Rapid Delivery of SIRT1-Mediated Neuroprotective Treatment for Traumatic Optic Neuropathy
Abstract
The main objective of this proposal is to evaluate the therapeutic potential and mechanisms of a novel therapy to prevent nerve damage in animal models of traumatic optic neuropathy (TON). TON can result from direct optic nerve injury, but more commonly occurs indirectly due to optic nerve stretching from blunt head trauma, in patients with traumatic brain injury. TON results in damage to the retinal ganglion cells (RGCs), the nerve cells that comprise the optic nerve and bring visual signals from the eye to the brain, with associated permanent visual deficits. Attempted medical and surgical treatments have all failed to improve visual outcomes. Thus, novel neuroprotective therapies are needed to prevent RGC loss and preserve vision following TON, and a potential therapy that can be deployed rapidly in the field will be studied. Previous studies showed that activation of the SIRT1 deacetylase by the polyphenol resveratrol, as well as genetic overexpression of SIRT1, reduces RGC loss in experimental optic neuropathies. However, high oral resveratrol doses that increase risk of side effects are required; thus, alternate strategies to upregulate SIRT1 are needed. In addition, mechanisms underlying SIRT1-mediated neuroprotection are not well understood, including whether SIRT1 signaling is required directly within RGCs, and which downstream signals play key roles. Development of novel experimental tools to deliver the SIRT1 gene, and innovative use of intranasal drug administration to target RGCs, place us in a unique position to address both the therapeutic potential of SIRT1-mediated RGC neuroprotection, and mechanisms underlying these effects. TON often occurs in patients with traumatic brain injury, a frequent sequela of blunt head trauma or blast-related injuries. Sixty percent of traumatic head injuries result in neuro-ophthalmic abnormalities, and 50% of those involve the optic nerves or visual pathways. TON was among the most common ocular injuries requiring specialized ophthalmic care during U.S. operations in Iraq, as nearly 20% of ocular combat injuries involved TON. The prevalence of these injuries, together with lack of available treatments, suggests TON is a devastating cause of vision loss in military and civilian settings. One major impediment making it difficult to develop treatments for TON is that trauma-induced damage to the optic nerve occurs at the time of injury, with a limited window of time available to deliver therapies prior to the damage becoming permanent. It is likely that any successful therapy will need to be delivered shortly after trauma and, ideally, would be available to be administered by first responders/medics during the initial encounter at the site of the trauma. Having an easily administered, rapid-acting therapeutic available for medics to use in the field during military operations or first responders to use in civilian settings, will represent a critical advancement in development of neuroprotective therapies for TON. Outcomes of the current proposal can directly affect these critical needs. Short-term outcomes will demonstrate key molecular mechanisms underlying the ability of SIRT1 to prevent RGC damage following trauma, and will confirm the ability of intranasal administration of a SIRT1 activating compound, resveratrol, to prevent RGC loss and preserve vision. Long-term outcomes will build off the short-term outcomes through the development of enhanced therapeutics targeting downstream signals of SIRT1, and through translational studies that will assess feasibility and efficacy of intranasal dosing of resveratrol in TON patients. Due to significant anatomic differences between mice and humans, following proof-of-concept intranasal delivery studies in mice in the current proposal, evaluation of doses and intranasal delivery methods for human use will need to be performed. Importantly, even if anatomical differences prove too significant to allow direct transla
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310725
Entities
People
- Kenneth Shindler
Organizations
- United States Army
- University of Pennsylvania