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 #
2P40OD010939-29
Application #
8413994
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
2013-03-01
Budget End
2013-12-31
Support Year
29
Fiscal Year
2013
Total Cost
$719,538
Indirect Cost
$269,827
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Serratrice, Nicolas; Cubizolle, Aurelie; Ibanes, Sandy et al. (2014) Corrective GUSB transfer to the canine mucopolysaccharidosis VII cornea using a helper-dependent canine adenovirus vector. J Control Release 181:22-31
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Cubizolle, Aurelie; Serratrice, Nicolas; Skander, Nadia et al. (2014) Corrective GUSB transfer to the canine mucopolysaccharidosis VII brain. Mol Ther 22:762-73
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Caviezel, L L; Raj, K; Giger, U (2014) Comparison of 4 direct Coombs' test methods with polyclonal antiglobulins in anemic and nonanemic dogs for in-clinic or laboratory use. J Vet Intern Med 28:583-91
Chiaro, Joseph A; O'Donnell, Patricia; Shore, Eileen M et al. (2014) Effects of neonatal enzyme replacement therapy and simvastatin treatment on cervical spine disease in mucopolysaccharidosis I dogs. J Bone Miner Res 29:2610-7
Brons, A-K; Henthorn, P S; Raj, K et al. (2013) SLC3A1 and SLC7A9 mutations in autosomal recessive or dominant canine cystinuria: a new classification system. J Vet Intern Med 27:1400-8

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