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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2022-01-01
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| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9202865/?tool=EBI |
| _version_ | 1818156829889265664 |
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| author | Steven Hyun Seung Lee Joo Yong Lee Jun-Sub Choi Hee Jong Kim Jin Kim Seho Cha Kyoung Jin Lee Ha-Na Woo Keerang Park Heuiran Lee |
| author_facet | Steven Hyun Seung Lee Joo Yong Lee Jun-Sub Choi Hee Jong Kim Jin Kim Seho Cha Kyoung Jin Lee Ha-Na Woo Keerang Park Heuiran Lee |
| author_sort | Steven Hyun Seung Lee |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-11T15:04:31Z |
| format | Article |
| id | doaj.art-dfbb858ec7644803bb7da0da6cc659fe |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T15:04:31Z |
| publishDate | 2022-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-dfbb858ec7644803bb7da0da6cc659fe2022-12-22T01:01:00ZengPublic Library of Science (PLoS)PLoS ONE1932-62032022-01-01176mTOR inhibition as a novel gene therapeutic strategy for diabetic retinopathySteven Hyun Seung LeeJoo Yong LeeJun-Sub ChoiHee Jong KimJin KimSeho ChaKyoung Jin LeeHa-Na WooKeerang ParkHeuiran LeeIn 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.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9202865/?tool=EBI |
| spellingShingle | Steven Hyun Seung Lee Joo Yong Lee Jun-Sub Choi Hee Jong Kim Jin Kim Seho Cha Kyoung Jin Lee Ha-Na Woo Keerang Park Heuiran Lee mTOR inhibition as a novel gene therapeutic strategy for diabetic retinopathy PLoS ONE |
| 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 |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9202865/?tool=EBI |
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