In vivo genome editing at the albumin locus to treat methylmalonic acidemia

Methylmalonic acidemia (MMA) is a metabolic disorder most commonly caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene. Although adeno-associated viral (AAV) gene therapy has been effective at correcting the disease phenotype in MMA mouse models, clinical translation may be impaired by l...
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Autor*in:	Jessica L. Schneller [verfasserIn] Ciaran M. Lee [verfasserIn] Leah E. Venturoni [verfasserIn] Randy J. Chandler [verfasserIn] Ang Li [verfasserIn] Sangho Myung [verfasserIn] Thomas J. Cradick [verfasserIn] Ayrea E. Hurley [verfasserIn] William R. Lagor [verfasserIn] Gang Bao [verfasserIn] Charles P. Venditti [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Schlagwörter:	adeno-associated virus albumin CRISPR-Cas9 metabolic disorders methylmalonic acidemia genome editing

Übergeordnetes Werk:	In: Molecular Therapy: Methods & Clinical Development - Elsevier, 2015, 23(2021), Seite 619-632
Übergeordnetes Werk:	volume:23 ; year:2021 ; pages:619-632

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1016/j.omtm.2021.11.004

Katalog-ID:	DOAJ054049733

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520			\|a Methylmalonic acidemia (MMA) is a metabolic disorder most commonly caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene. Although adeno-associated viral (AAV) gene therapy has been effective at correcting the disease phenotype in MMA mouse models, clinical translation may be impaired by loss of episomal transgene expression and magnified by the need to treat patients early in life. To achieve permanent correction, we developed a dual AAV strategy to express a codon-optimized MMUT transgene from Alb and tested various CRISPR-Cas9 genome-editing vectors in newly developed knockin mouse models of MMA. For one target site in intron 1 of Alb, we designed rescue cassettes expressing MMUT behind a 2A-peptide or an internal ribosomal entry site sequence. A second guide RNA targeted the initiator codon, and the donor cassette encompassed the proximal albumin promoter in the 5′ homology arm. Although all editing approaches were therapeutic, targeting the start codon of albumin allowed the use of a donor cassette that also functioned as an episome and after homologous recombination, even without the expression of Cas9, as an integrant. Targeting the albumin locus using these strategies would be effective for other metabolic disorders where early treatment and permanent long-term correction are needed.
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700	0		\|a Ang Li \|e verfasserin \|4 aut
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700	0		\|a Gang Bao \|e verfasserin \|4 aut
700	0		\|a Charles P. Venditti \|e verfasserin \|4 aut
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allfields	10.1016/j.omtm.2021.11.004 doi (DE-627)DOAJ054049733 (DE-599)DOAJ40477017c9594449b2c47c26ce788c14 DE-627 ger DE-627 rakwb eng QH426-470 QH573-671 Jessica L. Schneller verfasserin aut In vivo genome editing at the albumin locus to treat methylmalonic acidemia 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Methylmalonic acidemia (MMA) is a metabolic disorder most commonly caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene. Although adeno-associated viral (AAV) gene therapy has been effective at correcting the disease phenotype in MMA mouse models, clinical translation may be impaired by loss of episomal transgene expression and magnified by the need to treat patients early in life. To achieve permanent correction, we developed a dual AAV strategy to express a codon-optimized MMUT transgene from Alb and tested various CRISPR-Cas9 genome-editing vectors in newly developed knockin mouse models of MMA. For one target site in intron 1 of Alb, we designed rescue cassettes expressing MMUT behind a 2A-peptide or an internal ribosomal entry site sequence. A second guide RNA targeted the initiator codon, and the donor cassette encompassed the proximal albumin promoter in the 5′ homology arm. Although all editing approaches were therapeutic, targeting the start codon of albumin allowed the use of a donor cassette that also functioned as an episome and after homologous recombination, even without the expression of Cas9, as an integrant. Targeting the albumin locus using these strategies would be effective for other metabolic disorders where early treatment and permanent long-term correction are needed. adeno-associated virus albumin CRISPR-Cas9 metabolic disorders methylmalonic acidemia genome editing Genetics Cytology Ciaran M. Lee verfasserin aut Leah E. Venturoni verfasserin aut Randy J. Chandler verfasserin aut Ang Li verfasserin aut Sangho Myung verfasserin aut Thomas J. Cradick verfasserin aut Ayrea E. Hurley verfasserin aut William R. Lagor verfasserin aut Gang Bao verfasserin aut Charles P. Venditti verfasserin aut In Molecular Therapy: Methods & Clinical Development Elsevier, 2015 23(2021), Seite 619-632 (DE-627)863823203 (DE-600)2863173-0 23290501 nnns volume:23 year:2021 pages:619-632 https://doi.org/10.1016/j.omtm.2021.11.004 kostenfrei https://doaj.org/article/40477017c9594449b2c47c26ce788c14 kostenfrei http://www.sciencedirect.com/science/article/pii/S2329050121001765 kostenfrei https://doaj.org/toc/2329-0501 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 23 2021 619-632
