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Systemic gene therapy for methylmalonic acidemia using the novel adeno-associated viral vector 44.9
Methylmalonic acidemia (MMA) is a severe and potentially lethal autosomal recessive inborn error of metabolism most frequently caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene. Proof-of-concept adeno-associated virus (AAV) gene therapy studies using mouse models of MMA have demonstrat...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9490190/ https://www.ncbi.nlm.nih.gov/pubmed/36186952 http://dx.doi.org/10.1016/j.omtm.2022.09.001 |
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author | Chandler, Randy J. Di Pasquale, Giovanni Sloan, Jennifer L. McCoy, Samantha Hubbard, Brandon T. Kilts, Tina M. Manoli, Irini Chiorini, John A. Venditti, Charles P. |
author_facet | Chandler, Randy J. Di Pasquale, Giovanni Sloan, Jennifer L. McCoy, Samantha Hubbard, Brandon T. Kilts, Tina M. Manoli, Irini Chiorini, John A. Venditti, Charles P. |
author_sort | Chandler, Randy J. |
collection | PubMed |
description | Methylmalonic acidemia (MMA) is a severe and potentially lethal autosomal recessive inborn error of metabolism most frequently caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene. Proof-of-concept adeno-associated virus (AAV) gene therapy studies using mouse models of MMA have demonstrated promise for this therapeutic approach but translation to the clinic could be limited by preexisting capsid immunity and vector potency. Here we explore the efficacy of a novel clade E capsid, 44.9, as a serotype for systemic AAV gene therapy for MMA. An anti-AAV44.9 neutralizing antibody (NAb) survey in adult volunteers (n = 19) and a large cohort of MMA patients (n = 48) revealed a seroprevalence rate of ∼26% and 13%, respectively. The efficacy of AAV44.9 gene delivery was examined in two murine models of MMA, representing neonatal lethal and juvenile phenotypes of MMA. Systemic delivery of the AAV44.9-Mmut vector prevented lethality and lowered disease-related metabolites in MMA mice. Tissue biodistribution and transgene expression studies in treated MMA mice showed that AAV44.9 was efficient at transducing the liver and heart. In summary, we establish that AAV44.9 exhibits a low prevalence of preexisting NAb in humans, is highly efficacious in the treatment of clinically severe MMA mouse models and is therefore a promising vector for clinical translation. |
format | Online Article Text |
id | pubmed-9490190 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-94901902022-09-30 Systemic gene therapy for methylmalonic acidemia using the novel adeno-associated viral vector 44.9 Chandler, Randy J. Di Pasquale, Giovanni Sloan, Jennifer L. McCoy, Samantha Hubbard, Brandon T. Kilts, Tina M. Manoli, Irini Chiorini, John A. Venditti, Charles P. Mol Ther Methods Clin Dev Original Article Methylmalonic acidemia (MMA) is a severe and potentially lethal autosomal recessive inborn error of metabolism most frequently caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene. Proof-of-concept adeno-associated virus (AAV) gene therapy studies using mouse models of MMA have demonstrated promise for this therapeutic approach but translation to the clinic could be limited by preexisting capsid immunity and vector potency. Here we explore the efficacy of a novel clade E capsid, 44.9, as a serotype for systemic AAV gene therapy for MMA. An anti-AAV44.9 neutralizing antibody (NAb) survey in adult volunteers (n = 19) and a large cohort of MMA patients (n = 48) revealed a seroprevalence rate of ∼26% and 13%, respectively. The efficacy of AAV44.9 gene delivery was examined in two murine models of MMA, representing neonatal lethal and juvenile phenotypes of MMA. Systemic delivery of the AAV44.9-Mmut vector prevented lethality and lowered disease-related metabolites in MMA mice. Tissue biodistribution and transgene expression studies in treated MMA mice showed that AAV44.9 was efficient at transducing the liver and heart. In summary, we establish that AAV44.9 exhibits a low prevalence of preexisting NAb in humans, is highly efficacious in the treatment of clinically severe MMA mouse models and is therefore a promising vector for clinical translation. American Society of Gene & Cell Therapy 2022-09-06 /pmc/articles/PMC9490190/ /pubmed/36186952 http://dx.doi.org/10.1016/j.omtm.2022.09.001 Text en © 2022. 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 Chandler, Randy J. Di Pasquale, Giovanni Sloan, Jennifer L. McCoy, Samantha Hubbard, Brandon T. Kilts, Tina M. Manoli, Irini Chiorini, John A. Venditti, Charles P. Systemic gene therapy for methylmalonic acidemia using the novel adeno-associated viral vector 44.9 |
title | Systemic gene therapy for methylmalonic acidemia using the novel adeno-associated viral vector 44.9 |
title_full | Systemic gene therapy for methylmalonic acidemia using the novel adeno-associated viral vector 44.9 |
title_fullStr | Systemic gene therapy for methylmalonic acidemia using the novel adeno-associated viral vector 44.9 |
title_full_unstemmed | Systemic gene therapy for methylmalonic acidemia using the novel adeno-associated viral vector 44.9 |
title_short | Systemic gene therapy for methylmalonic acidemia using the novel adeno-associated viral vector 44.9 |
title_sort | systemic gene therapy for methylmalonic acidemia using the novel adeno-associated viral vector 44.9 |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9490190/ https://www.ncbi.nlm.nih.gov/pubmed/36186952 http://dx.doi.org/10.1016/j.omtm.2022.09.001 |
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