This program at the University of Minnesota is focused on gene therapy for metabolic disorders causing mental retardation. Toward this goal, the program currently has one clinical gene therapy protocol before the FDA to treat Hunter syndrome (mucopolysaccharidosis type II, iduronate-2- sulfatase deficiency) and is pursuing approval of clinical-grade retrovirus vector L2SN and the scale-up methods for ex vivo lymphocyte gene therapy. The program will develop clinically applicable large-scale methods to isolate, transduce and for cryopreservation of lymphocytes and hematopoietic stem cells (HSC) from bone marrow, peripheral blood and umbilical cord blood. In addition, it plans to improve recombinant enzyme delivery, potentially across the blood-brain barrier, by studying HSC transduction to treat Hurler syndrome(a-L-iduronidase deficiency) and by developing a new adeno-associated virus (AAV) based gene delivery vehicle appropriate for non-mitotic cells. The program also aims to develop a practical approach to treat the devastating neurologic insults of acute neonatal hyperammonemia associated with ornithine transcarbamylase (OTC) deficiency, carbamyl phosphate synthetase (CPS) deficiency and by other genetic and acquired forms of liver failure. By genetically engineering E. coli to serve as an enteric ammonia trap, bacteria simultaneously expressing OCT and CPS would utilize the natural enteric dialysis system to lower high levels of ammonia. The program is complemented by multiple units offering institutional resources and support including the Institute of Human Genetics, Minnesota Center for Disabilities Research on Developmental Disabilities, the University of Minnesota, Bone Marrow Transplantation Program, the Cancer Center and the Clinical Research Center. By the end of the five year grant period, this program intends to have developed and initiated clinical trials for multiple metabolic disorders causing mental retardation, a challenging but feasible goal which is particularly fitting for the end of 'the decade of the brain.'
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