spelling	10.1016/j.omtm.2021.11.004 doi (DE-627)DOAJ054049733 (DE-599)DOAJ40477017c9594449b2c47c26ce788c14 DE-627 ger DE-627 rakwb eng QH426-470 QH573-671 Jessica L. Schneller verfasserin aut In vivo genome editing at the albumin locus to treat methylmalonic acidemia 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Methylmalonic acidemia (MMA) is a metabolic disorder most commonly caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene. Although adeno-associated viral (AAV) gene therapy has been effective at correcting the disease phenotype in MMA mouse models, clinical translation may be impaired by loss of episomal transgene expression and magnified by the need to treat patients early in life. To achieve permanent correction, we developed a dual AAV strategy to express a codon-optimized MMUT transgene from Alb and tested various CRISPR-Cas9 genome-editing vectors in newly developed knockin mouse models of MMA. For one target site in intron 1 of Alb, we designed rescue cassettes expressing MMUT behind a 2A-peptide or an internal ribosomal entry site sequence. A second guide RNA targeted the initiator codon, and the donor cassette encompassed the proximal albumin promoter in the 5′ homology arm. Although all editing approaches were therapeutic, targeting the start codon of albumin allowed the use of a donor cassette that also functioned as an episome and after homologous recombination, even without the expression of Cas9, as an integrant. Targeting the albumin locus using these strategies would be effective for other metabolic disorders where early treatment and permanent long-term correction are needed. adeno-associated virus albumin CRISPR-Cas9 metabolic disorders methylmalonic acidemia genome editing Genetics Cytology Ciaran M. Lee verfasserin aut Leah E. Venturoni verfasserin aut Randy J. Chandler verfasserin aut Ang Li verfasserin aut Sangho Myung verfasserin aut Thomas J. Cradick verfasserin aut Ayrea E. Hurley verfasserin aut William R. Lagor verfasserin aut Gang Bao verfasserin aut Charles P. Venditti verfasserin aut In Molecular Therapy: Methods & Clinical Development Elsevier, 2015 23(2021), Seite 619-632 (DE-627)863823203 (DE-600)2863173-0 23290501 nnns volume:23 year:2021 pages:619-632 https://doi.org/10.1016/j.omtm.2021.11.004 kostenfrei https://doaj.org/article/40477017c9594449b2c47c26ce788c14 kostenfrei http://www.sciencedirect.com/science/article/pii/S2329050121001765 kostenfrei https://doaj.org/toc/2329-0501 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 23 2021 619-632
allfields_unstemmed	10.1016/j.omtm.2021.11.004 doi (DE-627)DOAJ054049733 (DE-599)DOAJ40477017c9594449b2c47c26ce788c14 DE-627 ger DE-627 rakwb eng QH426-470 QH573-671 Jessica L. Schneller verfasserin aut In vivo genome editing at the albumin locus to treat methylmalonic acidemia 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Methylmalonic acidemia (MMA) is a metabolic disorder most commonly caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene. Although adeno-associated viral (AAV) gene therapy has been effective at correcting the disease phenotype in MMA mouse models, clinical translation may be impaired by loss of episomal transgene expression and magnified by the need to treat patients early in life. To achieve permanent correction, we developed a dual AAV strategy to express a codon-optimized MMUT transgene from Alb and tested various CRISPR-Cas9 genome-editing vectors in newly developed knockin mouse models of MMA. For one target site in intron 1 of Alb, we designed rescue cassettes expressing MMUT behind a 2A-peptide or an internal ribosomal entry site sequence. A second guide RNA targeted the initiator codon, and the donor cassette encompassed the proximal albumin promoter in the 5′ homology arm. Although all editing approaches were therapeutic, targeting the start codon of albumin allowed the use of a donor cassette that also functioned as an episome and after homologous recombination, even without the expression of Cas9, as an integrant. Targeting the albumin