Smith Barbara K, Martin A Daniel, Lawson Lee Ann, Vernot Valerie, Marcus Jordan, Islam Saleem, Shafi Nadeem, Corti Manuela, Collins Shelley W, Byrne Barry J
Department of Physical Therapy, P.O. Box 100154, University of Florida, Gainesville, FL 32610, United States; Department of Pediatrics, P.O. Box 100144, University of Florida, Gainesville, FL 32610, United States.
Department of Physical Therapy, P.O. Box 100154, University of Florida, Gainesville, FL 32610, United States.
Exp Neurol. 2017 Jan;287(Pt 2):216-224. doi: 10.1016/j.expneurol.2016.07.013. Epub 2016 Jul 21.
Pompe disease is an inherited disorder due to a mutation in the gene that encodes acid α-glucosidase (GAA). Children with infantile-onset Pompe disease develop progressive hypotonic weakness and cardiopulmonary insufficiency that may eventually require mechanical ventilation (MV). Our team conducted a first in human trial of diaphragmatic gene therapy (AAV1-CMV-GAA) to treat respiratory neural dysfunction in infantile-onset Pompe. Subjects (aged 2-15years, full-time MV: n=5, partial/no MV: n=4) underwent a period of preoperative inspiratory muscle conditioning exercise. The change in respiratory function after exercise alone was compared to the change in function after intramuscular delivery of AAV1-CMV-GAA to the diaphragm with continued exercise. Since AAV-mediated gene therapy can reach phrenic motoneurons via retrograde transduction, we hypothesized that AAV1-CMV-GAA would improve dynamic respiratory motor function to a greater degree than exercise alone. Dependent measures were maximal inspiratory pressure (MIP), respiratory responses to inspiratory threshold loads (load compensation: LC), and physical evidence of diaphragm activity (descent on MRI, EMG activity). Exercise alone did not change function. After AAV1-CMV-GAA, MIP was unchanged. Flow and volume LC responses increased after dosing (p<0.05 to p<0.005), but only in the subjects with partial/no MV use. Changes in LC tended to occur on or after 180days. At Day 180, the four subjects with MRI evidence of diaphragm descent had greater maximal voluntary ventilation (p<0.05) and tended to be younger, stronger, and use fewer hours of daily MV. In conclusion, combined AAV1-CMV-GAA and exercise training conferred benefits to dynamic motor function of the diaphragm. Children with a higher baseline neuromuscular function may have greater potential for functional gains.
庞贝病是一种遗传性疾病，由编码酸性α-葡萄糖苷酶（GAA）的基因突变引起。婴儿型庞贝病患儿会出现进行性肌张力减退和心肺功能不全，最终可能需要机械通气（MV）。我们的团队进行了首例人类膈神经基因治疗（AAV1-CMV-GAA）试验，以治疗婴儿型庞贝病的呼吸神经功能障碍。受试者（年龄2至15岁，全时MV：n = 5，部分/无MV：n = 4）接受了一段时间的术前吸气肌条件训练。将单独运动后的呼吸功能变化与向膈肌肌内注射AAV1-CMV-GAA并持续运动后的功能变化进行比较。由于AAV介导的基因治疗可通过逆行转导到达膈运动神经元，我们假设AAV1-CMV-GAA比单独运动能更大程度地改善动态呼吸运动功能。相关测量指标包括最大吸气压力（MIP）、对吸气阈值负荷的呼吸反应（负荷补偿：LC）以及膈肌活动的物理证据（MRI上的下降、肌电图活动）。单独运动并未改变功能。注射AAV1-CMV-GAA后，MIP未变。给药后流量和容积LC反应增加（p<0.05至p<0.005），但仅在部分/无MV使用的受试者中出现。LC变化往往在180天及之后出现。在第180天，有MRI证据显示膈肌下降的四名受试者具有更大的最大自主通气量（p<0.05），且往往更年轻、更强壮，每日使用MV的时间更少。总之，AAV1-CMV-GAA与运动训练相结合对膈肌的动态运动功能有益。基线神经肌肉功能较高的儿童可能有更大的功能改善潜力。
