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Identification and characterization of modified antisense oligonucleotides targeting DMPK in mice and nonhuman primates for the treatment of myotonic dystrophy type 1.
Pandey, Sanjay K; Wheeler, Thurman M; Justice, Samantha L; Kim, Aneeza; Younis, Husam S; Gattis, Danielle; Jauvin, Dominic; Puymirat, Jack; Swayze, Eric E; Freier, Susan M; Bennett, C Frank; Thornton, Charles A; MacLeod, A Robert.
Affiliation
  • Pandey SK; Isis Pharmaceuticals Inc., Carlsbad, CA (S.K.P., S.L.J., A.K., H.S.Y., D.G., E.E.S., S.M.F., C.F.B., A.R.M.); Department of Neurology and Center of Neural Development and Disease, University of Rochester, Rochester, New York (T.M.W., C.A.T.); Department of Neurology, Massachusetts General Hospital,
  • Wheeler TM; Isis Pharmaceuticals Inc., Carlsbad, CA (S.K.P., S.L.J., A.K., H.S.Y., D.G., E.E.S., S.M.F., C.F.B., A.R.M.); Department of Neurology and Center of Neural Development and Disease, University of Rochester, Rochester, New York (T.M.W., C.A.T.); Department of Neurology, Massachusetts General Hospital,
  • Justice SL; Isis Pharmaceuticals Inc., Carlsbad, CA (S.K.P., S.L.J., A.K., H.S.Y., D.G., E.E.S., S.M.F., C.F.B., A.R.M.); Department of Neurology and Center of Neural Development and Disease, University of Rochester, Rochester, New York (T.M.W., C.A.T.); Department of Neurology, Massachusetts General Hospital,
  • Kim A; Isis Pharmaceuticals Inc., Carlsbad, CA (S.K.P., S.L.J., A.K., H.S.Y., D.G., E.E.S., S.M.F., C.F.B., A.R.M.); Department of Neurology and Center of Neural Development and Disease, University of Rochester, Rochester, New York (T.M.W., C.A.T.); Department of Neurology, Massachusetts General Hospital,
  • Younis HS; Isis Pharmaceuticals Inc., Carlsbad, CA (S.K.P., S.L.J., A.K., H.S.Y., D.G., E.E.S., S.M.F., C.F.B., A.R.M.); Department of Neurology and Center of Neural Development and Disease, University of Rochester, Rochester, New York (T.M.W., C.A.T.); Department of Neurology, Massachusetts General Hospital,
  • Gattis D; Isis Pharmaceuticals Inc., Carlsbad, CA (S.K.P., S.L.J., A.K., H.S.Y., D.G., E.E.S., S.M.F., C.F.B., A.R.M.); Department of Neurology and Center of Neural Development and Disease, University of Rochester, Rochester, New York (T.M.W., C.A.T.); Department of Neurology, Massachusetts General Hospital,
  • Jauvin D; Isis Pharmaceuticals Inc., Carlsbad, CA (S.K.P., S.L.J., A.K., H.S.Y., D.G., E.E.S., S.M.F., C.F.B., A.R.M.); Department of Neurology and Center of Neural Development and Disease, University of Rochester, Rochester, New York (T.M.W., C.A.T.); Department of Neurology, Massachusetts General Hospital,
  • Puymirat J; Isis Pharmaceuticals Inc., Carlsbad, CA (S.K.P., S.L.J., A.K., H.S.Y., D.G., E.E.S., S.M.F., C.F.B., A.R.M.); Department of Neurology and Center of Neural Development and Disease, University of Rochester, Rochester, New York (T.M.W., C.A.T.); Department of Neurology, Massachusetts General Hospital,
  • Swayze EE; Isis Pharmaceuticals Inc., Carlsbad, CA (S.K.P., S.L.J., A.K., H.S.Y., D.G., E.E.S., S.M.F., C.F.B., A.R.M.); Department of Neurology and Center of Neural Development and Disease, University of Rochester, Rochester, New York (T.M.W., C.A.T.); Department of Neurology, Massachusetts General Hospital,
