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Creation of non-human primate neurogenetic disease models by gene targeting and nuclear transfer

Genetically modified rhesus macaques are necessary because mouse models are not suitable for a number of important neurogenetic disorders; for example, Kallmann's syndrome, Lesch-Nyhan's disease and Ataxia-Telangiectasia. Mouse models may not be suitable because there may be no mouse ortho...

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Autor principal: Norgren, Robert B
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2004
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC455690/
https://www.ncbi.nlm.nih.gov/pubmed/15200671
http://dx.doi.org/10.1186/1477-7827-2-40
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author Norgren, Robert B
author_facet Norgren, Robert B
author_sort Norgren, Robert B
collection PubMed
description Genetically modified rhesus macaques are necessary because mouse models are not suitable for a number of important neurogenetic disorders; for example, Kallmann's syndrome, Lesch-Nyhan's disease and Ataxia-Telangiectasia. Mouse models may not be suitable because there may be no mouse ortholog of the human gene of interest, as is the case for Kallmann's syndrome, or because mutant mice do not exhibit the same phenotype observed in humans, as is the the case for Lesch-Nyhan's disease and Ataxia-Telangiectasia. Non-human primate models of neurogenetic diseases are expected to more closely resemble human diseases than existing mouse models. Genetically modified rhesus macaques can be created by modifying the genome of a somatic cell and then transferring the nucleus from this cell to an enucleated oocyte. Random integration of a transgene is sufficient to create models of gain-of-function genetic diseases. Stable expression of green fluorescent protein has been achieved in rhesus macaque fibroblasts. However, gene targeting is necessary to create models of loss-of-function genetic diseases. Several technical challenges must be overcome before null mutant non-human primates can be produced. In our experience, fetal fibroblasts frequently become senescent before selection procedures can be completed. We have overcome this problem by transfecting somatic cells with human telomerase reverse transcriptase. This enzyme extends the telomeres, and lifespan, of somatic cells. Long and accurate polymerase chain reaction can be used to obtain sufficient regions of homology of isogenic rhesus genomic DNA for targeting constructs. This should improve gene targeting efficiency. Gene targeting experiments are currently underway. Null mutant rhesus macaques will likely result in breakthrough advances in the understanding of neurogenetic disease and prove invaluable for preclinical trials of new therapies.
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spelling pubmed-4556902004-07-15 Creation of non-human primate neurogenetic disease models by gene targeting and nuclear transfer Norgren, Robert B Reprod Biol Endocrinol Review Genetically modified rhesus macaques are necessary because mouse models are not suitable for a number of important neurogenetic disorders; for example, Kallmann's syndrome, Lesch-Nyhan's disease and Ataxia-Telangiectasia. Mouse models may not be suitable because there may be no mouse ortholog of the human gene of interest, as is the case for Kallmann's syndrome, or because mutant mice do not exhibit the same phenotype observed in humans, as is the the case for Lesch-Nyhan's disease and Ataxia-Telangiectasia. Non-human primate models of neurogenetic diseases are expected to more closely resemble human diseases than existing mouse models. Genetically modified rhesus macaques can be created by modifying the genome of a somatic cell and then transferring the nucleus from this cell to an enucleated oocyte. Random integration of a transgene is sufficient to create models of gain-of-function genetic diseases. Stable expression of green fluorescent protein has been achieved in rhesus macaque fibroblasts. However, gene targeting is necessary to create models of loss-of-function genetic diseases. Several technical challenges must be overcome before null mutant non-human primates can be produced. In our experience, fetal fibroblasts frequently become senescent before selection procedures can be completed. We have overcome this problem by transfecting somatic cells with human telomerase reverse transcriptase. This enzyme extends the telomeres, and lifespan, of somatic cells. Long and accurate polymerase chain reaction can be used to obtain sufficient regions of homology of isogenic rhesus genomic DNA for targeting constructs. This should improve gene targeting efficiency. Gene targeting experiments are currently underway. Null mutant rhesus macaques will likely result in breakthrough advances in the understanding of neurogenetic disease and prove invaluable for preclinical trials of new therapies. BioMed Central 2004-06-16 /pmc/articles/PMC455690/ /pubmed/15200671 http://dx.doi.org/10.1186/1477-7827-2-40 Text en Copyright © 2004 Norgren; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
spellingShingle Review
Norgren, Robert B
Creation of non-human primate neurogenetic disease models by gene targeting and nuclear transfer
title Creation of non-human primate neurogenetic disease models by gene targeting and nuclear transfer
title_full Creation of non-human primate neurogenetic disease models by gene targeting and nuclear transfer
title_fullStr Creation of non-human primate neurogenetic disease models by gene targeting and nuclear transfer
title_full_unstemmed Creation of non-human primate neurogenetic disease models by gene targeting and nuclear transfer
title_short Creation of non-human primate neurogenetic disease models by gene targeting and nuclear transfer
title_sort creation of non-human primate neurogenetic disease models by gene targeting and nuclear transfer
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC455690/
https://www.ncbi.nlm.nih.gov/pubmed/15200671
http://dx.doi.org/10.1186/1477-7827-2-40
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