Adnan Dibas, Subrata Batabyal, Sanghoon Kim, Michael Carlson, Samarendra Mohanty, Najam A Sharif
{"title":"雷伯先天性失明小鼠模型中的玻璃体内多特征光蛋白(MCO-010)光遗传基因疗法的疗效。","authors":"Adnan Dibas, Subrata Batabyal, Sanghoon Kim, Michael Carlson, Samarendra Mohanty, Najam A Sharif","doi":"10.1089/jop.2024.0084","DOIUrl":null,"url":null,"abstract":"<p><p><b><i>Purpose:</i></b> Leber congenital amaurosis (LCA) is a sight-threatening inherited retinal disorder (IRD) caused by numerous genetic mutations. Multi-characteristic opsin (MCO)-based optogenetic therapy allows the recruitment of residual cells of the retina in LCA for alternative vision transduction while being mutation-agnostic. Using <i>rd12</i> mice, we investigated the <i>in vivo</i> efficacy of an adeno-associated virus2 (AAV2)-transduced ambient light-activatable MCO (MCO-010) containing a metabotropic glutamate receptor-6 bipolar cell-specific promoter/enhancer. <b><i>Methods:</i></b> Mice requiring > 40 s to reach and board a dimly lit hidden platform in a water-maze were selected and randomly divided into 2 cohorts. These mice were intravitreally (IVT) injected with either 1.7E9 gene copies/eye of MCO-010 or control AAV2 and re-tested in the water-maze. Spectral-domain optical coherence tomography (SD-OCT), hematoxylin and eosin staining of retinas, and electroretinographic (ERG) studies were also conducted. <b><i>Results:</i></b> Safety of MCO-010 in <i>rd12</i> mice was confirmed by the lack of significant detrimental changes in the mouse behavior, b-wave amplitudes and in retinal thickness. <i>rd12</i> control mice performed relatively poorly in the water-maze test requiring ≥ 30-60 s to find and board the platform. MCO-010-treated <i>rd12</i> mice reached the platform much faster than the AAV2-treated <i>rd12</i> mice, with some mice only requiring < 5 s to achieve this goal (<i>P</i> < 0.01-0.0024). <b><i>Conclusions:</i></b> IVT MCO-010 treatment was well tolerated by <i>rd12</i> mice, and it prevented the decrease in retinal thickness, and preserved ERG parameters. It also significantly improved the vision in <i>rd12</i> mice relative to control AAV2-injected mice. MCO-010 therefore represents a novel and efficacious optogenetic therapeutic to treat LCA and other IRDs irrespective of the genetic defect(s).</p>","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":1.9000,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Efficacy of Intravitreal Multi-Characteristic Opsin (MCO-010) Optogenetic Gene Therapy in a Mouse Model of Leber Congenital Amaurosis.\",\"authors\":\"Adnan Dibas, Subrata Batabyal, Sanghoon Kim, Michael Carlson, Samarendra Mohanty, Najam A Sharif\",\"doi\":\"10.1089/jop.2024.0084\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b><i>Purpose:</i></b> Leber congenital amaurosis (LCA) is a sight-threatening inherited retinal disorder (IRD) caused by numerous genetic mutations. Multi-characteristic opsin (MCO)-based optogenetic therapy allows the recruitment of residual cells of the retina in LCA for alternative vision transduction while being mutation-agnostic. Using <i>rd12</i> mice, we investigated the <i>in vivo</i> efficacy of an adeno-associated virus2 (AAV2)-transduced ambient light-activatable MCO (MCO-010) containing a metabotropic glutamate receptor-6 bipolar cell-specific promoter/enhancer. <b><i>Methods:</i></b> Mice requiring > 40 s to reach and board a dimly lit hidden platform in a water-maze were selected and randomly divided into 2 cohorts. These mice were intravitreally (IVT) injected with either 1.7E9 gene copies/eye of MCO-010 or control AAV2 and re-tested in the water-maze. Spectral-domain optical coherence tomography (SD-OCT), hematoxylin and eosin staining of retinas, and electroretinographic (ERG) studies were also conducted. <b><i>Results:</i></b> Safety of MCO-010 in <i>rd12</i> mice was confirmed by the lack of significant detrimental changes in the mouse behavior, b-wave amplitudes and in retinal thickness. <i>rd12</i> control mice performed relatively poorly in the water-maze test requiring ≥ 30-60 s to find and board the platform. MCO-010-treated <i>rd12</i> mice reached the platform much faster than the AAV2-treated <i>rd12</i> mice, with some mice only requiring < 5 s to achieve this goal (<i>P</i> < 0.01-0.0024). <b><i>Conclusions:</i></b> IVT MCO-010 treatment was well tolerated by <i>rd12</i> mice, and it prevented the decrease in retinal thickness, and preserved ERG parameters. It also significantly improved the vision in <i>rd12</i> mice relative to control AAV2-injected mice. MCO-010 therefore represents a novel and efficacious optogenetic therapeutic to treat LCA and other IRDs irrespective of the genetic defect(s).