locus using these strategies would be effective for other metabolic disorders where early treatment and permanent long-term correction are needed. adeno-associated virus albumin CRISPR-Cas9 metabolic disorders methylmalonic acidemia genome editing Genetics Cytology Ciaran M. Lee verfasserin aut Leah E. Venturoni verfasserin aut Randy J. Chandler verfasserin aut Ang Li verfasserin aut Sangho Myung verfasserin aut Thomas J. Cradick verfasserin aut Ayrea E. Hurley verfasserin aut William R. Lagor verfasserin aut Gang Bao verfasserin aut Charles P. Venditti verfasserin aut In Molecular Therapy: Methods & Clinical Development Elsevier, 2015 23(2021), Seite 619-632 (DE-627)863823203 (DE-600)2863173-0 23290501 nnns volume:23 year:2021 pages:619-632 https://doi.org/10.1016/j.omtm.2021.11.004 kostenfrei https://doaj.org/article/40477017c9594449b2c47c26ce788c14 kostenfrei http://www.sciencedirect.com/science/article/pii/S2329050121001765 kostenfrei https://doaj.org/toc/2329-0501 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 23 2021 619-632
allfieldsGer	10.1016/j.omtm.2021.11.004 doi (DE-627)DOAJ054049733 (DE-599)DOAJ40477017c9594449b2c47c26ce788c14 DE-627 ger DE-627 rakwb eng QH426-470 QH573-671 Jessica L. Schneller verfasserin aut In vivo genome editing at the albumin locus to treat methylmalonic acidemia 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Methylmalonic acidemia (MMA) is a metabolic disorder most commonly caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene. Although adeno-associated viral (AAV) gene therapy has been effective at correcting the disease phenotype in MMA mouse models, clinical translation may be impaired by loss of episomal transgene expression and magnified by the need to treat patients early in life. To achieve permanent correction, we developed a dual AAV strategy to express a codon-optimized MMUT transgene from Alb and tested various CRISPR-Cas9 genome-editing vectors in newly developed knockin mouse models of MMA. For one target site in intron 1 of Alb, we designed rescue cassettes expressing MMUT behind a 2A-peptide or an internal ribosomal entry site sequence. A second guide RNA targeted the initiator codon, and the donor cassette encompassed the proximal albumin promoter in the 5′ homology arm. Although all editing approaches were therapeutic, targeting the start codon of albumin allowed the use of a donor cassette that also functioned as an episome and after homologous recombination, even without the expression of Cas9, as an integrant. Targeting the albumin locus using these strategies would be effective for other metabolic disorders where early treatment and permanent long-term correction are needed. adeno-associated virus albumin CRISPR-Cas9 metabolic disorders methylmalonic acidemia genome editing Genetics Cytology Ciaran M. Lee verfasserin aut Leah E. Venturoni verfasserin aut Randy J. Chandler verfasserin aut Ang Li verfasserin aut Sangho Myung verfasserin aut Thomas J. Cradick verfasserin aut Ayrea E. Hurley verfasserin aut William R. Lagor verfasserin aut Gang Bao verfasserin aut Charles P. Venditti verfasserin aut In Molecular Therapy: Methods & Clinical Development Elsevier, 2015 23(2021), Seite 619-632 (DE-627)863823203 (DE-600)2863173-0 23290501 nnns volume:23 year:2021 pages:619-632 https://doi.org/10.1016/j.omtm.2021.11.004 kostenfrei https://doaj.org/article/40477017c9594449b2c47c26ce788c14 kostenfrei http://www.sciencedirect.com/science/article/pii/S2329050121001765 kostenfrei https://doaj.org/toc/2329-0501 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 23 2021 619-632
allfieldsSound	10.1016/j.omtm.2021.11.004 doi (DE-627)DOAJ054049733 (DE-599)DOAJ40477017c9594449b2c47c26ce788c14 DE-627 ger DE-627 rakwb eng QH426-470 QH573-671 Jessica L. Schneller verfasserin aut In vivo genome editing at the albumin locus to treat methylmalonic acidemia 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Methylmalonic acidemia (MMA) is a metabolic disorder most commonly caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene. Although adeno-associated viral (AAV) gene therapy has been effective at correcting the disease phenotype in MMA mouse models, clinical translation may be impaired by loss of episomal transgene expression and magnified by the need to treat patients early in life. To achieve permanent correction, we developed a dual AAV strategy to express a codon-optimized MMUT transgene from Alb and tested various CRISPR-Cas9 genome-editing vectors in newly developed knockin mouse models of MMA. For one target site in intron 1 of Alb, we designed rescue cassettes expressing MMUT behind a 2A-peptide or an internal ribosomal entry site sequence. A second guide RNA targeted the initiator codon, and