Genetically engineered minipigs model the major clinical features of human neurofibromatosis type 1

Sara H. Isakson, Anthony E. Rizzardi, Alexander W. Coutts, Daniel F. Carlson, Mark N. Kirstein, James Fisher, Jeremie Vitte, Kyle B. Williams, G. Elizabeth Pluhar, Sonika Dahiya, Brigitte C. Widemann, Eva Dombi, Tilat Rizvi, Nancy Ratner, Ludwine Messiaen, Anat O. Stemmer-Rachamimov, Scott C. Fahrenkrug, David H. Gutmann, Marco Giovannini, Christopher L. MoertelDavid A. Largaespada, Adrienne L. Watson

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Neurofibromatosis Type 1 (NF1) is a genetic disease caused by mutations in Neurofibromin 1 (NF1). 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. We describe a minipig model that exhibits clinical hallmarks of NF1, including café au lait macules, neurofibromas, and optic pathway glioma. Spontaneous loss of heterozygosity is observed in this model, a phenomenon also described in NF1 patients. Oral administration of a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor suppresses Ras signaling. To our knowledge, this model 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-targeted therapies.

Original languageEnglish
Article number158
JournalCommunications Biology
Issue number1
StatePublished - Dec 1 2018


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