterozygous and homozygous mouse lines; and (4) characterization of both the homozygous and heterozygous animal model. The availability of a well characterized model will provide a new resource and opportunities to test novel therapies for MSUD.PROPOSED COMMERCIAL APPLICATION: The most significant opportunity presented by the proposed animal model of MSUD is to develop candidate drugs and test novel therapies. Animal testing would subsequently lead to development of commercial products of clinical interest and application. Some of the potential areas of commercial application are described below: 1. Gene Therapy; 2. Design and Development of Vectors; 3. Prenatal Diagnosis and Detection of Carriers; 4. Dietary Formulas. The combined potential of using the proposed murine model of MSUD for the above outlined areas will be of significant commercial interest and application.
Thesaurus Terms:disease model, inborn branched chain aminoaciduria, laboratory mouse, method development, model design /development embryonic stem cell animal breeding, gene targeting, transgenic animalNAT INST OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
