One episode of low intensity aerobic exercise prior to systemic AAV9 administration augments transgene delivery to the heart and skeletal muscle.
One episode of low intensity aerobic exercise prior to systemic AAV9 administration augments transgene delivery to the heart and skeletal muscle.
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DOI：
10.1186/s12967-023-04626-1
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发表时间：
2023-10-24
影响因子：
7.4
通讯作者：
Cade, William Todd
中科院分区：
文献类型：
--
作者：
Pacak, Christina A.;Suzuki-Hatano, Silveli;Khadir, Fatemeh;Daugherty, Audrey L.;Sriramvenugopal, Mughil;Gosiker, Bennett J.;Kang, Peter B.;Cade, William Todd
关键词：
腺相关病毒（AAV）基因递送策略治疗遗传性疾病的潜力继续增长，最近美国食品和药物管理局批准了另外三种基于AAV的疗法，目前正在临床试验中评估其他数十种疗法。随着这些发展，越来越明显的是，目前有效性所需的高剂量具有毒性风险，并需要巨大的制造成本，特别是对于临床级产品。提高AAV介导的基因递送的治疗功效和降低最小有效剂量的策略将对该领域产生重大影响。我们假设，在全身静脉内（IV）施用AAV之前，通过急性有氧运动，运动诱导的体内组织灌注的重新分布有利于特定的靶器官，这可以增加功效。有氧运动引发了一系列下游生理效应，包括心脏和骨骼肌灌注增加，我们预计这可能会增强AAV转导。先前的临床前研究已经显示了基因治疗方法治疗Barth综合征（BTHS）的有希望的结果，BTHS是一种罕见的单基因心脏骨骼肌病，临床研究已经显示了低强度运动在这些患者中的益处，使其成为测试有氧运动增强AAV转导能力的合适疾病。将野生型（WT）和BTHS小鼠全身施用AAV9或在全身施用AAV9之前立即完成一次低强度跑步机运动。我们证明，与没有运动预处理的注射小鼠相比，在IV AAV9施用之前立即进行的单次急性低强度有氧运动改善了WT小鼠中的标志物转基因递送。在BTHS小鼠中，与未经运动治疗的小鼠相比，先前的运动改善了转基因递送，并额外增加了心脏和腓肠肌中线粒体基因转录水平和线粒体功能的改善。我们的研究结果表明，一次急性低强度有氧运动可以改善心脏和骨骼肌的AAV9转导。这种低风险，成本效益的干预措施可以在遗传性心脏骨骼疾病患者的临床试验中实施，作为改善人类基因治疗患者安全性的潜在手段。
The promising potential of adeno-associated virus (AAV) gene delivery strategies to treat genetic disorders continues to grow with an additional three AAV-based therapies recently approved by the Food and Drug Administration and dozens of others currently under evaluation in clinical trials. With these developments, it has become increasingly apparent that the high doses currently needed for efficacy carry risks of toxicity and entail enormous manufacturing costs, especially for clinical grade products. Strategies to increase the therapeutic efficacy of AAV-mediated gene delivery and reduce the minimal effective dose would have a substantial impact on this field. We hypothesized that an exercise-induced redistribution of tissue perfusion in the body to favor specific target organs via acute aerobic exercise prior to systemic intravenous (IV) AAV administration could increase efficacy. Aerobic exercise triggers an array of downstream physiological effects including increased perfusion of heart and skeletal muscle, which we expected could enhance AAV transduction. Prior preclinical studies have shown promising results for a gene therapy approach to treat Barth syndrome (BTHS), a rare monogenic cardioskeletal myopathy, and clinical studies have shown the benefit of low intensity exercise in these patients, making this a suitable disease in which to test the ability of aerobic exercise to enhance AAV transduction. Wild-type (WT) and BTHS mice were either systemically administered AAV9 or completed one episode of low intensity treadmill exercise immediately prior to systemic administration of AAV9. We demonstrate that a single episode of acute low intensity aerobic exercise immediately prior to IV AAV9 administration improves marker transgene delivery in WT mice as compared to mice injected without the exercise pre-treatment. In BTHS mice, prior exercise improved transgene delivery and additionally increased improvement in mitochondrial gene transcription levels and mitochondrial function in the heart and gastrocnemius muscles as compared to mice treated without exercise. Our findings suggest that one episode of acute low intensity aerobic exercise improves AAV9 transduction of heart and skeletal muscle. This low-risk, cost effective intervention could be implemented in clinical trials of individuals with inherited cardioskeletal disease as a potential means of improving patient safety for human gene therapy.
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DOI：
10.1111/j.1748-1716.1939.tb00462.x
发表时间：
1939-01-01
期刊：
SKANDINAVISCHES ARCHIV FUR PHYSIOLOGIE
影响因子：
--
作者：
Asmussen, E;Christensen, EH;Nielsen, M
通讯作者：
Nielsen, M
影响因子：
--
作者：
Kim, Jaetaek;Wende, Adam R.;Abel, E. Dale
通讯作者：
Abel, E. Dale
DOI：
10.1007/8904_2016_553
发表时间：
2017-01-01
期刊：
JIMD REPORTS, VOL 32
影响因子：
--
作者：
Cade, W. Todd;Reeds, Dominic N.;Taylor, Carolyn L.
通讯作者：
Taylor, Carolyn L.
影响因子：
2.7
作者：
Frydelund-Larsen, Lone;Penkowa, Milena;Pedersen, Bente Klarlund
通讯作者：
Pedersen, Bente Klarlund
影响因子：
4.6
作者：
Chandran JS;Sharp PS;Karyka E;Aves-Cruzeiro JMDC;Coldicott I;Castelli L;Hautbergue G;Collins MO;Azzouz M
通讯作者：
Azzouz M