A gene therapy for inherited blindness using dCas9-VPR-mediated transcriptional activation
Catalytically inactive dCas9 fused to transcriptional activators (dCas9-VPR) enables activation of silent genes. Many disease genes have counterparts, which serve similar functions but are expressed in distinct cell types. One attractive option to compensate for the missing function of a defective g...
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| Veröffentlicht in: | Science advances 2020-08, Vol.6 (34), p.eaba5614-eaba5614 |
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| creator | Böhm, Sybille Splith, Victoria Riedmayr, Lisa Maria Rötzer, René Dominik Gasparoni, Gilles Nordström, Karl J V Wagner, Johanna Elisabeth Hinrichsmeyer, Klara Sonnie Walter, Jörn Wahl-Schott, Christian Fenske, Stefanie Biel, Martin Michalakis, Stylianos Becirovic, Elvir |
| description | Catalytically inactive dCas9 fused to transcriptional activators (dCas9-VPR) enables activation of silent genes. Many disease genes have counterparts, which serve similar functions but are expressed in distinct cell types. One attractive option to compensate for the missing function of a defective gene could be to transcriptionally activate its functionally equivalent counterpart via dCas9-VPR. Key challenges of this approach include the delivery of dCas9-VPR, activation efficiency, long-term expression of the target gene, and adverse effects in vivo. Using dual adeno-associated viral vectors expressing split dCas9-VPR, we show efficient transcriptional activation and long-term expression of cone photoreceptor-specific M-opsin (
) in a rhodopsin-deficient mouse model for retinitis pigmentosa. One year after treatment, this approach yields improved retinal function and attenuated retinal degeneration with no apparent adverse effects. Our study demonstrates that dCas9-VPR-mediated transcriptional activation of functionally equivalent genes has great potential for the treatment of genetic disorders. |
| doi_str_mv | 10.1126/sciadv.aba5614 |
| format | Article |
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) in a rhodopsin-deficient mouse model for retinitis pigmentosa. One year after treatment, this approach yields improved retinal function and attenuated retinal degeneration with no apparent adverse effects. Our study demonstrates that dCas9-VPR-mediated transcriptional activation of functionally equivalent genes has great potential for the treatment of genetic disorders.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.aba5614</identifier><identifier>PMID: 32875106</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Animals ; Blindness - genetics ; Blindness - therapy ; CRISPR-Cas Systems ; Diseases and Disorders ; Genetic Therapy ; Mice ; Molecular Biology ; SciAdv r-articles ; Transcription Factors - genetics ; Transcriptional Activation</subject><ispartof>Science advances, 2020-08, Vol.6 (34), p.eaba5614-eaba5614</ispartof><rights>Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).</rights><rights>Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). 2020 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c456t-d678adb0a0a0e93a1328e86fb760c3ea553ee1ff6194fadf30234905d5b4cbd03</citedby><cites>FETCH-LOGICAL-c456t-d678adb0a0a0e93a1328e86fb760c3ea553ee1ff6194fadf30234905d5b4cbd03</cites><orcidid>0000-0002-0307-2507 ; 0000-0002-6423-4637 ; 0000-0001-8801-0649 ; 0000-0002-6994-8401 ; 0000-0001-5092-9238 ; 0000-0002-3654-3846 ; 0000-0001-6231-4417 ; 0000-0002-4862-9073</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438099/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438099/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32875106$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Böhm, Sybille</creatorcontrib><creatorcontrib>Splith, Victoria</creatorcontrib><creatorcontrib>Riedmayr, Lisa Maria</creatorcontrib><creatorcontrib>Rötzer, René Dominik</creatorcontrib><creatorcontrib>Gasparoni, Gilles</creatorcontrib><creatorcontrib>Nordström, Karl J V</creatorcontrib><creatorcontrib>Wagner, Johanna Elisabeth</creatorcontrib><creatorcontrib>Hinrichsmeyer, Klara