TSG6 Exosomes for Treatment of Visual Dysfunction as Related to Military-Relevant Trauma
Abstract
Objectives and Rationale: Each year, over 50,000 people in the U.S. suffer vision loss due to TBI, without any apparent eye damage. In addition, the use of small improvised explosive devices in warfare causes 4,500 cases of unrecognized vision impairment among military Service Members each year. Due to lack of immediate visual symptoms, most patients are given no treatment and are simply advised to rest. Unfortunately, delayed inflammatory reactions often occur in the eye for days or weeks following the initial injury, leading to long-term deficits in vision. Delayed effects can include blurred or double vision, loss of peripheral vision, sensitivity to light, or difficulty with reading or navigating through a crowd. Despite several advances, no therapies approved by the U.S. Food and Drug Administration are known currently for vision loss due to TBI. Recent reports demonstrate that mesenchymal stem cells (MSCs) from adipose tissue have the ability to relieve many types of inflammation. We have shown in mouse models that the MSCs secreted several beneficial proteins (secretome) that can protect against visual damage following mild concussive injury to the head. Further, we identified the microvesicle (exosome)-associated protein TNF-Stimulated Gene-6 protein (TSG-6) as the most likely therapeutic component of the MSC secretome. Developing an exosome therapeutic from MSCs, which are primary cells isolated from human donors, would be expensive, risky, and impractical for most situations. In the current proposal, we will engineer the HEK293 (kidney epithelial) cell line, which is commonly used for commercial production of therapeutics, to produce exosomes that display the TSG-6 protein on their surface. In Aim 1, we will engineer the TSG-6 protein for optimal activity on exosomes. We will confirm its anti-inflammatory activity on cells and then use our previously developed methods to produce and purify large quantities of the TSG-6 exosomes. In Aim 2, we will directly demonstrate the feasibility of using purified TSG-6 exosomes as a therapy in a mouse model of blast injury that was established in our lab to show reproducible inflammation and visual loss due to neurodegeneration. Potential Impact of the Research: We expect this proposal to provide the first therapeutic lead to treat vision loss from blast injury, a common but not widely appreciated injury. Future studies will involve additional models of ocular injury that are already available in the laboratory, possibly including more common causes of retinal nerve damage, such as diabetic retinopathy. In addition, TSG-6 exosomes have strong potential as therapeutics for other types of inflammatory pathology, such as neuronal damage caused by traumatic brain injury. If successful with the aims, use of TSG6-exosomes could become clinical practice within 5 to 10 years. Our commercial partner, Diadem Biotherapeutics, Inc., will help develop and commercialize exosome-based therapeutics and drug delivery systems. Over the last three years, Diadem has established patent-pending exosome engineering methods and cGMP-compliant, scalable manufacturing methods. As a result, we are uniquely poised to leverage basic research to enable product development and translational studies. Military Benefits: This proposal is of high interest to military service, Veterans, and their family members. Due to the nature of their work, military members are at an increased risk for TBI from explosive blast, ballistic, blunt, and penetrating trauma. Unfortunately, there is currently no effective treatment for TBI. The devastating lifelong effects of visual and cognitive loss seen in TBI severely affect the quality of life of the individual and their family members and communities in general. Furthermore, the economic cost of vision and cognitive impairment related to TBI is well in excess of $2 billion annually for the military. The development of an effective trea
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210697
Entities
People
- Rajashekhar Gangaraju
Organizations
- United States Army
- University of Tennessee Health Science Center