Department of Pediatrics, University of Oxford, Oxford OX3 9DU, UK.
Division of Child Neurology, Department of Paediatrics, Centre de Référence des Maladies Neuromusculaires, University Hospital of Liège, University of Liège, Boulevard Du 12e De Ligne, 4000 Liege, Belgium.
Int J Mol Sci. 2024 Sep 24;25(19):10273. doi: 10.3390/ijms251910273.
Spinal muscular atrophy (SMA) is a rare, genetic neurodegenerative disorder caused by insufficient production of survival motor neuron (SMN) protein. Diminished SMN protein levels lead to motor neuron loss, causing muscle atrophy and weakness that impairs daily functioning and reduces quality of life. SMN upregulators offer clinical improvements and increased survival in SMA patients, although significant unmet needs remain. Myostatin, a TGF-β superfamily signaling molecule that binds to the activin II receptor, negatively regulates muscle growth; myostatin inhibition is a promising therapeutic strategy for enhancing muscle. Combining myostatin inhibition with SMN upregulation, a comprehensive therapeutic strategy targeting the whole motor unit, offers promise in SMA. Taldefgrobep alfa is a novel, fully human recombinant protein that selectively binds to myostatin and competitively inhibits other ligands that signal through the activin II receptor. Given a robust scientific and clinical rationale and the favorable safety profile of taldefgrobep in patients with neuromuscular disease, the RESILIENT phase 3, randomized, placebo-controlled trial is investigating taldefgrobep as an adjunct to SMN upregulators in SMA (NCT05337553). This manuscript reviews the role of myostatin in muscle, explores the preclinical and clinical development of taldefgrobep and introduces the phase 3 RESILIENT trial of taldefgrobep in SMA.
脊髓性肌萎缩症（SMA）是一种罕见的遗传性神经退行性疾病，由生存运动神经元（SMN）蛋白产生不足引起。SMN 蛋白水平降低导致运动神经元丧失，导致肌肉萎缩和无力，从而影响日常功能并降低生活质量。SMN 上调剂可改善 SMA 患者的临床症状并延长其生存时间，但仍存在显著的未满足需求。肌肉生长抑制素（Myostatin）是 TGF-β 超家族信号分子，与激活素 II 受体结合，负向调节肌肉生长；抑制肌肉生长抑制素是增强肌肉的一种很有前途的治疗策略。将肌肉生长抑制素抑制与 SMN 上调相结合，针对整个运动单位的综合治疗策略，为 SMA 提供了希望。Taldefgrobep alfa 是一种新型的、完全人源的重组蛋白，可选择性结合肌肉生长抑制素并竞争性抑制通过激活素 II 受体信号传导的其他配体。鉴于其强大的科学和临床基础以及在神经肌肉疾病患者中的良好安全性特征，RESILIENT 是一项 3 期、随机、安慰剂对照试验，正在研究 taldefgrobep 作为 SMA 中 SMN 上调剂的辅助治疗药物（NCT05337553）。本文回顾了肌肉生长抑制素在肌肉中的作用，探讨了 taldefgrobep 的临床前和临床开发情况，并介绍了 taldefgrobep 在 SMA 中的 3 期 RESILIENT 试验。
