Department of Cardiology (R.H.B., F.N., C.P., M.A.T., M.P., M.E.S., P.W., J.C., F.L., C.L., P.B., E.M.K., D.Y., N.P., T.S., Q.M., D.J.A., V.J.B., W.T.P.).
Boston Children's Hospital, MA. Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.B.C., P.T.S.).
Circulation. 2024 Oct 8;150(15):1199-1210. doi: 10.1161/CIRCULATIONAHA.123.068111. Epub 2024 Aug 19.
Calmodulinopathies are rare inherited arrhythmia syndromes caused by dominant heterozygous variants in , , or , which each encode the identical CaM (calmodulin) protein. We hypothesized that antisense oligonucleotide (ASO)-mediated depletion of an affected calmodulin gene would ameliorate disease manifestations, whereas the other 2 calmodulin genes would preserve CaM level and function.
We tested this hypothesis using human induced pluripotent stem cell-derived cardiomyocyte and mouse models of pathogenic variants.
Human induced pluripotent stem cell-derived cardiomyocytes exhibited prolonged action potentials, modeling congenital long QT syndrome. CALM1 knockout or CALM1-depleting ASOs did not alter CaM protein level and normalized repolarization duration of induced pluripotent stem cell-derived cardiomyocytes. Similarly, an ASO targeting murine depleted transcript without affecting CaM protein level. This ASO alleviated drug-induced bidirectional ventricular tachycardia in mice without a deleterious effect on cardiac electrical or contractile function.
These results provide proof of concept that ASOs targeting individual calmodulin genes are potentially effective and safe therapies for calmodulinopathies.
钙调蛋白病是一种罕见的遗传性心律失常综合征，由 、 或 中的显性杂合变异引起，这三种基因均编码相同的钙调蛋白（CaM）蛋白。我们假设反义寡核苷酸（ASO）介导的受影响钙调蛋白基因耗竭将改善疾病表现，而其他 2 种钙调蛋白基因将维持 CaM 水平和功能。
我们使用人诱导多能干细胞衍生的心肌细胞和 致病变异的小鼠模型来检验这一假设。
人诱导多能干细胞衍生的心肌细胞表现出动作电位延长，模拟先天性长 QT 综合征。CALM1 敲除或 CALM1 耗竭 ASO 并未改变 CaM 蛋白水平，并使 诱导多能干细胞衍生的心肌细胞复极化时间正常化。同样，针对小鼠 的 ASO 靶向 转录本而不影响 CaM 蛋白水平。该 ASO 缓解了药物诱导的双向室性心动过速，而对心脏电或收缩功能没有不良影响。
这些结果提供了概念验证，即针对单个钙调蛋白基因的 ASO 可能是钙调蛋白病的有效且安全的治疗方法。
