It is now possible to isolate genes and understand disease mechanisms in terms of the underlying molecular derangements. This knowledge is essential to develop and test protein, somatic cell gene, and stem cell therapies for human genetic diseases. The full scope of understanding the pathogenesis of these disorders and testing therapy cannot be realized without authentic (gene-homologous, orthologous) animal models for the studies that are not possible for ethical and practical reasons in human patients. Gene knockout technology in mice has provided a valuable source, but additional models are needed for studies requiring long-lived animals of larger size and diverse genetic background to be able to monitor efficacy and safety long-term. A reservoir of such diseases is present in existing dog and cat breeds that are relatively inbred but that retain genetic heterogeneity similar to that present in the Old Order Amish and Ashkenazi Jewish populations. The objective of this grant is to continue to serve as a National and International Referral Center to identify, characterize, verify, preserve, and make available for research new and existing large animal models of human genetic disease. These models involve defects in homologous gene loci having the same molecular and clinical phenotypes as in human patients. Models offering new opportunities to investigate disease pathogenesis and approaches to therapy will be emphasized in consultation with an Advisory Committee. The Center will provide the clinical, pathological, and molecular genetic studies required to discover important large animal models, including, as a new direction, those with complex inheritance, and establish their homology with the human disorder. Verified models will be made available to other investigators for a nominal fee-for-service in the form of DNA, cells, frozen semen, and breeding stock. We will also serve as a resource for normal dogs and cats and their tissues, and we will continue to offer a facility and expertise for investigators to perform pathogenetic and therapy experiments in dog and cat models on a Program Income Fund, fee-for-service basis.

Public Health Relevance

This Referral Center finds, characterizes, and makes available dog and cat gene-homologous models of human genetic disorders for the study of the pathogenesis of disease and the development of effective, safe therapies for human patients.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Animal (Mammalian and Nonmammalian) Model, and Animal and Biological Material Resource Grants (P40)
Project #
5P40OD010939-30
Application #
8606273
Study Section
Special Emphasis Panel (ZTR1-CM-6 (01))
Program Officer
O'Neill, Raymond R
Project Start
1985-09-20
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
30
Fiscal Year
2014
Total Cost
$643,287
Indirect Cost
$238,542
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Genger, Seiche C; Mizukami, Keijiro; Martin, Michael P et al. (2018) Mucopolysaccharidosis IIIB (Sanfilippo syndrome B) in a commercial emu (Dromaius novaehollandiae) flock. Avian Pathol 47:100-107
Hinderer, Christian; Bell, Peter; Katz, Nathan et al. (2018) Evaluation of Intrathecal Routes of Administration for Adeno-Associated Viral Vectors in Large Animals. Hum Gene Ther 29:15-24
Wang, P; Henthorn, P S; Galban, E et al. (2018) Canine GM2-Gangliosidosis Sandhoff Disease Associated with a 3-Base Pair Deletion in the HEXB Gene. J Vet Intern Med 32:340-347
Fyfe, John C; Hemker, Shelby L; Frampton, Alycia et al. (2018) Inherited selective cobalamin malabsorption in Komondor dogs associated with a CUBN splice site variant. BMC Vet Res 14:418
Wang, Ping; Mazrier, Hamutal; Caverly Rae, Jessica et al. (2018) A GNPTAB nonsense variant is associated with feline mucolipidosis II (I-cell disease). BMC Vet Res 14:416
Lynch, Michael; McGrath, Ken; Raj, Karthik et al. (2017) HEREDITARY FACTOR VII DEFICIENCY IN THE ASIAN ELEPHANT (ELEPHAS MAXIMUS) CAUSED BY A F7 MISSENSE MUTATION. J Wildl Dis 53:248-257
Mauldin, Elizabeth A; Wang, Ping; Olivry, Thierry et al. (2017) Epidermolysis bullosa simplex in sibling Eurasier dogs is caused by a PLEC non-sense variant. Vet Dermatol 28:10-e3
Giger, Urs (2017) Update on WSAVA's work on hereditary diseases. Companion (Glos) 2017:26-27
Shao, Hongguang; Li, Xinshe; Lok, James B (2017) Heritable genetic transformation of Strongyloides stercoralis by microinjection of plasmid DNA constructs into the male germline. Int J Parasitol 47:511-515
Szelecsenyi, Arlette Cornelia; Giger, Urs; Golini, Lorenzo et al. (2017) Survival in 76 cats with epilepsy of unknown cause: a retrospective study. Vet Rec 181:479

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