Correction of a knock-in mouse model of acrodysostosis with gene therapy using a rAAV9-CAG-human PRKAR1A vector
Acrodysostosis is a rare skeletal dysplasia caused by loss-of-function mutations in the regulatory subunit of protein kinase A (PRKAR1A). In a knock-in mouse model (PRKAR1A wt/mut ) expressing one copy of the recurrent R368X mutation, we tested the effects of a rAAV9-CAG-human PRKR1A (hPRKAR1A) vect...
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Veröffentlicht in: | Gene therapy 2022-08, Vol.29 (7-8), p.441-448 |
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creator | Özgür-Günes, Yasemin Le Stunff, Catherine Chedik, Malha Belot, Marie-Pierre Becker, Pierre-Hadrien Blouin, Véronique Bougnères, Pierre |
description | Acrodysostosis is a rare skeletal dysplasia caused by loss-of-function mutations in the regulatory subunit of protein kinase A (PRKAR1A). In a knock-in mouse model (PRKAR1A
wt/mut
) expressing one copy of the recurrent R368X mutation, we tested the effects of a rAAV9-CAG-human PRKR1A (hPRKAR1A) vector intravenously administered at 4 weeks of age. Caudal vertebrae and tibial diaphyses contained 0.52 ± 0.7 and 0.13 ± 0.3 vector genome per cell (VGC), respectively, at 10 weeks of age and 0.22 ± 0.04 and 0.020 ± 0.04 at 16 weeks while renal cortex contained 0.57 ± 0.14 and 0.26 ± 0.05 VGC. Vector-mediated hPRKAR1A expression was found in growth plate chondrocytes, osteoclasts, osteoblasts, and kidney tubular cells. Chondrocyte architecture was restored in the growth plates. Body length, tail length, and body weight were improved in vector treated PRKAR1A
wt/mut
mice, not the bone length of their limbs. These results provide one of the few proofs for gene therapy efficacy in a mouse model of chondrodysplasia. In addition, the increased urinary cAMP of PRKAR1A
wt/mut
mice was corrected almost to normal. In conclusion, gene therapy with hPRKAR1A improved skeletal growth and kidney dysfunction, the hallmarks of acrodysostosis in R368X mutated mice and humans. |
doi_str_mv | 10.1038/s41434-021-00286-2 |
format | Article |
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wt/mut
) expressing one copy of the recurrent R368X mutation, we tested the effects of a rAAV9-CAG-human PRKR1A (hPRKAR1A) vector intravenously administered at 4 weeks of age. Caudal vertebrae and tibial diaphyses contained 0.52 ± 0.7 and 0.13 ± 0.3 vector genome per cell (VGC), respectively, at 10 weeks of age and 0.22 ± 0.04 and 0.020 ± 0.04 at 16 weeks while renal cortex contained 0.57 ± 0.14 and 0.26 ± 0.05 VGC. Vector-mediated hPRKAR1A expression was found in growth plate chondrocytes, osteoclasts, osteoblasts, and kidney tubular cells. Chondrocyte architecture was restored in the growth plates. Body length, tail length, and body weight were improved in vector treated PRKAR1A
wt/mut
mice, not the bone length of their limbs. These results provide one of the few proofs for gene therapy efficacy in a mouse model of chondrodysplasia. In addition, the increased urinary cAMP of PRKAR1A
wt/mut
mice was corrected almost to normal. In conclusion, gene therapy with hPRKAR1A improved skeletal growth and kidney dysfunction, the hallmarks of acrodysostosis in R368X mutated mice and humans.</description><identifier>ISSN: 0969-7128</identifier><identifier>EISSN: 1476-5462</identifier><identifier>DOI: 10.1038/s41434-021-00286-2</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>42/41 ; 42/44 ; 631/154/51 ; 631/61/201 ; 64 ; 64/60 ; Biomedical and Life Sciences ; Biomedicine ; Body length ; Body weight ; Bone dysplasia ; Cell Biology ; Chondrocytes ; Chondrodystrophy ; Gene Expression ; Gene Therapy ; Genomes ; Growth plate ; Human Genetics ; Kidney diseases ; Kinases ; Mutation ; Nanotechnology ; Osteoclasts ; Protein kinase A ; Renal cortex ; Skeleton ; Trinucleotide repeats ; Vertebrae</subject><ispartof>Gene therapy, 2022-08, Vol.29 (7-8), p.441-448</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021</rights><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c352t-bba057c6eefe2395531e21c78ec99586f9a58237460d1bdaab7045810297c2833</citedby><cites>FETCH-LOGICAL-c352t-bba057c6eefe2395531e21c78ec99586f9a58237460d1bdaab7045810297c2833</cites><orcidid>0000-0003-0017-4572</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Özgür-Günes, Yasemin</creatorcontrib><creatorcontrib>Le Stunff, Catherine</creatorcontrib><creatorcontrib>Chedik, Malha</creatorcontrib><creatorcontrib>Belot, Marie-Pierre</creatorcontrib><creatorcontrib>Becker, Pierre-Hadrien</creatorcontrib><creatorcontrib>Blouin, Véronique</creatorcontrib><creatorcontrib>Bougnères, Pierre</creatorcontrib><title>Correction of a knock-in mouse model of acrodysostosis with gene therapy using a rAAV9-CAG-human PRKAR1A vector</title><title>Gene therapy</title><addtitle>Gene Ther</addtitle><description>Acrodysostosis is a rare skeletal dysplasia caused by loss-of-function mutations in the regulatory subunit of protein kinase A (PRKAR1A). In a knock-in mouse model (PRKAR1A
wt/mut
