Small-Molecule Mas Agonist for the Amelioration of DMD-Associated Cardiomyophathy
Abstract
Duchenne muscular dystrophy (DMD) is a severe, progressive disease that is caused by a genetic mutation that stops the production an important structural protein in muscle cells. The loss of this protein results in muscles that are easily injured. With injury comes increased inflammation to clear out the injured muscle tissue, then regeneration of the lost muscle. As the muscles of DMD patients never produce this important structural protein, their muscles are constantly undergoing cycles of injury and repair. Over time, the continuous state of muscle injury in DMD patients overwhelms and exhausts the body’s healing processes, resulting in functional muscle being replaced by fat and scar tissue. This replacement of active muscle with scar tissue leads to the progressive loss of skeletal muscle, heart, and diaphragm (which is responsible for breathing) function and, ultimately, death. Angiotensin 1-7 (A(1-7)), a naturally occurring hormone activator of the Mas receptor, has been shown to improve heart function in a number of animal surrogates of heart disease and muscle function in mice with muscular dystrophies. Although A(1-7) administration has yielded these encouraging results, this hormone suffers from two debilitating liabilities: (1) it must be injected to be effective and (2) after injection, it is broken down and eliminated from the body in minutes. In order to minimize these limitations while still exploiting the benefits of activating the Mas receptor to positively increase both heart and muscle function, our laboratory has developed an oral, biologically stable activator of the Mas receptor. This experimental drug is called MMX1902. In two pilot studies, MMX1902 has been shown to significantly reduce muscle injury, increase muscle healing, and increase muscle strength and heart function in the same muscular dystrophy mice for which A(1-7) was shown to be effective. As reduced heart function is a major cause of death in patients with DMD, we plan to develop this molecule as a drug to improve heart function. Currently, patients with DMD take one of two drugs, ACE-Is or ARBs. As a result, we need to confirm that MMX1902 is both safe and still effective when given in combination with these drugs. Further, we are also setting out to confirm that Mas receptor activation is responsible for MMX1902’s ability to improve heart function in DMD mice and, thus, give us insights into how, beyond its activation of the Mas receptor, this agent is able to produce these improvements in dystrophic muscle function. Finally, we are seeking to meet with doctors who treat DMD patients, especially those focusing on heart diseases to help us plan the clinical trials that will be necessary to prove MMX1902 increases heart function in DMD patients. Finally, we will begin the animal safety studies required by the Food and Drug Administration (FDA) to show the drug is safe before it can be studied in humans. Specific Aims: To achieve the above goals, we have outlined four specific aims in this proposal. In Specific Aim 1, we seek to establish the safety and effectiveness of MMX1902 treatment in combination with an ACE-I and an ARB in DMD mice. In Specific Aim 2, we will use DMD mice to confirm that the Mas receptor is the target of MMX1902 responsible for its effects on heart function while better understanding how it works. In Specific Aim 3, we will consult both DMD and heart disease experts to develop a clinical design to test the effects of MMX1902 on heart function in DMD patients. This document will assist us in prepare for our first meeting with the FDA. Finally, in Specific Aim 4, we will find out the highest dose that we can safely give in initial animal studies, which will set the stage for larger safety studies required by the FDA to test this exciting experimental drugs in humans. Impact: DMD is a severe medical condition that has no cure or effective treatment option that can stop or slow down the d
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710599
Entities
People
- Kathleen Rodgers
Organizations
- United States Army
- University of Arizona