Soluble Guanylate Cyclase Stimulation as a Novel Treatment Modality for Duchenne Muscular Dystrophy
Abstract
Despite advances in patient care and medical management, there remains an urgent need for new palliative therapies for Duchenne muscular dystrophy (DMD) to slow disease progression and enhance quality of life. In this way, time can be bought for patients awaiting gene correction therapies that directly target dystrophin gene defects. In DMD and the mdx mouse models of DMD, there is a secondary defect in neuronal nitric oxide synthase (nNOS) signaling that promotes muscle damage and inflammation, prevents normal blood delivery, and promotes exercise intolerance. Defective nNOS reduces the activity of its major target called soluble guanylyl cyclase (sGC), which makes the messenger cGMP. Phosphodiesterase 5 (PDE5) breaks cGMP down and thus stops nNOS signaling through sGC. We and others have used phosphodiesterase 5 (PDE5) inhibitors such as Viagra (sildenafil) and Cialis (tadalafil) to increase nNOS-sGC activity and partially overcome these defects in nNOS-sGC activity. PDE5 inhibitors have shown promising results in mdx mice in reducing respiratory muscle fibrosis or scarring and weakness and can improve blood supply to exercising muscles of Becker and Duchenne patients. More clinical trials are planned to study the long-term benefits of PDE5 inhibition on skeletal muscle making nNOS-sGC signaling an important drug target in DMD. However, PDE5 inhibitors have limitations that prevent us from tapping the full therapeutic potential of nNOS-sGC signaling. For example, some patients don t respond to PDE5 inhibitors, and Becker patients lack PDE5 expression presumably to compensate for decrease nNOS signaling. To avoid the limitations of PDE5 inhibitors, we propose to use a different drug class called sGC stimulators that activate sGC independently of nNOS. In general, sGC stimulators have a greater therapeutic potential than PDE5 inhibitors. sGC stimulators are used to treat two types of pulmonary hypertension, so if our studies are successful, they could be rapidly and safely tested in Becker MD/DMD patients. Our objective is to determine if sGC stimulation can reduce skeletal muscle damage and weakness to the same or greater degree than PDE5 inhibitors in two different mdx mouse models of DMD that have moderate and severe muscular dystrophy. Showing that sGC stimulation improved muscle pathology in extremely dysfunctional dystrophic muscle would significantly enhance its attractiveness as a novel therapy for DMD. To help define drug specificity and its therapeutic benefits, we will generate control mdx mice that lack skeletal muscle sGC to understand whether the protection of sGC stimulation is due to activation of sGC in muscle or some other mechanism. Knowing this will assist in the planning, design, and interpretation of possible clinical trials in the future. Indeed, we have used our experience in the use of PDE5 inhibitors to treat DMD to design our experiments so that they will facilitate effective clinical trial design and interpretation in the future, thus making a potential transition from preclinical to clinical testing and to usage by patients as rapid and efficient as possible. By showing that sGC stimulators can decrease skeletal muscle dysfunction and slow disease progression in mouse models of DMD with moderate and severe muscular dystrophy, we will provide a proof-of-concept that sGC stimulation may be a useful and novel treatment for DMD. Because sGC stimulators are Food and Drug Administration-approved to treat pulmonary hypertension, they could be tested safely and expeditiously in DMD patients. A successful outcome will lay the preclinical groundwork and provide a strong rationale for clinical testing of sGC stimulators to reduce muscle damage and weakness and improve the quality of life of DMD patients. Assuming that sGC stimulators work as expected in mouse models of muscular dystrophy and that clinical testing occurs without delay and is also successful, it may only be a matter of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510326
Entities
People
- Justin Percival
Organizations
- United States Army
- University of Miami