Development of an Advanced Injectable Therapy for Ischemic Vascular Disease
Abstract
Diabetes and cardiovascular diseases are a worldwide problem with no long-term solutions. Chronic peripheral ischemia (reduction in blood flow to the extremities) is a common problem in elderly people with diabetes and peripheral vascular disease (PVD). There are over 336 million people with diabetes and 202 million people with PVD worldwide. The standard clinical treatments including exercise therapy, pharmacotherapy, and surgical intervention are able to provide short-term relief but often fail in the long term due to continued disease processes. Moreover, a number of new techniques like stem cells and growth factors have been explored but these have not had significant prolonged benefit in human clinical trials. Thus, there is a pressing clinical need for a long-lasting therapy of chronic peripheral ischemia. In this proposal, we aim to enhance the effectiveness of angiogenic growth factors like fibroblast growth factor-2 (FGF-2) and platelet derived growth factor-BB (PDGF-BB) in ischemic tissue using co-therapy with a growth factor co-receptor syndecan-4. We have found that syndecan-4 is reduced in the diabetic disease state, making the tissue resistant to responding to growth factor therapy alone. Thus, our overall goal is to make the tissues more responsive to angiogenic therapies, particularly in the diabetic disease state. The proposed work will develop the potential therapy through preclinical testing and develop methods for large-scale manufacturing of the compounds. We have completed an extensive set of preliminary studies that demonstrate the activity of syndecan-4 proteoliposomes in enhancing growth factor therapies in rodents and cell culture studies. The purpose of the proposed work is to take this promising potential therapy and perform studies that will allow us to file an Investigational New Drug (IND) application to enable initial studies in human patients. To optimize the therapy, we will create several drug delivery formulations that allow the therapy to be injected and released over time within the ischemic tissues. We will first assess toxicity of the formulations and conduct pharmacokinetics and pharmacodynamics studies. Thereafter, we will test the best formulations in a preclinical diabetic rabbit model of hind limb ischemia. In the animal model, we will find the baseline characteristics using control treatment and then optimize dosing, timing, and number of intramuscular injections. Finally, we will use both FGF-2 and PDGF-BB (implicated in vessel maturation) to find the most optimum timing, dosage, and order of treatment to enhance the effectiveness of the growth factor therapy in the rabbit model. Previous studies have attempted to use growth factor-based therapies for numerous applications such as ischemia, wound healing, and heart attack. We believe that many of clinical trials on these therapies have failed due to a growth factor resistant state caused by diabetes and hyperlipidemia. Our approach aims to overcome this limitation by providing the tissue with not only growth factors but a co-receptor that enhance their activity. If successful, the therapy would provide treatment for a large population of patients with peripheral vascular disease and limb ischemia. This treatment could be used as an alternative to invasive procedures and, unlike stenting and bypass surgery, could be repeated many times if the patient continues to have ischemia. In addition, the therapeutic compounds developed would be useful in many applications beyond peripheral ischemia including myocardial ischemia, enhancing wound healing in chronic and battlefield wounds, and enhancing surgical repair and transplantation procedures.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610582
Entities
People
- Aaron B Baker
Organizations
- United States Army
- University of Texas at Austin