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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46 Scopus citations


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 (US)
Article number158
JournalCommunications biology
Issue number1
StatePublished - Dec 1 2018

Bibliographical note

Funding Information:
The authors would like to thank Dr. Bennett Sviderskaya’s laboratory for their advice on culturing porcine melanocytes, the University of Minnesota’s Veterinary Clinical Investigation Center for assistance with in vivo imaging of the minipigs, Rory Williams of Dr. Largaespada’s lab at the University of Minnesota for his assistance in method development, Dr. Jeremy Schefers of the University of Minnesota Veterinary Diagnostic Laboratory for his pathology expertise, and Mark A. Sanders, program director of the University Imaging Centers, University of Minnesota. This work was funded by the Children’s Tumor Foundation Synodos for NF1, the National Institutes of Health under Award Number T32OD0100993 (S.H.I.), and the ACS Research Professorship #123939 (D.A.L.). D.H.G. is supported by a Research Program Award from the National Institute of Neurological Disorders and Stroke (1-R35-NS07211-01). We would like to acknowledge the assistance of the Clinical Pharmacology Shared Resource of the Masonic Cancer Center, a comprehensive cancer center designated by the National Cancer Institute, supported in part by P30 CA77598. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2018, The Author(s).


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