Biologics for Improved Aged Muscle Function

摘要 肌肉减少症是与衰老相关的肌肉消耗和力量丧失的疾病。这种疾病 在65岁以上的人群中，有10-25%的人患病，在80岁以上的人群中，患病率增加了50%。虽然它本身就很虚弱， 肌肉无力是跌倒损伤的主要危险因素，并使导致残疾的风险增加高达4.6倍， 给社会带来巨大的医疗负担。65岁以上的美国人中，每4个人中就有1个人跌倒。 每年有800多万病例需要医疗护理，其直接费用超过50美元 10亿美元用于美国医疗保健系统。因此，开发治疗和逆转肌肉减少症的疗法将是有益的。 这对于防止老年人受伤后经常陷入残疾至关重要。虽然疾控中心认识到 2016年，肌肉减少症作为可报销的临床适应症，不幸的是，FDA批准的治疗药物为0种 目前，还没有候选药物既安全又有效。使用专有 通过ML支持的高通量筛选平台，JuvenaTherapeutics已经确定了几种信号蛋白 由人类胚胎干细胞分泌，改善老年肌肉中肌肉减少症的关键细胞方面 纤维和祖细胞。在初步研究中，全身或局部给予这些蛋白质， 老年小鼠的肌肉力量和纤维尺寸得到改善，并增强了“老年”小鼠的再生能力。 肌肉干细胞第一阶段将重点开发两种主要候选产品的变体， 实现目标产品特征，具有延长的稳定性和有效治疗所需的更宽的治疗窗 临床应用和产品商业化。在目标1中，我们将：（1）添加稳定基序以调节稳定性， 将半衰期从数分钟延长至>96小时;（2）确认工程化变体维持其 使用经验证的体外损伤激活模型， 骨骼肌再生;和（3）使用2种给药途径（s.c.和静脉注射）到 通知目标2体内疗效研究。在目标2中，将在一个 使用老年小鼠的自然肌肉减少症模型。将通过证明电极导线生物学特性表明成功 产生最大或持续的肌肉力量生产（力量和耐力）的改善， 握力、跑步机性能、体内和原位直接肌肉的统计学显著增加 刺激和力量测量，改善肌肉纤维大小和减少纤维化。一旦可行性 经论证，二期将集中于大规模、GMP生产足够的物料开展CMC， IND使能研究以及体内疗效研究的安全性/毒性。长远来说，我们会扩大 我们的再生蛋白的治疗应用，包括与干细胞相关的其他适应症 随着年龄的增长，如急性损伤/术后护理、骨关节炎和/或肌萎缩侧索硬化， 硬化症

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.