Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 156.83K | Year: 2011
DESCRIPTION (provided by applicant): Ataxia-Telangiectasia (A-T) is a multi-systemic, recessively inherited disorder characterized primarily by early onset cerebellar ataxia and telangiectasia, from which the disease name is derived. In addition, patientsalso exhibit a number of other clinical symptoms including increased susceptibility to cancer (lymphomas, leukemia, brain tumors), immunodeficiency, insulin-resistant diabetes, chromosomal instability, sensitivity to ionizing radiation, susceptibility to bronchopulmonary disease, and the nearly complete absence of a thymus. A-T is a progressive and ultimately fatal disease, with most patients dying in their early twenties. Current treatments for A-T are directed primarily toward the management of symptoms.Physical and speech therapy may improve the daily lives of patients, and 3-globulin injections can be given to support the immune system. However, no treatment is currently directed at the underlying defect. The development of improved therapies for A-T iscurrently limited by the lack of an animal model that fully and accurately recapitulates the multi-systemic nature of this disease. A number of mouse models of A-T have been developed by the targeted disruption of the mouse Atm gene and have proved invaluable for studying some aspects of ATM function and A-T disease. However, no single mouse model fully replicates the complex clinical symptoms observed in human disease, and more importantly, none of the mouse models develop the severe neurological phenotype that is the hallmark of human A-T. The failure of mouse models to develop the classical symptoms of A-T is likely the result of physiological, anatomical, and developmental differences between the two species. In contrast, pigs may serve as a better model in which to study human disease because their development, anatomy, and physiology are more closely related to that of humans. Given that the development and anatomy of the pig brain more closely resembles that of humans than mice, mutations in the porcine ATM gene may result in many of the same neurological changes that are observed in A-T patients. The ultimate goal of this proposal is to develop and commercialize a porcine model of A-T by disrupting the ATM gene. We intend to accomplish this in two steps by combining gene targeting and somatic cell nuclear transfer (SCNT). This proposal specifically outlines the development of porcine fibroblasts with mutated ATM alleles. Gene targeting vectors will be constructed to disrupt the endogenous porcine ATM gene in a region frequently mutated in patients. Porcine fetal fibroblasts will be infected with a virus carrying the ATM targeting vectors. Our plans for generating properly targeted cells are designed to maximize the frequency of homologous recombination,minimize random integration, and minimize the number of cell passages before targeted cells are harvested. Subsequent work will use these cells for somatic cell nuclear transfer to produce ATM-targeted pigs and the subsequent characterization and validation of the pigs. This animal model will provide the academic and commercial research communities an opportunity to better understand the consequences of ATM dysfunction and the pathogenesis of A-T disease, and to develop and test new therapeutic strategies.PUBLIC HEALTH RELEVANCE: Project Narrative This proposal specifically outlines the development of porcine fibroblasts with mutated ATM alleles as a first step towards a new model of the human disease, Ataxia-Telangiectasia. Subsequent work will usethese cells for somatic cell nuclear transfer to produce affected pigs followed by characterization and validation of the animal model. This project is relevant to the NIH's mission because it will provide a resource to stimulate discovery, therapeutic application, and the development of new diagnostic tools.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.42M | Year: 2014
DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the DMD gene with a prevalence of 1 in 3500 male births. The consequent loss of functional dystrophin results in the progressive degeneration of skeletal and cardiac muscle. Despite significant progress in our understanding of this disease and advances in the development of new therapeutic approaches, DMD remains a fatal disease. Much of what is known about DMD has come from studying dystrophin-deficient animals, particularly murine and canine models. While useful for mechanistic studies, dystrophic mice fail to develop the muscle weakness phenotype that is typical of DMD in patients. The canine models are more representative of human DMD, but are difficult to study due to extreme phenotypic variability. The canine models also suffer from a limited choice of mutations, significant expense, and social acceptance concerns. Therapeutic strategies that have shown promise in these m
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 167.06K | Year: 2012
Project Summary/Abstract Cancer is the second deadliest disease in the United States, killing more than 500,000 Americans annually. This year, another 1.5 million will be diagnosed with one of nearly 200 different cancer types. Despite an ever---growing understanding of the environmental risk factors, genetic contributions, and tumorigenic mechanisms, the diagnoses and treatments for this disease remain inadequate. Much of what is known about cancer has come from studies of cells in culture and small animal models. While these model systems have been extremely informative, they also possess limitations and present challenges to translating promising therapies to the clinic. The lack of a large animal model that accurately replicates human cancer has been amajor barrier to the development of effective diagnostic tools, interventions, and therapies for this deadly disease. Pigs share many similarities with humans in anatomy, physiology, genetics, and importantly, size. While naturally