</p>\",\"PeriodicalId\":16689,\"journal\":{\"name\":\"Journal of Ocular Pharmacology and Therapeutics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.9000,\"publicationDate\":\"2024-10-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Ocular Pharmacology and Therapeutics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1089/jop.2024.0084\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"OPHTHALMOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Ocular Pharmacology and Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1089/jop.2024.0084","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"OPHTHALMOLOGY","Score":null,"Total":0}
Efficacy of Intravitreal Multi-Characteristic Opsin (MCO-010) Optogenetic Gene Therapy in a Mouse Model of Leber Congenital Amaurosis.
Purpose: Leber congenital amaurosis (LCA) is a sight-threatening inherited retinal disorder (IRD) caused by numerous genetic mutations. Multi-characteristic opsin (MCO)-based optogenetic therapy allows the recruitment of residual cells of the retina in LCA for alternative vision transduction while being mutation-agnostic. Using rd12 mice, we investigated the in vivo efficacy of an adeno-associated virus2 (AAV2)-transduced ambient light-activatable MCO (MCO-010) containing a metabotropic glutamate receptor-6 bipolar cell-specific promoter/enhancer. Methods: Mice requiring > 40 s to reach and board a dimly lit hidden platform in a water-maze were selected and randomly divided into 2 cohorts. These mice were intravitreally (IVT) injected with either 1.7E9 gene copies/eye of MCO-010 or control AAV2 and re-tested in the water-maze. Spectral-domain optical coherence tomography (SD-OCT), hematoxylin and eosin staining of retinas, and electroretinographic (ERG) studies were also conducted. Results: Safety of MCO-010 in rd12 mice was confirmed by the lack of significant detrimental changes in the mouse behavior, b-wave amplitudes and in retinal thickness. rd12 control mice performed relatively poorly in the water-maze test requiring ≥ 30-60 s to find and board the platform. MCO-010-treated rd12 mice reached the platform much faster than the AAV2-treated rd12 mice, with some mice only requiring < 5 s to achieve this goal (P < 0.01-0.0024). Conclusions: IVT MCO-010 treatment was well tolerated by rd12 mice, and it prevented the decrease in retinal thickness, and preserved ERG parameters. It also significantly improved the vision in rd12 mice relative to control AAV2-injected mice. MCO-010 therefore represents a novel and efficacious optogenetic therapeutic to treat LCA and other IRDs irrespective of the genetic defect(s).
期刊介绍:
Journal of Ocular Pharmacology and Therapeutics is the only peer-reviewed journal that combines the fields of ophthalmology and pharmacology to enable optimal treatment and prevention of ocular diseases and disorders. The Journal delivers the latest discoveries in the pharmacokinetics and pharmacodynamics of therapeutics for the treatment of ophthalmic disorders.
Journal of Ocular Pharmacology and Therapeutics coverage includes:
Glaucoma
Cataracts
Retinal degeneration
Ocular infection, trauma, and toxicology
Ocular drug delivery and biotransformation
Ocular pharmacotherapy/clinical trials
Ocular inflammatory and immune disorders
Gene and cell-based therapies
Ocular metabolic disorders
Ocular ischemia and blood flow
Proliferative disorders of the eye
Eyes on Drug Discovery - written by Gary D. Novack, PhD, featuring the latest updates on drug and device pipeline developments as well as policy/regulatory changes by the FDA.