Elverman Matthew, Goddard Melissa A, Mack David, Snyder Jessica M, Lawlor Michael W, Meng Hui, Beggs Alan H, Buj-Bello Ana, Poulard Karine, Marsh Anthony P, Grange Robert W, Kelly Valerie E, Childers Martin K
Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA.
Department of Physiology and Pharmacology, School of Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA.
Muscle Nerve. 2017 Nov;56(5):943-953. doi: 10.1002/mus.25658. Epub 2017 May 22.
X-linked myotubular myopathy (XLMTM), a devastating pediatric disease caused by the absence of the protein myotubularin, results from mutations in the MTM1 gene. While there is no cure for XLMTM, we previously reported effects of MTM1 gene therapy using adeno-associated virus (AAV) vector on muscle weakness and pathology in MTM1-mutant dogs. Here, we followed 2 AAV-infused dogs over 4 years.
We evaluated gait, strength, respiration, neurological function, muscle pathology, AAV vector copy number (VCN), and transgene expression.
Four years following AAV-mediated gene therapy, gait, respiratory performance, neurological function and pathology in AAV-infused XLMTM dogs remained comparable to their healthy littermate controls despite a decline in VCN and muscle strength.
AAV-mediated gene transfer of MTM1 in young XLMTM dogs results in long-term expression of myotubularin transgene with normal muscular performance and neurological function in the absence of muscle pathology. These findings support a clinical trial in patients. Muscle Nerve 56: 943-953, 2017.
X连锁性肌管性肌病（XLMTM）是一种由肌管素蛋白缺失引起的严重儿科疾病，由MTM1基因突变所致。虽然目前尚无治愈XLMTM的方法，但我们之前报道了使用腺相关病毒（AAV）载体进行MTM1基因治疗对MTM1突变犬肌肉无力和病理状况的影响。在此，我们对2只接受AAV注射的犬进行了4年的跟踪观察。
我们评估了步态、力量、呼吸、神经功能、肌肉病理、AAV载体拷贝数（VCN）和转基因表达。
在AAV介导的基因治疗4年后，尽管VCN和肌肉力量有所下降，但接受AAV注射的XLMTM犬的步态、呼吸功能、神经功能和病理状况仍与健康同窝对照犬相当。
在年轻的XLMTM犬中，AAV介导的MTM1基因转移导致肌管素转基因的长期表达，肌肉性能和神经功能正常，且无肌肉病理改变。这些发现支持在患者中开展临床试验。《肌肉与神经》56: 943 - 953, 2017年。
