Rodino-Klapac Louise R, Haidet Amanda M, Kota Janaiah, Handy Chalonda, Kaspar Brian K, Mendell Jerry R
Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, Ohio 43205 USA.
Muscle Nerve. 2009 Mar;39(3):283-96. doi: 10.1002/mus.21244.
In most cases, pharmacologic strategies to treat genetic muscle disorders and certain acquired disorders, such as sporadic inclusion body myositis, have produced modest clinical benefits. In these conditions, inhibition of the myostatin pathway represents an alternative strategy to improve functional outcomes. Preclinical data that support this approach clearly demonstrate the potential for blocking the myostatin pathway. Follistatin has emerged as a powerful antagonist of myostatin that can increase muscle mass and strength. Follistatin was first isolated from the ovary and is known to suppress follicle-stimulating hormone. This raises concerns for potential adverse effects on the hypothalamic-pituitary-gonadal axis and possible reproductive capabilities. In this review we demonstrate a strategy to bypass off-target effects using an alternatively spliced cDNA of follistatin (FS344) delivered by adeno-associated virus (AAV) to muscle. The transgene product is a peptide of 315 amino acids that is secreted from the muscle and circulates in the serum, thus avoiding cell-surface binding sites. Using this approach our translational studies show increased muscle size and strength in species ranging from mice to monkeys. Adverse effects are avoided, and no organ system pathology or change in reproductive capabilities has been seen. These findings provide the impetus to move toward gene therapy clinical trials with delivery of AAV-FS344 to increase size and function of muscle in patients with neuromuscular disease.
在大多数情况下，用于治疗遗传性肌肉疾病和某些获得性疾病（如散发性包涵体肌炎）的药物策略仅产生了适度的临床益处。在这些病症中，抑制肌生成抑制素途径是改善功能结局的一种替代策略。支持该方法的临床前数据清楚地证明了阻断肌生成抑制素途径的潜力。卵泡抑素已成为一种强大的肌生成抑制素拮抗剂，可增加肌肉质量和力量。卵泡抑素最初是从卵巢中分离出来的，已知它能抑制促卵泡激素。这引发了对下丘脑 - 垂体 - 性腺轴潜在不良反应以及可能的生殖能力的担忧。在本综述中，我们展示了一种策略，即使用腺相关病毒（AAV）递送至肌肉的卵泡抑素可变剪接cDNA（FS344）来绕过脱靶效应。转基因产物是一种由315个氨基酸组成的肽，它从肌肉中分泌并在血清中循环，从而避免了细胞表面结合位点。通过这种方法，我们的转化研究表明，从小鼠到猴子等物种的肌肉大小和力量都有所增加。避免了不良反应，未观察到任何器官系统病理学变化或生殖能力改变。这些发现为开展基因治疗临床试验提供了动力，即通过递送AAV - FS344来增加神经肌肉疾病患者的肌肉大小和功能。
