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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...

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Autores principales: 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.
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/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.
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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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