Abstract
Neurofibromatosis Type 1 (NF1) is a genetic disease caused by mutations in the neurofibromin 1 (NF1) gene. NF1 patients present with a variety of clinical manifestations and are predisposed to cancer development. Many NF1 animal models have been developed, yet none display the spectrum of disease seen in patients and the translational impact of these models has been limited. Using gene-editing technology, we have developed a minipig model of NF1 that exhibits clinical hallmarks of the disease, including café au lait macules, neurofibromas, and optic pathway glioma. We have conducted pharmacological studies in our NF1 minipigs to assess the pharmacokinetic and pharmacodynamic properties of MEK inhibitors for NF1. We have demonstrated that oral administration of several MEK inhibitors results in clinically relevant plasma concentrations and consequent inhibition of Ras signaling in immune cells, and certain MEK inhibitors can cross the blood brain barrier and have a pharmacodynamic effect, suggesting that they may be effective in treating NF1-associated brain tumors. Because over 20% of NF1 patients harbor NF1 nonsense mutations, we are assessing safety and efficacy of nonsense mutation suppressors that may be effective in treating NF1. We evaluated six drugs known to induce nonsense mutation suppression in several primary cell types isolated from NF1 minipigs and show that several of these drugs have the propensity to induce the production of full length neurofibromin protein, leading to a subsequent reduction in MAPK signaling. Information acquired from this NF1 minipig preclinical model will be leveraged towards initiating a clinical trial in NF1 patients. The NF1 minipig provides an unprecedented opportunity to study the complex biology and natural history of NF1 and could prove indispensable for development of imaging methods, biomarkers, and evaluation of safety and efficacy of NF1 therapies.
Gonosomal Mosaicism for a Nonsense Mutation (R1947X) in the NF1 Gene in Segmental Neurofibromatosis Type 1