  • Freier SM; Isis Pharmaceuticals Inc., Carlsbad, CA (S.K.P., S.L.J., A.K., H.S.Y., D.G., E.E.S., S.M.F., C.F.B., A.R.M.); Department of Neurology and Center of Neural Development and Disease, University of Rochester, Rochester, New York (T.M.W., C.A.T.); Department of Neurology, Massachusetts General Hospital,
  • Bennett CF; Isis Pharmaceuticals Inc., Carlsbad, CA (S.K.P., S.L.J., A.K., H.S.Y., D.G., E.E.S., S.M.F., C.F.B., A.R.M.); Department of Neurology and Center of Neural Development and Disease, University of Rochester, Rochester, New York (T.M.W., C.A.T.); Department of Neurology, Massachusetts General Hospital,
  • Thornton CA; Isis Pharmaceuticals Inc., Carlsbad, CA (S.K.P., S.L.J., A.K., H.S.Y., D.G., E.E.S., S.M.F., C.F.B., A.R.M.); Department of Neurology and Center of Neural Development and Disease, University of Rochester, Rochester, New York (T.M.W., C.A.T.); Department of Neurology, Massachusetts General Hospital,
  • MacLeod AR; Isis Pharmaceuticals Inc., Carlsbad, CA (S.K.P., S.L.J., A.K., H.S.Y., D.G., E.E.S., S.M.F., C.F.B., A.R.M.); Department of Neurology and Center of Neural Development and Disease, University of Rochester, Rochester, New York (T.M.W., C.A.T.); Department of Neurology, Massachusetts General Hospital,
J Pharmacol Exp Ther ; 355(2): 329-40, 2015 Nov.
Article in En | MEDLINE | ID: mdl-26330536
ABSTRACT
Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults. DM1 is caused by an expanded CTG repeat in the 3'-untranslated region of DMPK, the gene encoding dystrophia myotonica protein kinase (DMPK). Antisense oligonucleotides (ASOs) containing 2',4'-constrained ethyl-modified (cEt) residues exhibit a significantly increased RNA binding affinity and in vivo potency relative to those modified with other 2'-chemistries, which we speculated could translate to enhanced activity in extrahepatic tissues, such as muscle. Here, we describe the design and characterization of a cEt gapmer DMPK ASO (ISIS 486178), with potent activity in vitro and in vivo against mouse, monkey, and human DMPK. Systemic delivery of unformulated ISIS 486718 to wild-type mice decreased DMPK mRNA levels by up to 90% in liver and skeletal muscle. Similarly, treatment of either human DMPK transgenic mice or cynomolgus monkeys with ISIS 486178 led to up to 70% inhibition of DMPK in multiple skeletal muscles and ∼50% in cardiac muscle in both species. Importantly, inhibition of DMPK was well tolerated and was not associated with any skeletal muscle or cardiac toxicity. Also interesting was the demonstration that the inhibition of DMPK mRNA levels in muscle was maintained for up to 16 and 13 weeks post-treatment in mice and monkeys, respectively. These results demonstrate that cEt-modified ASOs show potent activity in skeletal muscle, and that this attractive therapeutic approach warrants further clinical investigation to inhibit the gain-of-function toxic RNA underlying the pathogenesis of DM1.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Oligonucleotides / Oligonucleotides, Antisense / Myotonin-Protein Kinase / Myotonic Dystrophy Type of study: Diagnostic_studies Limits: Animals / Humans / Male Language: En Journal: J Pharmacol Exp Ther Year: 2015 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Oligonucleotides / Oligonucleotides, Antisense / Myotonin-Protein Kinase / Myotonic Dystrophy Type of study: Diagnostic_studies Limits: Animals / Humans / Male Language: En Journal: J Pharmacol Exp Ther Year: 2015 Document type: Article