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In vivo CRISPR-Cas9 inhibition of hepatic LDH as treatment of primary hyperoxaluria

Genome-editing strategies, especially CRISPR-Cas9 systems, have substantially increased the efficiency of innovative therapeutic approaches for monogenic diseases such as primary hyperoxalurias (PHs). We have previously demonstrated that inhibition of glycolate oxidase using CRISPR-Cas9 systems repr...

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Autores principales: Martinez-Turrillas, Rebeca, Martin-Mallo, Angel, Rodriguez-Diaz, Saray, Zapata-Linares, Natalia, Rodriguez-Marquez, Paula, San Martin-Uriz, Patxi, Vilas-Zornoza, Amaia, Calleja-Cervantes, María E., Salido, Eduardo, Prosper, Felipe, Rodriguez-Madoz, Juan R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971349/
https://www.ncbi.nlm.nih.gov/pubmed/35402636
http://dx.doi.org/10.1016/j.omtm.2022.03.006
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author Martinez-Turrillas, Rebeca
Martin-Mallo, Angel
Rodriguez-Diaz, Saray
Zapata-Linares, Natalia
Rodriguez-Marquez, Paula
San Martin-Uriz, Patxi
Vilas-Zornoza, Amaia
Calleja-Cervantes, María E.
Salido, Eduardo
Prosper, Felipe
Rodriguez-Madoz, Juan R.
author_facet Martinez-Turrillas, Rebeca
Martin-Mallo, Angel
Rodriguez-Diaz, Saray
Zapata-Linares, Natalia
Rodriguez-Marquez, Paula
San Martin-Uriz, Patxi
Vilas-Zornoza, Amaia
Calleja-Cervantes, María E.
Salido, Eduardo
Prosper, Felipe
Rodriguez-Madoz, Juan R.
author_sort Martinez-Turrillas, Rebeca
collection PubMed
description Genome-editing strategies, especially CRISPR-Cas9 systems, have substantially increased the efficiency of innovative therapeutic approaches for monogenic diseases such as primary hyperoxalurias (PHs). We have previously demonstrated that inhibition of glycolate oxidase using CRISPR-Cas9 systems represents a promising therapeutic option for PH type I (PH1). Here, we extended our work evaluating the efficacy of liver-specific inhibition of lactate dehydrogenase (LDH), a key enzyme responsible for converting glyoxylate to oxalate; this strategy would not be limited to PH1, being applicable to other PH subtypes. In this work, we demonstrate a liver-specific inhibition of LDH that resulted in a drastic reduction of LDH levels in the liver of PH1 and PH3 mice after a single-dose delivery of AAV8 vectors expressing the CRISPR-Cas9 system, resulting in reduced urine oxalate levels and kidney damage without signs of toxicity. Deep sequencing analysis revealed that this approach was safe and specific, with no off-targets detected in the liver of treated animals and no on-target/off-tissue events. Altogether, our data provide evidence that in vivo genome editing using CRISPR-Cas9 systems would represent a valuable tool for improved therapeutic approaches for PH.
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spelling pubmed-89713492022-04-07 In vivo CRISPR-Cas9 inhibition of hepatic LDH as treatment of primary hyperoxaluria Martinez-Turrillas, Rebeca Martin-Mallo, Angel Rodriguez-Diaz, Saray Zapata-Linares, Natalia Rodriguez-Marquez, Paula San Martin-Uriz, Patxi Vilas-Zornoza, Amaia Calleja-Cervantes, María E. Salido, Eduardo Prosper, Felipe Rodriguez-Madoz, Juan R. Mol Ther Methods Clin Dev Original Article Genome-editing strategies, especially CRISPR-Cas9 systems, have substantially increased the efficiency of innovative therapeutic approaches for monogenic diseases such as primary hyperoxalurias (PHs). We have previously demonstrated that inhibition of glycolate oxidase using CRISPR-Cas9 systems represents a promising therapeutic option for PH type I (PH1). Here, we extended our work evaluating the efficacy of liver-specific inhibition of lactate dehydrogenase (LDH), a key enzyme responsible for converting glyoxylate to oxalate; this strategy would not be limited to PH1, being applicable to other PH subtypes. In this work, we demonstrate a liver-specific inhibition of LDH that resulted in a drastic reduction of LDH levels in the liver of PH1 and PH3 mice after a single-dose delivery of AAV8 vectors expressing the CRISPR-Cas9 system, resulting in reduced urine oxalate levels and kidney damage without signs of toxicity. Deep sequencing analysis revealed that this approach was safe and specific, with no off-targets detected in the liver of treated animals and no on-target/off-tissue events. Altogether, our data provide evidence that in vivo genome editing using CRISPR-Cas9 systems would represent a valuable tool for improved therapeutic approaches for PH. American Society of Gene & Cell Therapy 2022-03-16 /pmc/articles/PMC8971349/ /pubmed/35402636 http://dx.doi.org/10.1016/j.omtm.2022.03.006 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Martinez-Turrillas, Rebeca
Martin-Mallo, Angel
Rodriguez-Diaz, Saray
Zapata-Linares, Natalia
Rodriguez-Marquez, Paula
San Martin-Uriz, Patxi
Vilas-Zornoza, Amaia
Calleja-Cervantes, María E.
Salido, Eduardo
Prosper, Felipe
Rodriguez-Madoz, Juan R.
In vivo CRISPR-Cas9 inhibition of hepatic LDH as treatment of primary hyperoxaluria
title In vivo CRISPR-Cas9 inhibition of hepatic LDH as treatment of primary hyperoxaluria
title_full In vivo CRISPR-Cas9 inhibition of hepatic LDH as treatment of primary hyperoxaluria
title_fullStr In vivo CRISPR-Cas9 inhibition of hepatic LDH as treatment of primary hyperoxaluria
title_full_unstemmed In vivo CRISPR-Cas9 inhibition of hepatic LDH as treatment of primary hyperoxaluria
title_short In vivo CRISPR-Cas9 inhibition of hepatic LDH as treatment of primary hyperoxaluria
title_sort in vivo crispr-cas9 inhibition of hepatic ldh as treatment of primary hyperoxaluria
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971349/
https://www.ncbi.nlm.nih.gov/pubmed/35402636
http://dx.doi.org/10.1016/j.omtm.2022.03.006
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