ABSTRACT:
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.