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Antisense Oligonucleotide Therapy for Calmodulinopathy.
Bortolin, Raul H; Nawar, Farina; Park, Chaehyoung; Trembley, Michael A; Prondzynski, Maksymilian; Sweat, Mason E; Wang, Peizhe; Chen, Jiehui; Lu, Fujian; Liou, Carter; Berkson, Paul; Keating, Erin M; Yoshinaga, Daisuke; Pavlaki, Nikoleta; Samenuk, Thomas; Cavazzoni, Cecilia B; Sage, Peter T; Ma, Qing; Whitehill, Robert D; Abrams, Dominic J; Carreon, Chrystalle Katte; Putra, Juan; Alexandrescu, Sanda; Guo, Shuai; Tsai, Wen-Chin; Rubart, Michael; Kubli, Dieter A; Mullick, Adam E; Bezzerides, Vassilios J; Pu, William T.
Affiliation
  • Bortolin RH; 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.).
  • Nawar F; 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.).
  • Park C; 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.).
  • Trembley MA; 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.).
  • Prondzynski M; 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.).
  • Sweat ME; 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.).
  • Wang P; 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.).
  • Chen J; 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.).
  • Lu F; 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.).
  • Liou C; 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.).
  • Berkson P; 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.).
  • Keating EM; 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.).
  • Yoshinaga D; 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.).
  • Pavlaki N; 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.).
  • Samenuk T; 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.).
  • Cavazzoni CB; 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.).
  • Sage PT; 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.).
  • Ma Q; 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.).
  • Whitehill RD; Department of Pediatrics, Division of Cardiology, Emory University School of Medicine, Children's Healthcare of Atlanta, GA (R.D.W.).
  • Abrams DJ; 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.).
  • Carreon CK; Center for Cardiovascular Genetics (D.J.A., V.J.B., W.T.P.), Boston Children's Hospital and Harvard Medical School, MA.
  • Putra J; Cardiac Registry, Departments of Cardiology, Pathology, and Cardiac Surgery (C.K.C.).
  • Alexandrescu S; Department of Pathology (C.K.C., J.P., S.A.), Boston Children's Hospital and Harvard Medical School, MA.
  • Guo S; Department of Pathology (C.K.C., J.P., S.A.), Boston Children's Hospital and Harvard Medical School, MA.
  • Tsai WC; Department of Pathology (C.K.C., J.P., S.A.), Boston Children's Hospital and Harvard Medical School, MA.
  • Rubart M; Wells Centre for Pediatric Research, Indiana University School of Medicine, Indianapolis (S.G., W.-C.T., M.R.).
  • Kubli DA; Wells Centre for Pediatric Research, Indiana University School of Medicine, Indianapolis (S.G., W.-C.T., M.R.).
  • Mullick AE; Wells Centre for Pediatric Research, Indiana University School of Medicine, Indianapolis (S.G., W.-C.T., M.R.).
  • Bezzerides VJ; Ionis Pharmaceuticals, Carlsbad, CA (D.A.K., A.E.M.).
  • Pu WT; Ionis Pharmaceuticals, Carlsbad, CA (D.A.K., A.E.M.).
Circulation ; 150(15): 1199-1210, 2024 Oct 08.
Article in En | MEDLINE | ID: mdl-39155863
ABSTRACT

BACKGROUND:

Calmodulinopathies are rare inherited arrhythmia syndromes caused by dominant heterozygous variants in CALM1, CALM2, or CALM3, 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.

METHODS:

We tested this hypothesis using human induced pluripotent stem cell-derived cardiomyocyte and mouse models of CALM1 pathogenic variants.

RESULTS:

Human CALM1F142L/+ 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 CALM1F142L/+ induced pluripotent stem cell-derived cardiomyocytes. Similarly, an ASO targeting murine Calm1 depleted Calm1 transcript without affecting CaM protein level. This ASO alleviated drug-induced bidirectional ventricular tachycardia in Calm1N98S/+ mice without a deleterious effect on cardiac electrical or contractile function.

CONCLUSIONS:

These results provide proof of concept that ASOs targeting individual calmodulin genes are potentially effective and safe therapies for calmodulinopathies.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Calmodulin / Oligonucleotides, Antisense / Myocytes, Cardiac Limits: Animals / Humans Language: En Journal: Circulation Year: 2024 Document type: Article Country of publication:
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Calmodulin / Oligonucleotides, Antisense / Myocytes, Cardiac Limits: Animals / Humans Language: En Journal: Circulation Year: 2024 Document type: Article Country of publication: