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mTOR inhibition as a novel gene therapeutic strategy for diabetic retinopathy

In addition to laser photocoagulation, therapeutic interventions for diabetic retinopathy (DR) have heretofore consisted of anti-VEGF drugs, which, besides drawbacks inherent to the treatments themselves, are limited in scope and may not fully address the condition’s complex pathophysiology. This is...

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Autores principales: Lee, Steven Hyun Seung, Lee, Joo Yong, Choi, Jun-Sub, Kim, Hee Jong, Kim, Jin, Cha, Seho, Lee, Kyoung Jin, Woo, Ha-Na, Park, Keerang, Lee, Heuiran
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9202865/
https://www.ncbi.nlm.nih.gov/pubmed/35709240
http://dx.doi.org/10.1371/journal.pone.0269951
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author Lee, Steven Hyun Seung
Lee, Joo Yong
Choi, Jun-Sub
Kim, Hee Jong
Kim, Jin
Cha, Seho
Lee, Kyoung Jin
Woo, Ha-Na
Park, Keerang
Lee, Heuiran
author_facet Lee, Steven Hyun Seung
Lee, Joo Yong
Choi, Jun-Sub
Kim, Hee Jong
Kim, Jin
Cha, Seho
Lee, Kyoung Jin
Woo, Ha-Na
Park, Keerang
Lee, Heuiran
author_sort Lee, Steven Hyun Seung
collection PubMed
description In addition to laser photocoagulation, therapeutic interventions for diabetic retinopathy (DR) have heretofore consisted of anti-VEGF drugs, which, besides drawbacks inherent to the treatments themselves, are limited in scope and may not fully address the condition’s complex pathophysiology. This is because DR is a multifactorial condition, meaning a gene therapy focused on a target with broader effects, such as the mechanistic target of rapamycin (mTOR), may prove to be the solution in overcoming these concerns. Having previously demonstrated the potential of a mTOR-inhibiting shRNA packaged in a recombinant adeno-associated virus to address a variety of angiogenic retinal diseases, here we explore the effects of rAAV2-shmTOR-SD in a streptozotocin-induced diabetic mouse model. Delivered via intravitreal injection, the therapeutic efficacy of the virus vector upon early DR processes was examined. rAAV2-shmTOR-SD effectively transduced mouse retinas and therein downregulated mTOR expression, which was elevated in sham-treated and control shRNA-injected (rAAV2-shCon-SD) control groups. mTOR inhibition additionally led to marked reductions in pericyte loss, acellular capillary formation, vascular permeability, and retinal cell layer thinning, processes that contribute to DR progression. Immunohistochemistry showed that rAAV2-shmTOR-SD decreased ganglion cell loss and pathogenic Müller cell activation and proliferation, while also having anti-apoptotic activity, with these effects suggesting the therapeutic virus vector may be neuroprotective. Taken together, these results build upon our previous work to demonstrate the broad ability of rAAV2-shmTOR-SD to address aspects of DR pathophysiology further evidencing its potential as a human gene therapeutic strategy for DR.
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spelling pubmed-92028652022-06-17 mTOR inhibition as a novel gene therapeutic strategy for diabetic retinopathy Lee, Steven Hyun Seung Lee, Joo Yong Choi, Jun-Sub Kim, Hee Jong Kim, Jin Cha, Seho Lee, Kyoung Jin Woo, Ha-Na Park, Keerang Lee, Heuiran PLoS One Research Article In addition to laser photocoagulation, therapeutic interventions for diabetic retinopathy (DR) have heretofore consisted of anti-VEGF drugs, which, besides drawbacks inherent to the treatments themselves, are limited in scope and may not fully address the condition’s complex pathophysiology. This is because DR is a multifactorial condition, meaning a gene therapy focused on a target with broader effects, such as the mechanistic target of rapamycin (mTOR), may prove to be the solution in overcoming these concerns. Having previously demonstrated the potential of a mTOR-inhibiting shRNA packaged in a recombinant adeno-associated virus to address a variety of angiogenic retinal diseases, here we explore the effects of rAAV2-shmTOR-SD in a streptozotocin-induced diabetic mouse model. Delivered via intravitreal injection, the therapeutic efficacy of the virus vector upon early DR processes was examined. rAAV2-shmTOR-SD effectively transduced mouse retinas and therein downregulated mTOR expression, which was elevated in sham-treated and control shRNA-injected (rAAV2-shCon-SD) control groups. mTOR inhibition additionally led to marked reductions in pericyte loss, acellular capillary formation, vascular permeability, and retinal cell layer thinning, processes that contribute to DR progression. Immunohistochemistry showed that rAAV2-shmTOR-SD decreased ganglion cell loss and pathogenic Müller cell activation and proliferation, while also having anti-apoptotic activity, with these effects suggesting the therapeutic virus vector may be neuroprotective. Taken together, these results build upon our previous work to demonstrate the broad ability of rAAV2-shmTOR-SD to address aspects of DR pathophysiology further evidencing its potential as a human gene therapeutic strategy for DR. Public Library of Science 2022-06-16 /pmc/articles/PMC9202865/ /pubmed/35709240 http://dx.doi.org/10.1371/journal.pone.0269951 Text en © 2022 Lee et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Lee, Steven Hyun Seung
Lee, Joo Yong
Choi, Jun-Sub
Kim, Hee Jong
Kim, Jin
Cha, Seho
Lee, Kyoung Jin
Woo, Ha-Na
Park, Keerang
Lee, Heuiran
mTOR inhibition as a novel gene therapeutic strategy for diabetic retinopathy
title mTOR inhibition as a novel gene therapeutic strategy for diabetic retinopathy
title_full mTOR inhibition as a novel gene therapeutic strategy for diabetic retinopathy
title_fullStr mTOR inhibition as a novel gene therapeutic strategy for diabetic retinopathy
title_full_unstemmed mTOR inhibition as a novel gene therapeutic strategy for diabetic retinopathy
title_short mTOR inhibition as a novel gene therapeutic strategy for diabetic retinopathy
title_sort mtor inhibition as a novel gene therapeutic strategy for diabetic retinopathy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9202865/
https://www.ncbi.nlm.nih.gov/pubmed/35709240
http://dx.doi.org/10.1371/journal.pone.0269951
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