作者: Gurtner, Geoffrey C. ; Stern-Buchbinder, Zachary A. ; Dallas, Anne ; Kosaric, Nina ; Barrera, Janos A. ; Engel, Karl ; Ilves, Heini ; Bonham, Clark A. ; Trotsyuk, Artem ; Hammond, Paula T. ; Mansbridge, Jonathan ; Rodrigues, Melanie ; Jayasena, Sumedha ; Johnston, Brian H. ; White, Aleksandr ; Mandell, Kenneth J.

In diabetes-associated chronic wounds, the normal response to hypoxia is impaired and many cellular processes involved in wound healing are hindered. Central to the hypoxia response is hypoxia-inducible factor-1α (HIF-1α), which activates multiple factors that enhance wound healing by promoting cellular motility and proliferation, new vessel formation, and re-epithelialization. Prolyl hydroxylase domain-containing protein 2 (PHD2) regulates HIF-1α activity by targeting it for degradation under normoxia. HIF-1α also upregulates microRNA miR-210, which in turn regulates proteins involved in cell cycle control, DNA repair, and mitochondrial respiration in ways that are antagonistic to wound repair. We have identified a highly potent short synthetic hairpin RNA (sshRNA) that inhibits expression of PHD2 and an antisense oligonucleotide (antimiR) that inhibits miR-210. Both oligonucleotides were chemically modified for improved biostability and to mitigate potential immunostimulatory effects. Using the sshRNA to silence PHD2 transcripts stabilizes HIF-1α and, in combination with the antimiR targeting miR-210, increases proliferation and migration of keratinocytes in vitro. To assess activity and delivery in an impaired wound healing model in diabetic mice, PHD2-targeting sshRNAs and miR-210 antimiRs both alone and in combination were formulated for local delivery to wounds using layer-by-layer (LbL) technology. LbL nanofabrication was applied to incorporate sshRNA into a thin polymer coating on a Tegaderm mesh. This coating gradually degrades under physiological conditions, releasing sshRNA and antimiR for sustained cellular uptake. Formulated treatments were applied directly to splinted full-thickness excisional wounds in db/db mice. Cellular uptake was confirmed using fluorescent sshRNA. Wounds treated with a single application of PHD2 sshRNA or antimiR-210 closed 4 days faster than untreated wounds, and wounds treated with both oligonucleotides closed on average 4.75 days faster. Markers for neovascularization and cell proliferation (CD31 and Ki67, respectively) were increased in the wound area following treatment, and vascular endothelial growth factor (VEGF) was increased in sshRNA-treated wounds. Our results suggest that silencing of PHD2 and miR-210 either together or separately by localized delivery of sshRNAs and antimiRs is a promising approach for the treatment of chronic wounds, with the potential for rapid clinical translation.

项与 Layerbio, Inc. 相关的新闻（医药）

2023-11-03

·layerbio.com

LayerBio CEO Presents at American Academy of Ophthalmology

LayerBio’s CEO, Dr. Ken Mandell, presented in the Innovation section of Refractive Surgery Subspecialty Day at the American Academy of Ophthalmology Annual Meeting in San Francisco, CA on November 3, 2023. His talk entitled “Drug Eluting IOLs” reviewed the general strategy of delivering drug from intraocular lenses (IOLs) and the advantages of the OcuRing™ platform for use in cataract surgery. A video summary of the talk is provided by EyeTube.net.

2022-04-25

·layerbio.com

LayerBio Presents at the American Society for Cataract and Refractive Surgery

Layerbio’s CEO Dr. Ken Mandell presentated “OcuRing: The Future of Dropless Cataract Surgery” in the Innovators General Session at American Society of Cataract and Refractive Surgeons on April 25, 2022.

2020-07-01

·layerbio.com

LayerBio Awarded $3M from U.S. Department of Defense (DoD) to Advance OcuRing™ for Cataract Surgery

OcuRing™ is a novel drug delivery platform for cataract surgery with potential to eliminate the need for postoperative topical eye drops. $3M DoD award will fund IND-enabling toxicology and manufacturing activities. LayerBio plans to develop OcuRing™ products for multiple cataract surgery-related indications. LEXINGTON, Mass., July 1, 2020 (Newswire.com) - OcuRing™ is a novel sustained-release technology designed to deliver therapies to cataract surgery patients, potentially eliminating the need for postoperative topical drops. The drug eluting device is attached to an intraocular lens (IOL) for implantation during cataract surgery. Because of its unique elastomeric properties, the OcuRing™ can be attached to most standard one-piece or three-piece IOLs and inserted into the eye using the standard injector systems without modification of surgical technique. OcuRing™ is a modular platform with the capacity to deliver multiple medications from the same IOL. LayerBio is developing OcuRing™ formulations for drugs used to prevent complications of cataract surgery, including corticosteroids and NSAIDs. “Cataract surgeons have been anxiously awaiting the day when we could offer our patients a highly effective alternative to traditional eye drops. While patients usually sail through cataract surgery, they are quick to complain about the cost, discomfort, waste, inconvenience, and frequency of using drops for a month or two following their operation,” commented Robert H. Osher, M.D., a pioneer and innovator in the field of modern cataract surgery. “It is with great excitement that we anticipate the development of a sustained drug delivery system which can be implanted at the time of surgery to safely deliver an optimal regimen of medication, which the patient and surgeon will likely prefer,” added Dr. Osher. LayerBio today announced receipt of a $3 million Technology/Therapeutic Development Award (TTDA) from the U.S. Department of Defense (DoD) through the Congressionally Directed Medical Research Programs (CDMRP). This funding will support advancement of its lead OcuRing™ product for cataract surgery. This DoD award adds to the previous $5 million in non-dilutive funding that LayerBio has raised through Small Business Innovation Research (SBIR) grants from the National Institutes of Health (NIH) and National Science Foundations (NSF) and sponsored research collaborations with industry partners. “We’re excited to receive this important award from the DoD to advance OcuRing™ development,” commented Ken Mandell, MD, PhD, LayerBio’s founder and CEO. “LayerBio is committed to developing this innovative technology with the goal of enhancing surgical outcomes and patient satisfaction. We are honored to have the DoD support this important project.” About LayerBio: LayerBio, Inc. is clinical-stage biotechnology company developing innovative therapies to address unmet needs in the field of ophthalmology and other therapeutic areas. LayerBio was founded as a spinoff of Massachusetts Institute of Technology (MIT) based on drug delivery technology developed in the laboratory of LayerBio’s co-founder Dr. Paula Hammond, David H. Koch Professor in Engineering and Head of the Department of Chemical Engineering at MIT. More information about LayerBio is available at www.layerbio.com. About Robert H. Osher: Robert H. Osher, M.D., is Professor of Ophthalmology, University of Cincinnati College of Medicine, Medical Director Emeritus, Cincinnati Eye Institute. Dr. Osher has been awarded the Binkhorst Medal and Innovator’s Award by the American Society of Cataract and Refractive Surgeons (ASCRS) and the Lifetime Achievement Award and Kelman Award by the American Academy of Ophthalmology (AAO).

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