Twice Weekly Steroids and Exercise as Therapy for DMD

This innovative proposal focuses on developing an efficacious therapeutic strategy involving low dose twice weekly glucocorticoid (GC) administration and exercise training for boys affected with Duchenne muscular dystrophy (DMD), a currently incurable disease characterized by rapidly progressive muscle weakness, early loss of ambulation and death. While GC are the only proven treatment to reduce fibrosis and delay loss of ambulation in DMD, chronic daily administration (which is most commonly prescribed) is associated with adverse, often debilitating effects. As an alternate dosing regimen, weekend-only use was shown to retain the benefits and have less impact on weight gain and linear growth, however high doses were used and associated with behavioral issues. Recent work in mice suggests that the same daily dose administered transiently may be effective and have a greater impact on gains in muscle mass, strength and resistance to fatigue compared to daily dosing due to differential effects on gene expression signaling pathways important for muscle remodeling. Exercise, which also induces signaling pathways that lead to remodeling in healthy muscle, may beneficially impact pathophysiology of DMD by recruiting compensatory pathways. Although high intensity or eccentric actions are damaging to dystrophic muscle, a few studies suggest that submaximal exercise is safe and may delay the loss of muscle function in boys with DMD. Despite these exploratory studies suggesting potential, there is a paucity of research on exercise, which reflects our current lack of understanding of specific exercise prescription parameters (type, intensity, target muscle groups) that may be safe and effective for patients with DMD, as well as lack of accessibility to exercise equipment that appropriately and sufficiently induces adaptation in dystrophic muscle. The objective of this work is to define an efficacious GC regimen with minimal side effects, and understand if exercise training can potentially delay disease progression, reverse secondary effects of disuse, and induce beneficial adaptations in boys with DMD.

AIM 1: To determine the 12-month impact of a low dose (0.75 mg/kg x 2 days of prednisone) regimen on weight gain, DMD muscle pathophysiology and physical function. We hypothesize that compared to the standard daily regimen, a twice-weekly regimen will have less impact on body mass index, and equal improvements in the 1-year change in physical function and muscle fat fraction.

AIM 2: To determine impact of a 6-month in-home, moderate intensity, leg exercise training program on muscle pathophysiology and physical function in DMD.

Inclusion criteria

• Diagnosis of DMD confirmed by 1) clinical history with features before the age of five, 2) physical examination, 3) elevated serum creatine kinase level and 4) absence of dystrophin expression, as determined by immunostain or Western blot (<2%) and/or DNA confirmation of dystrophin mutation.
• Age 5.0 to 9 years: a lower age limit of 5.0 years is selected as children younger than that are likely unable to cooperate and comply with all of the exercise measures as needed. An upper age limit of 9 years has been set as boys with DMD tend to reach a rapid progression into a late ambulatory phase soon after this age.
• Ambulatory at the time of the first visit, defined as the ability to walk for at least 100 m without an external assistive device and able to climb four stairs.
• Aim 1 only: GC-naïve at baseline (and prior 6 months)
• Aim 2 only: on stable daily GC regimen for 6 months prior to baseline

Exclusion criteria

• Contraindication to an MR examination (e.g. aneurysm clip, severe claustrophobia, magnetic implants)
• Presence of unstable medical problems, significant concomitant illness including cardiomyopathy or cardiac conduction abnormalities
• Presence of a secondary condition that impacts muscle function or muscle metabolism (e.g. myasthenia gravis, endocrine disorder, mitochondrial disease)
• Presence of a secondary condition leading to developmental delay or impaired motor control (e.g. cerebral palsy)
• Presence of an unstable medical condition (e.g. uncontrolled seizure disorder)
• Behavioral problems causing an inability to cooperate during testing or understand exercise instruction
• Participation in other forms of drug or gene therapy during the period of the study