Two of the major pathways targeted enhance the actions of insulin-like growth factor I (IGF-I), and inhibit the anti-growth pathways of Myostatin/Gdf8 and its related family members. Several clinical trials have occurred and/or are underway examining protein/antibody and gene therapy approaches. While these approaches may provide potent regulation of these pathways, and potentially preserve functional muscle mass, no study to date has developed an orally bioavailable compound that can promote muscle growth. Thus, we assert that a major challenge for delivery of pro-growth compounds is the lack of oral bioavailability, as all current options rely on intramuscular or intravenous/arterial injections. In this application, we propose to capitalize on the oral biovailability and stability of chloroplast bioencapsulation to produce myostatin propeptide and IGF-I, which enable high production of protein relative to the total soluble protein in plants. The collaborative team will combine expertise in chloroplast expression with expertise in skeletal muscle physiology to determine if a novel delivery strategy for growth promoting agents can increase functional muscle mass in mice.
In Aim 1, the murine myostatin propeptide fused to the Fc domain of IgG will be expressed in Nicotiana benthamiana and evaluated for cell-based activity and in vivo efficacy of myostatin inhibition. Likewise, in Aim 2, a similar construct of Pro-IGF-I-Fc will be made, and also tested in the same manner. At the completion of this project, a thorough evaluation of this strategy will be complete, and potentially at least 1 candidate will be identified to move forward into production in lettuce, which is a platform that is clinically relevant and affords marker free production of therapeutic proteins. Ultimately, the chloroplast expression system may be established as a potential strategy to express and deliver established factors as well as newly discovered proteins that can promote muscle growth.
Preservation of muscle mass and function, and countering their loss is a clinically important goal in situations spanning from imposed bed rest during hospital stays, aging-related loss of muscle (sarcopenia), neuromuscular disease, to muscle wasting (cachexia). As such, significant effort into the development of strategies to boost muscle mass and/or prevent its loss. Two of the major pathways targeted enhance the actions of insulin-like growth factor I (IGF-I), and inhibit the anti-growth pathways of Myostatin/Gdf8 and its related family members, and these will be evaluated using a new strategy that enables oral delivery of therapeutic proteins. This will simplify treatment regimens for many individuals in need of muscle boosting therapies.
