Development of Novel Therapeutic Approaches for Improving Resistant Hypertension and Cardiomyopathy
Abstract
The Central Critical Problem or Question to Be Addressed: Treatment-resistant hypertension (tRHTN) is defined as persistent elevation of blood pressure (BP) above goal despite compliance with at least three antihypertensive medications, each of unique class including a diuretic included among the treatment regimen, and with all drugs at maximum tolerated doses or BP controlled on at least four drugs. Roughly, RHTN occurs in 20%-35% patients with either at least three atherosclerotic risk factors or established disease, and 10% of these patients are refractory to hypertensive treatment even after treatment with 5-6 different classes of antihypertensive drug. Despite major advances in the treatment of coronary and vascular diseases in the last three decades, physicians are having difficulties to achieve controlled BP in tRHTN patients, perhaps due to the lack of effective therapeutics that can actively improve tRHTN. As a result, hypertension is unchecked and continues to damage cardiovascular systems every day in millions of tRHTN patients, and these patients have a significantly increased risk of all-cause mortality and cardiovascular mortality when compared with those with controlled hypertension. Clearly novel strategies that can actively improve vascular functions in tRHTN patients are much needed. The Innovation of the Idea: The proposed therapy has the potential to treat the root cause of RHTN by providing long-acting Fc fusion proteins of ADM and IMD that are very effective in promoting vascular and lymphatic angiogenesis, but it may not be effective when administered as a native ADM or IMD peptide. (1) Novel targets in tRHTN: Overcoming tRHTN by activating both ADM’s cognate receptors (i.e., CLR/RAMP2 and 3 receptors) with the newly invented ADM-Fc/IMD-Fc fusion protein should be truly innovative. (2) Mechanism of action distinct from prior art: Previously described studies have shown that encapsulation of ADM by a hydrogel allows ADM to effectively promote wound healing in vivo and that nanoparticles that slowly release VEGF are more potent in improving vascular regeneration than free VEGF. However, the long-term efficacies of these slow-release drugs in improving RHTN are rather limited in vivo. Through a novel mechanism of action, the novel ADM-Fc/IMD-Fc fusion proteins have the potential to prevent a multitude of RHTN-associated pathology, including endothelial cell apoptosis, vascular leakage, tissue fibrosis, infections, etc. in the long term. (3) Intellectual property: To our knowledge, no patents or patent applications cover the approach presented in this proposal. Once proof of concept is established, we will file a provisional patent on our novel ADM-Fc/IMD-Fc fusion proteins for treating tRHTN. The Ultimate Applicability of the Research: Which Topic Area does this research address? This research addresses the topic area of Cardiomyopathy [the multiple etiologies of cardiomyopathy (e.g., hypertension)]. What are the potential clinical applications, benefits, and risks? The potential clinical applications and benefits will be providing an innovative novel therapies, the stable ADM-Fc and IMD-Fc fusion hormonal therapeutics, that are capable of delivering effective and durable clinical responses against tRHTN and/or cardiac hypertrophy in tRHTN patients without having life-threatening toxicities and potentially without the recurrence of tRHTN and/or cardiac hypertrophy in tRHTN patients. What Is the Impact of the Research? The proposed novel therapies with novel fusion hormonal therapeutics are designed to tackle the clinical problem of tRHTN and/or cardiac hypertrophy and the recurrence of tRHTN in patients. Despite improved targeted therapies, there is currently no effective therapy for improving or healing tRHTN and/or cardiac hypertrophy effectively in patients. Certainly, promising new therapies that deliver effective and durable clinical responses against tRHTN and/or card
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010260
Entities
People
- Mickey C.‐T. Hu
Organizations
- Panorama Research (United States)
- United States Army