A novel chemical-combination screen in zebrafish identifies epigenetic small molecule candidates for the treatment of Duchenne muscular dystrophy.
A novel chemical-combination screen in zebrafish identifies epigenetic small molecule candidates for the treatment of Duchenne muscular dystrophy.
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DOI：
10.1186/s13395-020-00251-4
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发表时间：
2020-10-15
期刊：
影响因子：
4.9
通讯作者：
Maves L
中科院分区：
文献类型：
--
作者：
Farr GH 3rd;Morris M;Gomez A;Pham T;Kilroy E;Parker EU;Said S;Henry C;Maves L
Duchenne肌营养不良症(DMD)是一种严重的神经肌肉疾病，是最常见的肌营养不良症之一。目前几乎没有有效的治疗方法来治疗这种疾病，尽管人们正在寻求许多小分子方法。某些组蛋白脱乙酰酶抑制剂(HDACi)已被证明可以改善小鼠和斑马鱼动物模型的DMD表型。HDACi givinostat已在临床试验中显示出对DMD的前景。然而，除了一小群HDACi外，其他类别的表观遗传小分子还没有被广泛和系统地研究它们对DMD的好处。我们使用了一种已建立的DMD动物模型，即斑马鱼DMD突变株Sapje。商业上可用的表观遗传小分子文库被用于治疗DMD突变斑马鱼的胚胎-幼体阶段。我们使用定量肌肉双折射分析来评估和比较小分子治疗对DMD突变斑马鱼骨骼肌结构的影响。我们使用斑马鱼DMD模型对表观遗传化合物文库进行了一种新的化学组合筛选。我们确定了可改善DMD突变斑马鱼骨骼肌结构的候选表观遗传化合物池。然后，我们确定了两种HDACi化合物的特定组合，奥沙明和沙拉胺，可以改善DMD突变斑马鱼骨骼肌的退化。我们在一个独立的实验室中验证了奥沙明和沙乐胺对DMD突变斑马鱼的影响。此外，我们还发现奥沙明和沙拉胺联合使用可以增加斑马鱼幼体中组蛋白H4的乙酰化水平。我们的结果为斑马鱼的小分子筛选提供了新的、有效的方法。我们的结果也增加了越来越多的证据，即表观遗传小分子可能是治疗DMD的有希望的候选者。
Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder and is one of the most common muscular dystrophies. There are currently few effective therapies to treat the disease, although many small-molecule approaches are being pursued. Certain histone deacetylase inhibitors (HDACi) have been shown to ameliorate DMD phenotypes in mouse and zebrafish animal models. The HDACi givinostat has shown promise for DMD in clinical trials. However, beyond a small group of HDACi, other classes of epigenetic small molecules have not been broadly and systematically studied for their benefits for DMD. We used an established animal model for DMD, the zebrafish dmd mutant strain sapje. A commercially available library of epigenetic small molecules was used to treat embryonic-larval stages of dmd mutant zebrafish. We used a quantitative muscle birefringence assay in order to assess and compare the effects of small-molecule treatments on dmd mutant zebrafish skeletal muscle structure. We performed a novel chemical-combination screen of a library of epigenetic compounds using the zebrafish dmd model. We identified candidate pools of epigenetic compounds that improve skeletal muscle structure in dmd mutant zebrafish. We then identified a specific combination of two HDACi compounds, oxamflatin and salermide, that ameliorated dmd mutant zebrafish skeletal muscle degeneration. We validated the effects of oxamflatin and salermide on dmd mutant zebrafish in an independent laboratory. Furthermore, we showed that the combination of oxamflatin and salermide caused increased levels of histone H4 acetylation in zebrafish larvae. Our results provide novel, effective methods for performing a combination of small-molecule screen in zebrafish. Our results also add to the growing evidence that epigenetic small molecules may be promising candidates for treating DMD.
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影响因子：
4.9
作者：
Campbell AE;Oliva J;Yates MP;Zhong JW;Shadle SC;Snider L;Singh N;Tai S;Hiramuki Y;Tawil R;van der Maarel SM;Tapscott SJ;Sverdrup FM
通讯作者：
Sverdrup FM
影响因子：
2.8
作者：
Berger, Joachim;Berger, Silke;Currie, Peter D.
通讯作者：
Currie, Peter D.
影响因子：
4.5
作者：
Chalkiadaki A;Igarashi M;Nasamu AS;Knezevic J;Guarente L
通讯作者：
Guarente L
DOI：
10.1073/pnas.0805514105
发表时间：
2008-12-09
影响因子：
11.1
作者：
Colussi, Claudia;Mozzetta, Chiara;Gaetano, Carlo
通讯作者：
Gaetano, Carlo
影响因子：
5.7
作者：
Consalvi, Silvia;Mozzetta, Chiara;Saccone, Valentina
通讯作者：
Saccone, Valentina