It is proposed to investigate the use of somatic cell gene therapy for the correction of genetic diseases using domestic animals as test systems. A large number of models of human genetic disease have been discovered in domestic animals and characterized in detail at the Univ. of Pennsylvania School of Veterinary Medicine. Among these diseases are the mucopolysaccaridoses (MPS) which are recessive and result from defects in single genes encoding enzymes involved in the degradation of glycosaminoglycans (GAGs). Breeding colonies of MPS cats and dogs have been established. Thus, diseased animals are immediately available as test subjects. MPS cells can endocytose exogenous normal enzyme and degrade GAGs. Therefore, the experimental strategy will be to construct retrovirus vectors containing cDNA copies of normal genes, introduce the vectors by infection into bone marrow cells, and autologously transplant the cells to repopulate the donor/patient with cells producing normal enzyme. The sponsors, Drs. D. Patterson and M. Haskins, are members of the University-wide NIH Human Genetics Center and have extensive interactions with scientists working on genetic diseases in man. However, there is no one at the Veterinary School who has the expertise in molecular genetics who can concentrate on constructing and testing the vectors that are needed to perform the proposed experiments. Therefore, it is proposed that the candidate, Dr. John Wolfe, receive the necessary further training in molecular genetics to enable him to conduct these experiments. Therefore, it is proposed that the candidate, Dr. John Wolfe, receive the necessary further training in molecular genetics to enable him to conduct these experiments. He is a graduate of the NIH Veterinary Medical Scientist Training Program where he received training in immunogenetics, retrovirology and protein chemistry and is now an Exxon Fellow in Molecular Genetics at Sloan-Kettering Institute. Thus, he has training in most of the techniques needed to do the proposed experiments. A leading researcher on retroviral vectors, Dr. E. Gilboa of Princeton Univ., has agreed to collaborate with him on the construction and evaluation of the vectors. Dr. R. Schmikel of the Medical School who is the principle investigator of the Genetics Center and Dr. R. Brinster of the Veterinary School who is a leading investigator in the technology of gene transfer into embryo cells have agreed to participate in Dr. Wolfe's training. It is anticipated that the proposed training in recombinant DNA technology will enable him to establish a laboratory at the Veterinary School that will concentrate on the molecular aspects of genetic diseases and gene therapy using the domestic animal models at test systems.
