Research Project
9253697
PROJECT SUMMARY Neurofibromatosis type 2 (NF2) 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 NF2 gene. While the prevalence of NF2 syndrome is only 1:33,000, NF2 is commonly lost sporadically, and up to 1:300 people will develop a tumor with an underlying NF2 mutation; therefore, developing therapies that target NF2 mutant tumors is critical for NF2 patients and the general population. The current standard of care for NF2 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 NF2, but can be associated with chronic neurologic dysfunction and/or malignant transformation. The goal of this proposal is to establish a swine model of NF2 that recapitulates the disease seen in NF2 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 NF2 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 NF2 allele. At 6 months of age these NF2 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 NF2-related hearing deficits, often seen in NF2 patients. This model would allow the field to overcome two major hurdles in NF2 research. First, the mouse models of NF2 and NF2- related tumors do not fully recapitulate the disease seen in NF2 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 NF2 therapeutics and candidate drug prioritization for a patient population that is too small to recruit enough patients for many clinical trials. Further, the NF2 mutation that was engineered in our swine model is a premature termination codon in exon 2 of the NF2 gene, allowing our model to serve as a platform for testing premature termination codon suppression therapies which are applicable to NF2, but also in the one-third of genetic disorders characterized by premature termination codons including cystic fibrosis and Duchenne muscular dystrophy.
