Duchenne muscular dystrophy (DMD) caused by a genetic mutation that prevents the production of dystrophin, a protein that muscles need to work properly. DMD patients exhibit progressive muscle weakness occurs in both skeletal and cardiac muscle. Cardiac fibrosis is ultimately the leading cause of their premature death. There is no cure for DMD, thus it remains an unmet medical need. Any therapeutic strategy that improves symptoms, quality of life, or survival would have a broad and meaningful impact for DMD patients. Numerous studies have demonstrated that dystrophic muscle exhibits high levels of oxidative stress, which is associated with increased NADPH-oxidases (Nox's) a major cellular sources of ROS generation. Nox2 is the primary source of ROS in skeletal muscle, whereas Nox4 has been identified as the primary source of ROS in cardiomyocytes and cardiac myofibroblasts. Recent studies patients have implicated Nox2 in skeletal muscle dysfunction, and Nox4 in cardiac fibrosis. However, despite strong evidence implicating Nox2 and 4 in DMD pathogenesis, a critical barrier to progress in this area is that selective Nox2 or Nox4 inhibitors have not been available. This STTR Phase I application is a collaboration between biotech startup company, Fibronox LLC, and two academic entities, University of Pittsburgh (UP) and University of Arizona (UA). The PI (Dr. Hecker) is the Founder and Chief Scientific Officer of Fibronox, and was the first to define a novel role for the oxidant- generating enzyme, Nox4, in mediating tissue fibrosis. Dr. Hecker recently identified the first selective Nox4 inhibitor lead drug candidate, where Fibronox has obtained exclusive licensing rights. Dr. Pagano (UP) has identified the first selective Nox2 inhibitor lead drug candidate. Using these innovative selective Nox2 and Nox4 inhibitors, it is now feasible, for the first time, to target the primary source of oxidant generation in DMD. Dr. Colson (UA) rounds out this team by providing expertise in skeletal and cardiac muscle mechanics. The overall goal of this project is to demonstrate proof-of-concept that pharmacologic targeting of Nox2 in DMD mice is sufficient to reduce ROS-mediated inflammation and improve skeletal muscle function, whereas pharmacologic targeting of Nox4 will reduce ROS-mediated cardiac fibrosis, leading to improved cardiac function and increased survival. Aim 1 studies will determine the therapeutic efficacy of Nox4 inhibitors on cardiac fibrosis, performance, and survival in DMD mice. Aim 2 studies will determine the therapeutic efficacy of Nox2 inhibitors on inflammatory responses and the ability to restore skeletal muscle function in a DMD mouse model. The long-term STTR goal is to address the unmet need for novel therapies for DMD. Our objective is to provide proof-of-concept for the development of these first-in-class selective Nox inhibitors for a DMD indication. These novel therapeutic strategies address the key pathological features of DMD: Nox2 inhibition to restore skeletal muscle function and Nox4 inhibition to reduce fibrosis and restore cardiac function. This two-pronged approach offers independent opportunities to improve DMD patient quality of life and survival.
Public Health Relevance Statement: Public Health Relevance: Duchenne muscular dystrophy (DMD) patients experience a progressive loss of skeletal muscle function (associated with debilitating loss of mobility), and they develop cardiac fibrosis (the leading cause of their premature death). There is no cure for DMD, thus it remains an unmet medical need. This STTR seeks to develop novel therapeutic strategies address the key pathological features of DMD; pharmacologic targeting of Nox2 to restore skeletal muscle function and Nox4 to reduce fibrosis and restore cardiac function. This two-pronged approach offers independent opportunities to improve DMD patient quality of life and survival.
Project Terms: Address; ADME Study; Age-Months; Animal Model; Area; Arizona; Biotechnology; Cardiac; Cardiac Myocytes; Cessation of life; clinically relevant; Collaborations; Contractile Proteins; coronary fibrosis; Development; Dilated Cardiomyopathy; DNA Sequence Alteration; drug candidate; Duchenne muscular dystrophy; Dystrophin; Enzymes; Exhibits; experience; FDA approved; Fibrosis; Functional disorder; Generations; Goals; heart function; human disease; improved; In Situ; Inflammation; Inflammation Mediators; Inflammatory Response; inhibitor/antagonist; innovation; Lead; Licensing; Limb structure; Link; Mechanics; Mediating; Medical; Microtubules; mouse model; Mus; Muscle; Muscle function; Muscle Proteins; Muscle Weakness; Muscular Atrophy; muscular dystrophy mouse model; Myocardium; Myofibroblast; NADPH Oxidase; novel; novel therapeutics; Oral; Oxidants; oxidation; Oxidative Stress; Pathogenesis; Pathologic; Patients; Performance; Pharmacology; Phase; preclinical study; premature; prevent; Production; Property; Proteins; Protocols documentation; public health relevance; Quality of life; Reactive Oxygen Species; Rights; Role; skeletal; Skeletal Muscle; skeletal muscle wasting; Small Business Technology Transfer Research; Source; Standardization; Sulfhydryl Compounds; symptom treatment; symptomatic improvement; Therapeutic; therapeutic development; therapeutic target; Time; Tissues; Treatment Efficacy; treatment strategy; Universities; Work