the donor cassette encompassed the proximal albumin promoter in the 5′ homology arm. Although all editing approaches were therapeutic, targeting the start codon of albumin allowed the use of a donor cassette that also functioned as an episome and after homologous recombination, even without the expression of Cas9, as an integrant. Targeting the albumin locus using these strategies would be effective for other metabolic disorders where early treatment and permanent long-term correction are needed. adeno-associated virus albumin CRISPR-Cas9 metabolic disorders methylmalonic acidemia genome editing Genetics Cytology Ciaran M. Lee verfasserin aut Leah E. Venturoni verfasserin aut Randy J. Chandler verfasserin aut Ang Li verfasserin aut Sangho Myung verfasserin aut Thomas J. Cradick verfasserin aut Ayrea E. Hurley verfasserin aut William R. Lagor verfasserin aut Gang Bao verfasserin aut Charles P. Venditti verfasserin aut In Molecular Therapy: Methods & Clinical Development Elsevier, 2015 23(2021), Seite 619-632 (DE-627)863823203 (DE-600)2863173-0 23290501 nnns volume:23 year:2021 pages:619-632 https://doi.org/10.1016/j.omtm.2021.11.004 kostenfrei https://doaj.org/article/40477017c9594449b2c47c26ce788c14 kostenfrei http://www.sciencedirect.com/science/article/pii/S2329050121001765 kostenfrei https://doaj.org/toc/2329-0501 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 23 2021 619-632
language	English
source	In Molecular Therapy: Methods & Clinical Development 23(2021), Seite 619-632 volume:23 year:2021 pages:619-632
sourceStr	In Molecular Therapy: Methods & Clinical Development 23(2021), Seite 619-632 volume:23 year:2021 pages:619-632
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	adeno-associated virus albumin CRISPR-Cas9 metabolic disorders methylmalonic acidemia genome editing Genetics Cytology
isfreeaccess_bool	true
container_title	Molecular Therapy: Methods & Clinical Development
authorswithroles_txt_mv	Jessica L. Schneller @@aut@@ Ciaran M. Lee @@aut@@ Leah E. Venturoni @@aut@@ Randy J. Chandler @@aut@@ Ang Li @@aut@@ Sangho Myung @@aut@@ Thomas J. Cradick @@aut@@ Ayrea E. Hurley @@aut@@ William R. Lagor @@aut@@ Gang Bao @@aut@@ Charles P. Venditti @@aut@@
publishDateDaySort_date	2021-01-01T00:00:00Z
hierarchy_top_id	863823203
id	DOAJ054049733
language_de	englisch
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Schneller</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">In vivo genome editing at the albumin locus to treat methylmalonic acidemia</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2021</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Methylmalonic acidemia (MMA) is a metabolic disorder most commonly caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene. 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callnumber-first	Q - Science
author	Jessica L. Schneller
spellingShingle	Jessica L. Schneller misc QH426-470 misc QH573-671 misc adeno-associated virus misc albumin misc CRISPR-Cas9 misc metabolic disorders misc methylmalonic acidemia misc genome editing misc Genetics misc Cytology In vivo genome editing at the albumin locus to treat methylmalonic acidemia
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topic_title	QH426-470 QH573-671 In vivo genome editing at the albumin locus to treat methylmalonic acidemia adeno-associated virus albumin CRISPR-Cas9 metabolic disorders methylmalonic acidemia genome editing
topic	misc QH426-470 misc QH573-671 misc adeno-associated virus misc albumin misc CRISPR-Cas9 misc metabolic disorders misc methylmalonic acidemia misc genome editing misc Genetics misc Cytology
topic_unstemmed	misc QH426-470 misc QH573-671 misc adeno-associated virus misc albumin misc CRISPR-Cas9 misc metabolic disorders misc methylmalonic acidemia misc genome editing misc Genetics misc Cytology
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title	In vivo genome editing at the albumin locus to treat methylmalonic acidemia
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title_full	In vivo genome editing at the albumin locus to treat methylmalonic acidemia
author_sort	Jessica L. Schneller
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author_browse	Jessica L. Schneller Ciaran M. Lee Leah E. Venturoni Randy J. Chandler Ang Li Sangho Myung Thomas J. Cradick Ayrea E. Hurley William R. Lagor Gang Bao Charles P. Venditti
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title_sort	in vivo genome editing at the albumin locus to treat methylmalonic acidemia
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title_auth	In vivo genome editing at the albumin locus to treat methylmalonic acidemia
