Skeletal muscle atrophy is a highly prevalent condition caused by advanced age, muscle disuse, chronic illness, critical illness, and malnutrition. In addition to being very common, muscle atrophy has serious consequences, including weakness, reduced activity and quality of life, falls, fractures, extended hospitalizatio and rehabilitation, nursing home placement, and increased mortality in chronic disease patients and the elderly. However, despite its broad clinical impact, muscle atrophy lacks a medical therapy, and current therapeutic approaches (physical rehabilitation, nutritional optimization, and treatment of underlying disease) are often ineffective and/or unfeasible. Thus, skeletal muscle atrophy represents an enormous unmet medical need. A major goal of Emmyon, Inc. is to develop a medical therapy for skeletal muscle atrophy. In our preliminary studies, we discovered ursolic acid (UA) as a novel small molecule inhibitor of skeletal muscle atrophy. A natural compound found in apple peel and other edible plant materials, UA possesses a favorable safety profile and improves muscle function in both mice and humans. However, UA has limited potential as a pharmaceutical because composition-of-matter claims (which are critical for pharmaceutical development) are not possible for natural compounds. Thus, to translate UA into a medicine, Emmyon initiated a medicinal chemistry program to discover UA derivatives that enable composition-of-matter claims and also possess improved pharmacologic characteristics relative to native UA. Through these efforts, Emmyon has generated and tested a series of UA derivatives and discovered two novel derivatives (EMMY1-05 and EMMY1-06) that significantly increase muscle strength when administered orally to young adult mice that lack muscle atrophy. Furthermore, our data suggest that EMMY1-05 and EMMY1-06 may be more potent than native UA. In this phase I SBIR study, Emmyon will determine if EMMY1-05 and EMMY1-06 reduce muscle atrophy. In the proposed studies, we will determine the feasibility of EMMY1-05 and EMMY1-06 as therapies for muscle atrophy induced by two distinct causes: limb immobilization and aging. EMMY1-05 and EMMY1-06 will orally administered to mice with immobilization-induced muscle atrophy and mice with age-related muscle atrophy (sarcopenia). Both UA derivatives will be directly compared to native UA, which is known to reduce muscle atrophy following limb immobilization and during aging. Compound efficacy will be determined by assessing grip strength, specific force, muscle mass, muscle fiber size, and molecular atrophy mediators. Our goal is to identify at least one UA derivative that reduces muscle atrophy in both mouse models. In Phase II studies, Emmyon will carry the most promising UA derivative forward into pharmacokinetic and toxicology studies in rats and dogs, and then an IND application. Depending on the results of these studies, the initial clinical study would be geared towards FDA approval for the treatment of disuse muscle atrophy and/or age-related muscle atrophy.
Skeletal muscle atrophy is a widespread and serious medical problem, but lacks a medical therapy. In this phase I SBIR study, Emmyon, Inc. will generate new chemical compounds and test them in mice to determine if these compounds reduce muscle atrophy. Effective compounds will represent promising potential medicines for skeletal muscle atrophy, and will be carried towards human patients in phase II studies.
| Moro, Tatiana; Ebert, Scott M; Adams, Christopher M et al. (2016) Amino Acid Sensing in Skeletal Muscle. Trends Endocrinol Metab 27:796-806 |
