Biologics for Improved Aged Muscle Function

改善老年肌肉功能的生物制剂

• 批准号: 10323586
• 负责人: Jeremy O'Connell
• 金额: $ 25.43万
• 依托单位: JUVENA THERAPEUTICS INC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323586
• 关键词: Acute; Address; Adipose tissue; Age; Aged, 80 and over; Aging; American; Amyotrophic Lateral Sclerosis; Biological; Biological Markers; C-terminal; Caring; Cell Count; Cells; Centers for Disease Control and Prevention (U.S.); Chimeric Proteins; Clinical; Degenerative polyarthritis; Direct Costs; Disease; Dose; Elderly; Engineering; Environment; Etiology; FDA approved; Fc domain; Fiber; Fibrosis; Fracture; Generations; Half-Life; Hand Strength; Health Care Costs; Healthcare; Healthcare Systems; Histologic; Homeostasis; Hour; Human; IgG4; In Situ; In Vitro; Individual; Injectable; Injury; Insulin-Like Growth Factor II; Lead; Length; Measurement; Measures; Medical; Modeling; Molecular Sieve Chromatography; Mus; Muscle; Muscle Fibers; Muscle Weakness; Muscle function; Muscle satellite cell; Muscular Atrophy; Mutation; Myoblasts; Myopathy; Neuromuscular Junction; Patient Care; Performance; Phase; Pilot Projects; Postoperative Care; Production; Property; Proteins; Regenerative capacity; Risk; Risk Factors; Route; Running; Safety; Serum; Signal Transduction; Signaling Protein; Site; Skeletal Muscle; Societies; Speed; Therapeutic; Therapeutic Agents; Treatment Cost; Variant; age-related muscle loss; aged; bone morphogenic protein; commercialization; disability; disability risk; drug candidate; efficacy study; experimental study; extracellular; fall injury; falls; fiber cell; high throughput screening; human embryonic stem cell; human old age (65+); improved; in vivo; lead candidate; muscle aging; muscle form; muscle regeneration; muscle strength; myogenesis; nerve supply; prevent; progenitor; regenerative; sarcopenia; screening; stem; stem cells; subcutaneous; success; therapeutic candidate; treadmill

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.

抽象的 肌肉减少症是肌肉浪费和与衰老相关的力量下降的疾病。这种疾病 折磨65岁以上的人中有10-25％增加了80岁以上的人中的50％。 肌肉无力是秋季受伤的主要危险因素，并增加导致残疾的风险高达4.6倍， 给社会带来了巨大的医疗保健负担。 65岁以上的四分之一的美国人每人跌倒 一年，导致每年需要医疗的800万例案件，其直接费用超过50美元 美国医疗保健系统十亿。因此，开发治疗和逆转肌肉减少症的治疗剂将是 对于防止老年人受伤后频繁的螺旋性残疾至关重要。而疾病预防控制中心识别 不幸的是，肌肉减少症是2016年可报销的临床指示，有0个FDA批准的治疗剂 今天可以使用，因为没有候选药物既表现出安全性和功效。使用专有 Juvena Therapeutics启用了ML启用的高通量筛查平台，已确定了几种信号蛋白 由人类胚胎干细胞分泌，可改善肌肉减少症的关键细胞方面 纤维和祖细胞。在试点研究中，这些蛋白质在肌肉减少症中的全身性或局部给药， 老年小鼠改善了肌肉力量和纤维尺寸，并增强了“老化”的再生能力 肌肉干细胞。该阶段我将重点介绍开发两个已修改为的主要候选者的变体 实现目标产品概况，具有延长的稳定性和更宽的治疗窗口才能有效 临床用途和产品商业化。在AIM 1中，我们将：（1）添加稳定图案以调节稳定性， 将半衰期从几分钟延长到96小时； （2）确认工程变体维护 使用经过验证的体外损伤激活模型的老鼠和人成肌细胞的再生特性 骨骼肌再生； （3）使用2种给药途径（S.C.和I.V.）进行PILOT PK研究 了解AIM 2体内功效研究。在AIM 2中，将在A中评估改良的主要候选者的功效 天然肌肉减少症模型使用老年小鼠。成功将通过证明铅生物学来指示 作为一个最大或持续的肌肉力量产生（强度和耐力）的改善 握力强度，跑步机的性能，体内和原位直接肌肉的统计显着提高 刺激和力测量，肌肉纤维大小的改善以及纤维化减少。一旦可行性 事实证明，第二阶段将集中于大规模的GMP生产足够的材料来执行CMC， 安全/托克斯用于IND促进研究以及体内功效研究。从长远来看，我们将扩展 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 衰老失调，例如急性损伤 /术后护理，骨关节炎和 /或肌萎缩性侧面 硬化。