Department of Physiology, Wayne State University School of Medicine, Detroit, MI, United States of America.
PLoS One. 2023 Sep 27;18(9):e0286380. doi: 10.1371/journal.pone.0286380. eCollection 2023.
Barth Syndrome is a rare, X-linked disorder caused by mutation of the gene TAFAZZIN (TAZ). The corresponding Tafazzin protein is involved in the remodeling of cardiolipin, a phospholipid with critical roles in mitochondrial function. While recent clinical trials have been promising, there is still no cure for Barth Syndrome. Because TAZ is highly conserved, multiple animal and cell culture models exist for pre-clinical testing of therapeutics. However, since the same mutation in different patients can lead to different symptoms and responses to treatment, isogenized experimental models can't fully account for human disease conditions. On the other hand, isogenized animal models allow for sufficient numbers to thoroughly establish efficacy for a given genetic background. Therefore, a combined method for testing treatments in a panel of isogenized cohorts that are genetically distinct from each other would be transformative for testing emerging pre-clinical therapies. To aid in this effort, we've created a novel panel of 10 Drosophila lines, each with the same TAZ mutation in highly diverse genetic backgrounds, to serve as a helpful resource to represent natural variation in background genetics in pre-clinical studies. As a proof of principle, we test our panel here using nicotinamide riboside (NR), a treatment with established therapeutic value, to evaluate how robust this therapy is across the 10 genetic backgrounds in this novel reference panel. We find substantial variation in the response to NR across backgrounds. We expect this resource will be valuable in pre-clinical testing of emerging therapies for Barth Syndrome.
巴德-希利综合征是一种罕见的 X 连锁疾病，由 TAFAZZIN（TAZ）基因突变引起。相应的 Tafazzin 蛋白参与心磷脂的重塑，心磷脂是一种在线粒体功能中起关键作用的磷脂。虽然最近的临床试验有希望，但仍然没有治愈巴德-希利综合征的方法。由于 TAZ 高度保守，存在多种动物和细胞培养模型，可用于治疗药物的临床前测试。然而，由于不同患者的相同突变可能导致不同的症状和对治疗的反应，同基因实验模型不能完全解释人类疾病状况。另一方面，同基因动物模型允许有足够数量的动物来彻底确定给定遗传背景下的疗效。因此，一种在遗传上彼此不同的同基因队列面板中测试治疗方法的组合方法将对测试新兴的临床前治疗方法具有变革性。为了帮助实现这一目标，我们创建了一个由 10 个果蝇系组成的新面板，每个系都具有高度多样化的遗传背景中的相同 TAZ 突变，作为一个有用的资源，以代表临床前研究中背景遗传的自然变异。作为一个原理验证，我们在这里使用烟酰胺核糖苷（NR）测试我们的面板，NR 是一种具有既定治疗价值的治疗方法，以评估这种疗法在这个新的参考面板的 10 个遗传背景中的稳健性。我们发现，NR 在不同背景下的反应存在很大差异。我们预计，这个资源将在巴德-希利综合征的新兴治疗方法的临床前测试中非常有价值。