occurring tumors are rarely seen due to standard pork production practices, spontaneous and induced cancers have been studied in pigs and are highly representative of what is seen in humans. However, the extended timeframe required for inducing cancer in pigs and the accompanyingphenotypic variability limit their usefulness. Our objective is to create a genetically engineered pig in which tumorigenesis can be conditionally induced in any tissue. We intend to accomplish this by mutating two of the most commonly affected genes in human cancer, KRAS and TP53 (encoding p53). KRAS is in oncogene encoding a small GTPase that couples receptor activation and downstream effectors to control cell proliferation, differentiation and survival. Activating mutations in KRAS are common in many human tumors. Known as the guardian of the genome , p53 is a transcription factor that regulates critical cell functions including cell---cycle arrest and apoptosis. The loss of proper p53 function predisposes cells to unregulated growth, tumor formation,and metastasis. Mouse models expressing conditional mutations in KRAS and TP53 have yielded excellent models representative of human cancers of the lung, pancreas, colon, and other tissues. We hypothesize that mutations in porcine KRAS and TP53 will produce similar results in pigs. Therefore, the ultimate goal of this project is to develop and commercialize KRAS/TP53--mutated pigs to serve as a platform for models of human cancer. We intend to accomplish this by combining gene targeting and somatic cell nuclear transfer. This proposal specifically outlines the development of porcine fibroblasts with mutated KRAS and TP53 alleles. A gene targeting vector will be developed and used to disrupt the endogenous porcine KRAS via homologous recombination in both TP53---targeted and wild---type cells. Subsequent work will use these cells as nuclear donors for somatic cell nuclear transfer to produce KRAS/TP53---mutated pigs. These models will provide academic and industry researchers with an opportunity to better understand cancer and its pathogenesis and to develop and test new diagnostic, therapeutic, and preventative strategies.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.25M | Year: 2011
DESCRIPTION (provided by applicant): Atherosclerosis is the primary cause of cardiovascular disease, which is the most common cause of death in the United States. Atherosclerosis is characterized by the accumulation of lipids, cholesterol, calcium deposits, and cellular debris in vessel walls, and results in plaque formation, arterial obstruction, and diminished blood flow to organs. These plaques often rupture, causing myocardial infarction, stroke, or death. The main risk factors include elevated lipid levels, hypertension, and diabetes. Current treatment strategies are directed at changing patient lifestyle/diet and decreasing cholesterol via pharmacological methods. Surgical interventions with medical devices such as stents are used for advanced cases. While these therapeutic approaches have benefited many patients with this disease, they are far from ideal. One reason is that no drug or device is actually developed and tested in a model system that accurately recreates the disease being treated. Thus, there is a significant gap between early phase preclinical studies and human drug trials. The lack of an animal model that accurately replicates all of the manifestations of human atherosclerosis has been a major barrier to the development of effective therapies and interventions for this deadly disease. Several mouse models have been generated with mutations in genes important for lipoprotein metabolism, and while these models have been informative, they fail to develop the complex atherosclerotic lesions that are typical of the human disease. In contrast to mice, the physiology and anatomy of the porcine cardiovascular system closely resembles that of humans. In fact, pigs have long been used as models of cardiovascular disease, and pigs with naturally occurring mutations in their LDL receptor (LDLR) gene, and therefore possessing elevated LDL, have been reported. Although the hypercholesterolemic pig is an attractive model, the mild nature of the mutation, the high variability of the disease, the limited access by other researchers, and the expense prevent its wide use in the research community. Therefore, the ultimate goal of this project is to develop and commercialize a gene- targeted porcine model of atherosclerosis. LDLR fetal fibroblasts that we developed in Phase I will be used as nuclear donors for somatic cell nuclear transfer. Nuclear transfer embryos will be transferred to recipient females for gestation. Resulting piglets will have one targeted LDLR gene. We will characterize the LDLR- targeted pigs at the molecular and biochemical level. We will determine the lipid and lipoprotein profile in LDLR-targeted pigs and perform morphometric analysis to determine the presence and extent of atherosclerosis. Finally, we will establish breeding herds to generate LDLR-/- pigs and to expand and propagate the colony. This project will produce a porcine model of atherosclerosis that will provide academic and industry researchers with an opportunity to better understand the disease and to develop and test new therapeutics and preventative strategies. Thus, this work will accelerate the discovery of novel therapies for this costly and deadly disease. PUBLIC HEALTH RELEVANCE: This proposal specifically outlines the development, characterization and propagation of a genetically engineered porcine model of atherosclerosis. This project is relevant to the NIH's mission because it will provide a resource to stimulate discovery, therapeutic application, and the development of new diagnostic tools.
Exemplar Genetics, Llc | Date: 2014-03-14
The present invention provides transgenic, large non-human animal models of cancer, as well as methods of using such animal models in the identification and characterization of therapies for cancer.