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

Research output: Contribution to journalArticle

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Abstract

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
Volume1
Issue number1
DOIs
StatePublished - Dec 1 2018

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Miniature Swine
Neurofibromatosis 1
mitogen-activated protein kinase
Neurofibromin 1
genetic disorders
optics
natural history
oral administration
Extracellular Signal-Regulated MAP Kinases
Biomarkers
biomarkers
Optic Nerve Glioma
heterozygosity
Mitogen-Activated Protein Kinases
animal models
Neurofibroma
image analysis
Inborn Genetic Diseases
Optics
mutation

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Genetically engineered minipigs model the major clinical features of human neurofibromatosis type 1. / Isakson, Sara H.; Rizzardi, Anthony E.; Coutts, Alexander W.; Carlson, Daniel F.; Kirstein, Mark N.; Fisher, James; Vitte, Jeremie; Williams, Kyle B.; Pluhar, G. Elizabeth; Dahiya, Sonika; Widemann, Brigitte C.; Dombi, Eva; Rizvi, Tilat; Ratner, Nancy; Messiaen, Ludwine; Stemmer-Rachamimov, Anat O.; Fahrenkrug, Scott C.; Gutmann, David H.; Giovannini, Marco; Moertel, Christopher L.; Largaespada, David A.; Watson, Adrienne L.

In: Communications biology, Vol. 1, No. 1, 158, 01.12.2018.

Research output: Contribution to journalArticle

Isakson, SH, Rizzardi, AE, Coutts, AW, Carlson, DF, Kirstein, MN, Fisher, J, Vitte, J, Williams, KB, Pluhar, GE, Dahiya, S, Widemann, BC, Dombi, E, Rizvi, T, Ratner, N, Messiaen, L, Stemmer-Rachamimov, AO, Fahrenkrug, SC, Gutmann, DH, Giovannini, M, Moertel, CL, Largaespada, DA & Watson, AL 2018, 'Genetically engineered minipigs model the major clinical features of human neurofibromatosis type 1', Communications biology, vol. 1, no. 1, 158. https://doi.org/10.1038/s42003-018-0163-y
Isakson, Sara H. ; Rizzardi, Anthony E. ; Coutts, Alexander W. ; Carlson, Daniel F. ; Kirstein, Mark N. ; Fisher, James ; Vitte, Jeremie ; Williams, Kyle B. ; Pluhar, G. Elizabeth ; Dahiya, Sonika ; Widemann, Brigitte C. ; Dombi, Eva ; Rizvi, Tilat ; Ratner, Nancy ; Messiaen, Ludwine ; Stemmer-Rachamimov, Anat O. ; Fahrenkrug, Scott C. ; Gutmann, David H. ; Giovannini, Marco ; Moertel, Christopher L. ; Largaespada, David A. ; Watson, Adrienne L. / Genetically engineered minipigs model the major clinical features of human neurofibromatosis type 1. In: Communications biology. 2018 ; Vol. 1, No. 1.
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abstract = "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 caf{\'e} 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.",
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AU - Kirstein, Mark N.

AU - Fisher, James

AU - Vitte, Jeremie

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AU - Stemmer-Rachamimov, Anat O.

AU - Fahrenkrug, Scott C.

AU - Gutmann, David H.

AU - Giovannini, Marco

AU - Moertel, Christopher L.

AU - Largaespada, David A.

AU - Watson, Adrienne L.

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