) expressing one copy of the recurrent R368X mutation, we tested the effects of a rAAV9-CAG-human PRKR1A (hPRKAR1A) vector intravenously administered at 4 weeks of age. Caudal vertebrae and tibial diaphyses contained 0.52 ± 0.7 and 0.13 ± 0.3 vector genome per cell (VGC), respectively, at 10 weeks of age and 0.22 ± 0.04 and 0.020 ± 0.04 at 16 weeks while renal cortex contained 0.57 ± 0.14 and 0.26 ± 0.05 VGC. Vector-mediated hPRKAR1A expression was found in growth plate chondrocytes, osteoclasts, osteoblasts, and kidney tubular cells. Chondrocyte architecture was restored in the growth plates. Body length, tail length, and body weight were improved in vector treated PRKAR1A
wt/mut
mice, not the bone length of their limbs. These results provide one of the few proofs for gene therapy efficacy in a mouse model of chondrodysplasia. In addition, the increased urinary cAMP of PRKAR1A
wt/mut
mice was corrected almost to normal. In conclusion, gene therapy with hPRKAR1A improved skeletal growth and kidney dysfunction, the hallmarks of acrodysostosis in R368X mutated mice and humans.</description><subject>42/41</subject><subject>42/44</subject><subject>631/154/51</subject><subject>631/61/201</subject><subject>64</subject><subject>64/60</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Body length</subject><subject>Body weight</subject><subject>Bone dysplasia</subject><subject>Cell Biology</subject><subject>Chondrocytes</subject><subject>Chondrodystrophy</subject><subject>Gene Expression</subject><subject>Gene Therapy</subject><subject>Genomes</subject><subject>Growth plate</subject><subject>Human Genetics</subject><subject>Kidney diseases</subject><subject>Kinases</subject><subject>Mutation</subject><subject>Nanotechnology</subject><subject>Osteoclasts</subject><subject>Protein kinase A</subject><subject>Renal 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plate</topic><topic>Human Genetics</topic><topic>Kidney diseases</topic><topic>Kinases</topic><topic>Mutation</topic><topic>Nanotechnology</topic><topic>Osteoclasts</topic><topic>Protein kinase A</topic><topic>Renal cortex</topic><topic>Skeleton</topic><topic>Trinucleotide repeats</topic><topic>Vertebrae</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Özgür-Günes, Yasemin</creatorcontrib><creatorcontrib>Le Stunff, Catherine</creatorcontrib><creatorcontrib>Chedik, Malha</creatorcontrib><creatorcontrib>Belot, Marie-Pierre</creatorcontrib><creatorcontrib>Becker, Pierre-Hadrien</creatorcontrib><creatorcontrib>Blouin, Véronique</creatorcontrib><creatorcontrib>Bougnères, Pierre</creatorcontrib><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids 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therapy</jtitle><stitle>Gene Ther</stitle><date>2022-08-01</date><risdate>2022</risdate><volume>29</volume><issue>7-8</issue><spage>441</spage><epage>448</epage><pages>441-448</pages><issn>0969-7128</issn><eissn>1476-5462</eissn><abstract>Acrodysostosis is a rare skeletal dysplasia caused by loss-of-function mutations in the regulatory subunit of protein kinase A (PRKAR1A). In a knock-in mouse model (PRKAR1A
wt/mut
) expressing one copy of the recurrent R368X mutation, we tested the effects of a rAAV9-CAG-human PRKR1A (hPRKAR1A) vector intravenously administered at 4 weeks of age. Caudal vertebrae and tibial diaphyses contained 0.52 ± 0.7 and 0.13 ± 0.3 vector genome per cell (VGC), respectively, at 10 weeks of age and 0.22 ± 0.04 and 0.020 ± 0.04 at 16 weeks while renal cortex contained 0.57 ± 0.14 and 0.26 ± 0.05 VGC. Vector-mediated hPRKAR1A expression was found in growth plate chondrocytes, osteoclasts, osteoblasts, and kidney tubular cells. Chondrocyte architecture was restored in the growth plates. Body length, tail length, and body weight were improved in vector treated PRKAR1A
wt/mut
mice, not the bone length of their limbs. These results provide one of the few proofs for gene therapy efficacy in a mouse model of chondrodysplasia. In addition, the increased urinary cAMP of PRKAR1A
wt/mut
mice was corrected almost to normal. In conclusion, gene therapy with hPRKAR1A improved skeletal growth and kidney dysfunction, the hallmarks of acrodysostosis in R368X mutated mice and humans.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><doi>10.1038/s41434-021-00286-2</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0003-0017-4572</orcidid></addata></record> |
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source | Alma/SFX Local Collection |
subjects | 42/41 42/44 631/154/51 631/61/201 64 64/60 Biomedical and Life Sciences Biomedicine Body length Body weight Bone dysplasia Cell Biology Chondrocytes Chondrodystrophy Gene Expression Gene Therapy Genomes Growth plate Human Genetics Kidney diseases Kinases Mutation Nanotechnology Osteoclasts Protein kinase A Renal cortex Skeleton Trinucleotide repeats Vertebrae |
title | Correction of a knock-in mouse model of acrodysostosis with gene therapy using a rAAV9-CAG-human PRKAR1A vector |
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