Mendell Jerry R, Sahenk Zarife, Malik Vinod, Gomez Ana M, Flanigan Kevin M, Lowes Linda P, Alfano Lindsay N, Berry Katherine, Meadows Eric, Lewis Sarah, Braun Lyndsey, Shontz Kim, Rouhana Maria, Clark Kelly Reed, Rosales Xiomara Q, Al-Zaidy Samiah, Govoni Alessandra, Rodino-Klapac Louise R, Hogan Mark J, Kaspar Brian K
1] Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA [2] Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA [3] Department of Neurology, The Ohio State University, Columbus, Ohio, USA.
Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA.
Mol Ther. 2015 Jan;23(1):192-201. doi: 10.1038/mt.2014.200. Epub 2014 Oct 17.
Becker muscular dystrophy (BMD) is a variant of dystrophin deficiency resulting from DMD gene mutations. Phenotype is variable with loss of ambulation in late teenage or late mid-life years. There is currently no treatment for this condition. In this BMD proof-of-principle clinical trial, a potent myostatin antagonist, follistatin (FS), was used to inhibit the myostatin pathway. Extensive preclinical studies, using adeno-associated virus (AAV) to deliver follistatin, demonstrated an increase in strength. For this trial, we used the alternatively spliced FS344 to avoid potential binding to off target sites. AAV1.CMV.FS344 was delivered to six BMD patients by direct bilateral intramuscular quadriceps injections. Cohort 1 included three subjects receiving 3 × 10(11) vg/kg/leg. The distance walked on the 6MWT was the primary outcome measure. Patients 01 and 02 improved 58 meters (m) and 125 m, respectively. Patient 03 showed no change. In Cohort 2, Patients 05 and 06 received 6 × 10(11) vg/kg/leg with improved 6MWT by 108 m and 29 m, whereas, Patient 04 showed no improvement. No adverse effects were encountered. Histological changes corroborated benefit showing reduced endomysial fibrosis, reduced central nucleation, more normal fiber size distribution with muscle hypertrophy, especially at high dose. The results are encouraging for treatment of dystrophin-deficient muscle diseases.
贝克尔肌营养不良症（BMD）是由DMD基因突变导致的肌营养不良蛋白缺乏的一种变体。其表型具有变异性，在青少年晚期或中年后期会出现行走能力丧失。目前这种疾病尚无治疗方法。在这项BMD原理验证临床试验中，一种强效的肌肉生长抑制素拮抗剂，卵泡抑素（FS），被用于抑制肌肉生长抑制素通路。广泛的临床前研究使用腺相关病毒（AAV）来递送卵泡抑素，结果显示力量有所增加。在本试验中，我们使用了选择性剪接的FS344以避免与脱靶位点潜在结合。通过双侧股四头肌直接肌肉注射将AAV1.CMV.FS344递送至6名BMD患者体内。队列1包括3名接受3×10¹¹vg/kg/腿剂量的受试者。6分钟步行试验（6MWT）中的行走距离是主要结局指标。患者01和02分别提高了58米（m）和125米。患者03没有变化。在队列2中，患者05和06接受了6×10¹¹vg/kg/腿的剂量，6MWT分别提高了108米和29米，而患者04没有改善。未出现不良反应。组织学变化证实了治疗效果，表现为肌内膜纤维化减轻、中央核化减少、纤维大小分布更正常且伴有肌肉肥大，尤其是在高剂量时。这些结果对于治疗肌营养不良蛋白缺乏的肌肉疾病是令人鼓舞的。
