Neurofibromatosis Type I: Preclinical Modeling

Neurofibromatosis type I (NF1) is a common, autosomal-dominantly inherited disorder with an incidence of ~1 in 3000 live births, and thus, one of the most common RASopathies. Most individuals with NF1 develop plexiform neurofibromas (PNFs, 30–50%) or cutaneous neurofibromas (>90%), nerve tumors caused by NF1 loss of function in Schwann cells. Cell culture/in vitro models and genetically engineered mouse models of Nf1 are being used successfully to test drug efficacy in preclinical trials. Thus, work in in vivo animal models, followed by clinical trials, led to FDA approval for use of MEK inhibitors to shrink most inoperable plexiform neurofibromas, and these inhibitors are now being tested in other NF1 indications and in other RASopathies. This chapter details methods used for testing preclinical models that led to FDA approval, and remain in use, and outlines newer models that may identify additional, curative, strategies.