Recombinetics, Inc. — Department of Health and Human Services SBIR Phase I: 101

Description

PROJECT SUMMARY Neurofibromatosis type NF is a genetic disorder associated with the development of nervous system tumors including vestibular schwannomas meningiomas cranial nerve tumors and spinal tumors due to germline loss of one copy of the NF gene While the prevalence of NF syndrome is only NF is commonly lost sporadically and up to people will develop a tumor with an underlying NF mutation therefore developing therapies that target NF mutant tumors is critical for NF patients and the general population The current standard of care for NF patients is surgical resection of the tumors although surgery is often not feasible and there is a high risk of hearing loss facial weakness and dysphagia Radiation therapy has been utilized in NF but can be associated with chronic neurologic dysfunction and or malignant transformation The goal of this proposal is to establish a swine model of NF that recapitulates the disease seen in NF patients to better understand disease etiology and progression and provide a reliable preclinical model for establishing safety and efficacy of new therapies prior to clinical trials A common human NF disease allele will be engineered into the genome of swine fibroblasts using site specific nucleases and those fibroblasts will undergo somatic cell nuclear transfer to generate pigs that harbor the human mutant NF allele At months of age these NF pigs will be evaluated by MRI for the presence of brain tumors and by brain auditory evoked response and compared to control animals to determine if they have NF related hearing deficits often seen in NF patients This model would allow the field to overcome two major hurdles in NF research First the mouse models of NF and NF related tumors do not fully recapitulate the disease seen in NF patients and have been poor predictors of clinical efficacy Second due to a small patient population and orphan disease status the ability to recruit enough patients for clinical trials is nearly impossible A large animal model that could serve as a preclinical platform for drug safety toxicology and efficacy would dramatically progress the development of NF therapeutics and candidate drug prioritization for a patient population that is too small to recruit enough patients for many clinical trials Further the NF mutation that was engineered in our swine model is a premature termination codon in exon of the NF gene allowing our model to serve as a platform for testing premature termination codon suppression therapies which are applicable to NF but also in the one third of genetic disorders characterized by premature termination codons including cystic fibrosis and Duchenne muscular dystrophy PROJECT NARRATIVE This SBIR aims to develop a swine model of Neurofibromatosis type NF a genetic disorder associated with a high risk of cancer and the development of nervous system tumors and a desperate need for better treatments and disease management While NF is a rare genetic disorder up to people will develop a tumor with the NF gene mutated in their lifetime and therapeutics aimed at treating NF patients may also be applicable for NF mutant tumors The goal of this application is to concentrate on research efforts that will significantly contribute to proving the scientific and technical feasibility of establishing a swine model of NF that can be applied to better understand NF etiology disease development and progression the application of novel imaging and monitoring techniques and the identification and testing of new therapies