Biologics for Improved Aged Muscle Function

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ABSTRACT Sarcopenia is the disease of muscle wasting and loss of strength associated with aging. This disease afflicts 10-25% of those over age 65, increasing > 50% of those over age 80. While debilitating in its own right, muscle weakness is a major risk factor for fall injury and increases the risk of resulting disability up to 4.6-fold, resulting in an immense healthcare burden to society. 1 in 4 Americans over the age of 65 suffers a fall every year, leading to over 8 million cases requiring medical care annually, the direct costs of which exceed $50 billion to the US healthcare system. Thus, developing therapeutics to treat and reverse sarcopenia will be essential for preventing the frequent spiral into disability after injury in the elderly. While the CDC recognized sarcopenia as a reimbursable clinical indication in 2016, unfortunately, there are 0 FDA approved therapeutics available today, as no drug candidates have demonstrated both safety and efficacy. Using a proprietary ML-enabled high-throughput screening platform, Juvena Therapeutics has identified several signaling proteins secreted by human embryonic stem cells that ameliorate key cellular aspects of sarcopenia in aged muscle fibers and progenitor cells. In pilot studies, systemic or local administration of these proteins in sarcopenic, aged mice improved muscle strength and fiber size, and enhanced the regenerative capability of "aged" muscle stem cells. This Phase I will focus on developing variants of two of the lead candidates modified to achieve a target product profile with extended stability and wider therapeutic window required for effective clinical use and product commercialization. In Aim 1, we will: (1) add stabilization motifs to modulate stability, extending half-lives from minutes to >96 hours; (2) confirm that the engineered variants maintain their regenerative properties in aged mouse and human myoblasts using validated in vitro injury-activate models of skeletal muscle regeneration; and (3) conduct pilot PK studies using 2 routes of administration (s.c. and i.v.) to inform Aim 2 in vivo efficacy studies. In Aim 2, efficacy of the modified lead candidates will be assessed in a natural sarcopenia model using aged mice. Success will be indicated by demonstrating the lead biologic produces an improvement in maximal or sustained muscle force production (strength and endurance) as a statistically significant increase in grip strength, treadmill performance, in vivo and in situ direct muscle stimulation and force measurement, improvements in muscle fiber size and reduced fibrosis. Once feasibility is demonstrated, Phase II will focus on large-scale, GMP production of sufficient material to carry out CMC, Safety/tox for IND enabling studies as well as in vivo efficacy studies. In the long term, we will expand the therapeutic applications for our regenerative proteins to include other indications associated with stem cell dysregulation with aging such as acute injury / post-operative care, osteoarthritis, and/or Amyotrophic lateral sclerosis.