Sonnie</creatorcontrib><creatorcontrib>Walter, Jörn</creatorcontrib><creatorcontrib>Wahl-Schott, Christian</creatorcontrib><creatorcontrib>Fenske, Stefanie</creatorcontrib><creatorcontrib>Biel, Martin</creatorcontrib><creatorcontrib>Michalakis, Stylianos</creatorcontrib><creatorcontrib>Becirovic, Elvir</creatorcontrib><title>A gene therapy for inherited blindness using dCas9-VPR-mediated transcriptional activation</title><title>Science advances</title><addtitle>Sci Adv</addtitle><description>Catalytically inactive dCas9 fused to transcriptional activators (dCas9-VPR) enables activation of silent genes. Many disease genes have counterparts, which serve similar functions but are expressed in distinct cell types. One attractive option to compensate for the missing function of a defective gene could be to transcriptionally activate its functionally equivalent counterpart via dCas9-VPR. Key challenges of this approach include the delivery of dCas9-VPR, activation efficiency, long-term expression of the target gene, and adverse effects in vivo. Using dual adeno-associated viral vectors expressing split dCas9-VPR, we show efficient transcriptional activation and long-term expression of cone photoreceptor-specific M-opsin (
) in a rhodopsin-deficient mouse model for retinitis pigmentosa. One year after treatment, this approach yields improved retinal function and attenuated retinal degeneration with no apparent adverse effects. Our study demonstrates that dCas9-VPR-mediated transcriptional activation of functionally equivalent genes has great potential for the treatment of genetic disorders.</description><subject>Animals</subject><subject>Blindness - genetics</subject><subject>Blindness - therapy</subject><subject>CRISPR-Cas Systems</subject><subject>Diseases and Disorders</subject><subject>Genetic Therapy</subject><subject>Mice</subject><subject>Molecular Biology</subject><subject>SciAdv r-articles</subject><subject>Transcription Factors - genetics</subject><subject>Transcriptional Activation</subject><issn>2375-2548</issn><issn>2375-2548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1LAzEQDaKoqFePskcvW5PNx24ughS_oKCIevASZpPZNrLN1mRb6L93S6soc5gZ5s17Dx4h54yOGCvUVbIe3GoENUjFxB45Lngp80KKav_PfETOUvqklDKhlGT6kBzxoiolo-qYfNxkUwyY9TOMsFhnTRczH4bF9-iyuvXBBUwpWyYfppkbQ9L5-_NLPkfnYQPpI4Rko1_0vgvQZmB7v4LNckoOGmgTnu36CXm7u30dP-STp_vH8c0kt0KqPneqrMDVFIZCzYEN5rBSTV0qajmClByRNY1iWjTgGk4LLjSVTtbC1o7yE3K95V0s68GWxTB4as0i-jnEtenAm_-X4Gdm2q1MKXhFtR4ILncEsftaYurN3CeLbQsBu2UyheBaFZqyjdZoC7WxSyli8yvDqNlkYraZmF0mw8PFX3O_8J8E-DcMGowY</recordid><startdate>20200801</startdate><enddate>20200801</enddate><creator>Böhm, Sybille</creator><creator>Splith, Victoria</creator><creator>Riedmayr, Lisa Maria</creator><creator>Rötzer, René Dominik</creator><creator>Gasparoni, Gilles</creator><creator>Nordström, Karl J V</creator><creator>Wagner, Johanna Elisabeth</creator><creator>Hinrichsmeyer, Klara Sonnie</creator><creator>Walter, Jörn</creator><creator>Wahl-Schott, Christian</creator><creator>Fenske, Stefanie</creator><creator>Biel, Martin</creator><creator>Michalakis, Stylianos</creator><creator>Becirovic, Elvir</creator><general>American Association for the Advancement of Science</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-0307-2507</orcidid><orcidid>https://orcid.org/0000-0002-6423-4637</orcidid><orcidid>https://orcid.org/0000-0001-8801-0649</orcidid><orcidid>https://orcid.org/0000-0002-6994-8401</orcidid><orcidid>https://orcid.org/0000-0001-5092-9238</orcidid><orcidid>https://orcid.org/0000-0002-3654-3846</orcidid><orcidid>https://orcid.org/0000-0001-6231-4417</orcidid><orcidid>https://orcid.org/0000-0002-4862-9073</orcidid></search><sort><creationdate>20200801</creationdate><title>A gene therapy for inherited blindness using dCas9-VPR-mediated transcriptional activation</title><author>Böhm, Sybille ; Splith, Victoria ; Riedmayr, Lisa Maria ; Rötzer, René Dominik ; Gasparoni, Gilles ; Nordström, Karl J V ; Wagner, Johanna Elisabeth ; Hinrichsmeyer, Klara Sonnie ; Walter, Jörn ; Wahl-Schott, Christian ; Fenske, Stefanie ; Biel, Martin ; Michalakis, Stylianos ; Becirovic, Elvir</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c456t-d678adb0a0a0e93a1328e86fb760c3ea553ee1ff6194fadf30234905d5b4cbd03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Blindness - genetics</topic><topic>Blindness - therapy</topic><topic>CRISPR-Cas Systems</topic><topic>Diseases and Disorders</topic><topic>Genetic Therapy</topic><topic>Mice</topic><topic>Molecular Biology</topic><topic>SciAdv r-articles</topic><topic>Transcription Factors - genetics</topic><topic>Transcriptional Activation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Böhm, Sybille</creatorcontrib><creatorcontrib>Splith, Victoria</creatorcontrib><creatorcontrib>Riedmayr, Lisa Maria</creatorcontrib><creatorcontrib>Rötzer, René Dominik</creatorcontrib><creatorcontrib>Gasparoni, Gilles</creatorcontrib><creatorcontrib>Nordström, Karl J V</creatorcontrib><creatorcontrib>Wagner, Johanna Elisabeth</creatorcontrib><creatorcontrib>Hinrichsmeyer, Klara Sonnie</creatorcontrib><creatorcontrib>Walter, Jörn</creatorcontrib><creatorcontrib>Wahl-Schott, Christian</creatorcontrib><creatorcontrib>Fenske, Stefanie</creatorcontrib><creatorcontrib>Biel, Martin</creatorcontrib><creatorcontrib>Michalakis, Stylianos</creatorcontrib><creatorcontrib>Becirovic, Elvir</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science advances</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Böhm, Sybille</au><au>Splith, Victoria</au><au>Riedmayr, Lisa Maria</au><au>Rötzer, René Dominik</au><au>Gasparoni, Gilles</au><au>Nordström, Karl J V</au><au>Wagner, Johanna Elisabeth</au><au>Hinrichsmeyer, Klara Sonnie</au><au>Walter, Jörn</au><au>Wahl-Schott, Christian</au><au>Fenske, Stefanie</au><au>Biel, Martin</au><au>Michalakis, Stylianos</au><au>Becirovic, Elvir</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A gene therapy for inherited blindness using dCas9-VPR-mediated transcriptional activation</atitle><jtitle>Science advances</jtitle><addtitle>Sci Adv</addtitle><date>2020-08-01</date><risdate>2020</risdate><volume>6</volume><issue>34</issue><spage>eaba5614</spage><epage>eaba5614</epage><pages>eaba5614-eaba5614</pages><issn>2375-2548</issn><eissn>2375-2548</eissn><abstract>Catalytically inactive dCas9 fused to transcriptional activators (dCas9-VPR) enables activation of silent genes. Many disease genes have counterparts, which serve similar functions but are expressed in distinct cell types. One attractive option to compensate for the missing function of a defective gene could be to transcriptionally activate its functionally equivalent counterpart via dCas9-VPR. Key challenges of this approach include the delivery of dCas9-VPR, activation efficiency, long-term expression of the target gene, and adverse effects in vivo. Using dual adeno-associated viral vectors expressing split dCas9-VPR, we show efficient transcriptional activation and long-term expression of cone photoreceptor-specific M-opsin (
) in a rhodopsin-deficient mouse model for retinitis pigmentosa. One year after treatment, this approach yields improved retinal function and attenuated retinal degeneration with no apparent adverse effects. Our study demonstrates that dCas9-VPR-mediated transcriptional activation of functionally equivalent genes has great potential for the treatment of genetic disorders.</abstract><cop>United States</cop><pub>American Association for the Advancement of Science</pub><pmid>32875106</pmid><doi>10.1126/sciadv.aba5614</doi><orcidid>https://orcid.org/0000-0002-0307-2507</orcidid><orcidid>https://orcid.org/0000-0002-6423-4637</orcidid><orcidid>https://orcid.org/0000-0001-8801-0649</orcidid><orcidid>https://orcid.org/0000-0002-6994-8401</orcidid><orcidid>https://orcid.org/0000-0001-5092-9238</orcidid><orcidid>https://orcid.org/0000-0002-3654-3846</orcidid><orcidid>https://orcid.org/0000-0001-6231-4417</orcidid><orcidid>https://orcid.org/0000-0002-4862-9073</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; PubMed Central; EZB Electronic Journals Library |
| subjects | Animals Blindness - genetics Blindness - therapy CRISPR-Cas Systems Diseases and Disorders Genetic Therapy Mice Molecular Biology SciAdv r-articles Transcription Factors - genetics Transcriptional Activation |
| title | A gene therapy for inherited blindness using dCas9-VPR-mediated transcriptional activation |
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