Michael O’Hare, William P. Miller, Said Arevalo-Alquichire, Dhanesh Amarnani, Evhy Apryani, Paula Perez-Corredor, Claudia Marino, Daisy Y. Shu, Timothy E. Vanderleest, Andres Muriel-Torres, Harper B. Gordon, Audrey L. Gunawan, Bryan A. Kaplan, Karim W. Barake, Romy P. Bejjani, Tri H. Doan, Rose Lin, Santiago Delgado-Tirado, Lucia Gonzalez-Buendia, Elizabeth J. Rossin, Guannan Zhao, Dean Eliott, Christine Weinl-Tenbruck, Frédéric Chevessier-Tünnesen, Joanna Rejman, Fabio Montrasio, Leo A. Kim, Joseph F. Arboleda-Velasquez
{"title":"一种mRNA编码的转录因子RUNX1显性阴性抑制剂可抑制实验模型中的玻璃体视网膜疾病。","authors":"Michael O’Hare, William P. Miller, Said Arevalo-Alquichire, Dhanesh Amarnani, Evhy Apryani, Paula Perez-Corredor, Claudia Marino, Daisy Y. Shu, Timothy E. Vanderleest, Andres Muriel-Torres, Harper B. Gordon, Audrey L. Gunawan, Bryan A. Kaplan, Karim W. Barake, Romy P. Bejjani, Tri H. Doan, Rose Lin, Santiago Delgado-Tirado, Lucia Gonzalez-Buendia, Elizabeth J. Rossin, Guannan Zhao, Dean Eliott, Christine Weinl-Tenbruck, Frédéric Chevessier-Tünnesen, Joanna Rejman, Fabio Montrasio, Leo A. Kim, Joseph F. Arboleda-Velasquez","doi":"10.1126/scitranslmed.adh0994","DOIUrl":null,"url":null,"abstract":"<div >Messenger RNA (mRNA)–based therapies are a promising approach to medical treatment. Except for infectious diseases, no other disease has mRNA-based therapies available. The eye is an ideal model for mRNA therapeutic development because it requires limited dosing. Proliferative vitreoretinopathy (PVR) is a blinding condition caused by retinal detachment that now lacks available medical treatment, with surgery as the only treatment option. We previously implicated runt-related transcription factor-1 (RUNX1) as a driver of epithelial-to-mesenchymal transition (EMT) in PVR and as a critical mediator of aberrant ocular angiogenesis when up-regulated. On the basis of these findings, an mRNA was designed to express a dominant-negative inhibitor of RUNX1 (RUNX1-Trap). We show that RUNX1-Trap delivered in polymer-lipidoid complexes or lipid nanoparticles sequestered RUNX1 in the cytosol and strongly reduced proliferation in primary cell cultures established from fibrotic membranes derived from patients with PVR. We assessed the preclinical efficacy of intraocular delivery of mRNA-encoded RUNX1-Trap in a rabbit model of PVR and in a laser-induced mouse model of aberrant angiogenesis often used to study wet age-related macular degeneration. mRNA-encoded RUNX1-Trap suppressed ocular pathology, measured as pathological scores in the rabbit PVR model and leakage and lesion size in the laser-induced choroidal neovascularization mouse model. mRNA-encoded RUNX1-Trap also strongly reduced proliferation in a human ex vivo explant model of PVR. These data demonstrate the therapeutic potential of mRNA-encoded therapeutic molecules with dominant-negative properties, highlighting the potential of mRNA-based therapies beyond standard gene supplementation approaches.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 775","pages":""},"PeriodicalIF":15.8000,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"An mRNA-encoded dominant-negative inhibitor of transcription factor RUNX1 suppresses vitreoretinal disease in experimental models\",\"authors\":\"Michael O’Hare, William P. Miller, Said Arevalo-Alquichire, Dhanesh Amarnani, Evhy Apryani, Paula Perez-Corredor, Claudia Marino, Daisy Y. Shu, Timothy E. Vanderleest, Andres Muriel-Torres, Harper B. Gordon, Audrey L. Gunawan, Bryan A. Kaplan, Karim W. Barake, Romy P. Bejjani, Tri H. Doan, Rose Lin, Santiago Delgado-Tirado, Lucia Gonzalez-Buendia, Elizabeth J. Rossin, Guannan Zhao, Dean Eliott, Christine Weinl-Tenbruck, Frédéric Chevessier-Tünnesen, Joanna