Background for the use of albuterol in treating DMD

Although gene therapeutic approaches offer the most promise for an ultimate cure for DMD, gene therapeutics are not expected to be available for several years or longer so that many patients diagnosed at the present time are not likely to benefit from gene therapy. Our goal at the DMDRC-UCLA and specifically in the clinical trial of albuterol is to identify pharmacological approaches to reduce the loss of muscle mass and strength in DMD boys, so that they may be able to take advantage of gene therapy treatments when they become available in the future. Albuterol, a beta-agonist, is a promising agent for this type of pharmacological approach. Beta-agonists are a class of drug that have been shown to improve the quality and functional properties of muscle, both in healthy and sick individuals. This drug already has FDA approval for the treatment of asthma, and could be readily available to patients if promising results ensue from this study. It is a drug with minimal side effects and is safe for a pediatric population. However, when albuterol is administered as an inhaled aerosol in the treatment of asthma, it has no effect on skeletal muscle. Albuterol effects on skeletal muscle require long-term release of the albuterol into the circulatory system, which can occur when the drug is taken as a slowly releasing tablet.

Rationale for the expected beneficial effects of albuterol administration to DMD boys
A substantial body of scientific and clinical research shows that albuterol is an effective drug for increasing muscle mass and strength. First, several animal studies have shown increases in lean muscle mass following administration of beta-agonists [1-13]. Collectively, these studies show that beta-agonist treatment of healthy animals can increase muscle protein content, muscle mass and muscle strength and that these increases can occur after only a few weeks of treatment.

Human studies have also shown increases in muscle mass following a regimen of beta-agonist treatment [14-16]. Healthy males treated with slow release albuterol for 14 days (16 mg/day) improved their quadriceps strength by 12% [14]. The increase in strength remained 7 days following treatment. In the same study, the strength of the hamstring muscles increased by 22% after 21 days of treatment. Caruso et al. [17] also documented increases in strength following 16 mg/day of albuterol treatment of healthy individuals. Unhealthy patients have been shown to experience even greater benefits from beta-agonist treatment than healthy patients. For example, orthopedic patients demonstrated a more rapid recovery following beta-agonist administration [16]. Thus, all current evidence supports the view that albuterol can be administered safely to humans to improve muscle strength and mass.

Beta-agonists improvemuscle mass and strength in mdx mice
Several investigations have provided the most compelling evidence of the efficacy of beta-agonist administration for the treatment of muscle pathology attributable to the absence of dystrophin [18-23]. Six separate investigations using the mdx mousemodel of DMD, have shown that treatment with clenbuterol (another ß agonist) increases muscle mass and strength [18-23]. In these investigations, mdx mice were treated with clenbuterol for 15 weeks [21, 22], 2 months [18], 4 months [23] or 1 year [18], and in all cases the treatment was beneficial in reducing the wasting normally associated with the disease process.