abstract	Methylmalonic acidemia (MMA) is a metabolic disorder most commonly caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene. Although adeno-associated viral (AAV) gene therapy has been effective at correcting the disease phenotype in MMA mouse models, clinical translation may be impaired by loss of episomal transgene expression and magnified by the need to treat patients early in life. To achieve permanent correction, we developed a dual AAV strategy to express a codon-optimized MMUT transgene from Alb and tested various CRISPR-Cas9 genome-editing vectors in newly developed knockin mouse models of MMA. For one target site in intron 1 of Alb, we designed rescue cassettes expressing MMUT behind a 2A-peptide or an internal ribosomal entry site sequence. A second guide RNA targeted the initiator codon, and the donor cassette encompassed the proximal albumin promoter in the 5′ homology arm. Although all editing approaches were therapeutic, targeting the start codon of albumin allowed the use of a donor cassette that also functioned as an episome and after homologous recombination, even without the expression of Cas9, as an integrant. Targeting the albumin locus using these strategies would be effective for other metabolic disorders where early treatment and permanent long-term correction are needed.
abstractGer	Methylmalonic acidemia (MMA) is a metabolic disorder most commonly caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene. Although adeno-associated viral (AAV) gene therapy has been effective at correcting the disease phenotype in MMA mouse models, clinical translation may be impaired by loss of episomal transgene expression and magnified by the need to treat patients early in life. To achieve permanent correction, we developed a dual AAV strategy to express a codon-optimized MMUT transgene from Alb and tested various CRISPR-Cas9 genome-editing vectors in newly developed knockin mouse models of MMA. For one target site in intron 1 of Alb, we designed rescue cassettes expressing MMUT behind a 2A-peptide or an internal ribosomal entry site sequence. A second guide RNA targeted the initiator codon, and the donor cassette encompassed the proximal albumin promoter in the 5′ homology arm. Although all editing approaches were therapeutic, targeting the start codon of albumin allowed the use of a donor cassette that also functioned as an episome and after homologous recombination, even without the expression of Cas9, as an integrant. Targeting the albumin locus using these strategies would be effective for other metabolic disorders where early treatment and permanent long-term correction are needed.
abstract_unstemmed	Methylmalonic acidemia (MMA) is a metabolic disorder most commonly caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene. Although adeno-associated viral (AAV) gene therapy has been effective at correcting the disease phenotype in MMA mouse models, clinical translation may be impaired by loss of episomal transgene expression and magnified by the need to treat patients early in life. To achieve permanent correction, we developed a dual AAV strategy to express a codon-optimized MMUT transgene from Alb and tested various CRISPR-Cas9 genome-editing vectors in newly developed knockin mouse models of MMA. For one target site in intron 1 of Alb, we designed rescue cassettes expressing MMUT behind a 2A-peptide or an internal ribosomal entry site sequence. A second guide RNA targeted the initiator codon, and the donor cassette encompassed the proximal albumin promoter in the 5′ homology arm. Although all editing approaches were therapeutic, targeting the start codon of albumin allowed the use of a donor cassette that also functioned as an episome and after homologous recombination, even without the expression of Cas9, as an integrant. Targeting the albumin locus using these strategies would be effective for other metabolic disorders where early treatment and permanent long-term correction are needed.
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title_short	In vivo genome editing at the albumin locus to treat methylmalonic acidemia
url	https://doi.org/10.1016/j.omtm.2021.11.004 https://doaj.org/article/40477017c9594449b2c47c26ce788c14 http://www.sciencedirect.com/science/article/pii/S2329050121001765 https://doaj.org/toc/2329-0501
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Although all editing approaches were therapeutic, targeting the start codon of albumin allowed the use of a donor cassette that also functioned as an episome and after homologous recombination, even without the expression of Cas9, as an integrant. 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In vivo genome editing at the albumin locus to treat methylmalonic acidemia

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