Rejman, Fabio Montrasio, Leo A. Kim, Joseph F. Arboleda-Velasquez\",\"doi\":\"10.1126/scitranslmed.adh0994\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >Messenger RNA (mRNA)–based therapies are a promising approach to medical treatment. Except for infectious diseases, no other disease has mRNA-based therapies available. The eye is an ideal model for mRNA therapeutic development because it requires limited dosing. Proliferative vitreoretinopathy (PVR) is a blinding condition caused by retinal detachment that now lacks available medical treatment, with surgery as the only treatment option. We previously implicated runt-related transcription factor-1 (RUNX1) as a driver of epithelial-to-mesenchymal transition (EMT) in PVR and as a critical mediator of aberrant ocular angiogenesis when up-regulated. On the basis of these findings, an mRNA was designed to express a dominant-negative inhibitor of RUNX1 (RUNX1-Trap). We show that RUNX1-Trap delivered in polymer-lipidoid complexes or lipid nanoparticles sequestered RUNX1 in the cytosol and strongly reduced proliferation in primary cell cultures established from fibrotic membranes derived from patients with PVR. We assessed the preclinical efficacy of intraocular delivery of mRNA-encoded RUNX1-Trap in a rabbit model of PVR and in a laser-induced mouse model of aberrant angiogenesis often used to study wet age-related macular degeneration. mRNA-encoded RUNX1-Trap suppressed ocular pathology, measured as pathological scores in the rabbit PVR model and leakage and lesion size in the laser-induced choroidal neovascularization mouse model. mRNA-encoded RUNX1-Trap also strongly reduced proliferation in a human ex vivo explant model of PVR. 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An mRNA-encoded dominant-negative inhibitor of transcription factor RUNX1 suppresses vitreoretinal disease in experimental models
Messenger RNA (mRNA)–based therapies are a promising approach to medical treatment. Except for infectious diseases, no other disease has mRNA-based therapies available. The eye is an ideal model for mRNA therapeutic development because it requires limited dosing. Proliferative vitreoretinopathy (PVR) is a blinding condition caused by retinal detachment that now lacks available medical treatment, with surgery as the only treatment option. We previously implicated runt-related transcription factor-1 (RUNX1) as a driver of epithelial-to-mesenchymal transition (EMT) in PVR and as a critical mediator of aberrant ocular angiogenesis when up-regulated. On the basis of these findings, an mRNA was designed to express a dominant-negative inhibitor of RUNX1 (RUNX1-Trap). We show that RUNX1-Trap delivered in polymer-lipidoid complexes or lipid nanoparticles sequestered RUNX1 in the cytosol and strongly reduced proliferation in primary cell cultures established from fibrotic membranes derived from patients with PVR. We assessed the preclinical efficacy of intraocular delivery of mRNA-encoded RUNX1-Trap in a rabbit model of PVR and in a laser-induced mouse model of aberrant angiogenesis often used to study wet age-related macular degeneration. mRNA-encoded RUNX1-Trap suppressed ocular pathology, measured as pathological scores in the rabbit PVR model and leakage and lesion size in the laser-induced choroidal neovascularization mouse model. mRNA-encoded RUNX1-Trap also strongly reduced proliferation in a human ex vivo explant model of PVR. These data demonstrate the therapeutic potential of mRNA-encoded therapeutic molecules with dominant-negative properties, highlighting the potential of mRNA-based therapies beyond standard gene supplementation approaches.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.