Molecular therapy in myotonic dystrophy: focus on RNA gain-of-function.

Myotonic dystrophy (DM) is a complex, dominantly inherited, multisystem disorder and the archetypal example of an RNA gain-of-function disease. Unstable expansions of (CTG*CAG)n or (CCTG*CAGG)n repeat tracts in the DMPK and ZNF9 genes cause the two known subtypes of myotonic dystrophy, DM1 and DM2, for which no cure or effective molecular treatment exists. Focus in therapeutic development is currently on toxic, expanded (C/CUG)n RNAs. A series of recent papers provide proof of concept of promising strategies using antisense oligonucleotides or small organic compounds aimed at either complete elimination of expanded (CUG)n RNA transcripts or prevention of detrimental protein binding to thermodynamically stable (C/CUG)n hairpin structures. These developments offer new hope to patients with DM, even though several hurdles still have to be overcome before they can be introduced into clinical practice.

[1]  H. Smeets,et al.  Variant CCG and GGC repeats within the CTG expansion dramatically modify mutational dynamics and likely contribute toward unusual symptoms in some myotonic dystrophy type 1 patients. , 2010, Human molecular genetics.

[2]  T. Cooper,et al.  Heart-specific overexpression of CUGBP1 reproduces functional and molecular abnormalities of myotonic dystrophy type 1. , 2010, Human molecular genetics.

[3]  Jessica L. Childs-Disney,et al.  The Role of Flexibility in the Rational Design of Modularly Assembled Ligands Targeting the RNAs that Cause the Myotonic Dystrophies , 2010, Chembiochem : a European journal of chemical biology.

[4]  Tyson A. Clark,et al.  Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy , 2010, Nature Structural &Molecular Biology.

[5]  A. Paetau,et al.  Differences in aberrant expression and splicing of sarcomeric proteins in the myotonic dystrophies DM1 and DM2 , 2010, Acta Neuropathologica.

[6]  Jessica L. Childs-Disney,et al.  Controlling the specificity of modularly assembled small molecules for RNA via ligand module spacing: targeting the RNAs that cause myotonic muscular dystrophy. , 2009, Journal of the American Chemical Society.

[7]  Guey-Shin Wang,et al.  PKC inhibition ameliorates the cardiac phenotype in a mouse model of myotonic dystrophy type 1. , 2009, The Journal of clinical investigation.

[8]  M. Nakamori,et al.  Pentamidine reverses the splicing defects associated with myotonic dystrophy , 2009, Proceedings of the National Academy of Sciences.

[9]  A. Baranger,et al.  A simple ligand that selectively targets CUG trinucleotide repeats and inhibits MBNL protein binding , 2009, Proceedings of the National Academy of Sciences.

[10]  B. Wieringa,et al.  Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy , 2009, Proceedings of the National Academy of Sciences.

[11]  B. Schoser,et al.  Expression of RNA CCUG repeats dysregulates translation and degradation of proteins in myotonic dystrophy 2 patients. , 2009, The American journal of pathology.

[12]  Jessica L. Childs-Disney,et al.  Rational design of ligands targeting triplet repeating transcripts that cause RNA dominant disease: application to myotonic muscular dystrophy type 1 and spinocerebellar ataxia type 3. , 2009, Journal of the American Chemical Society.

[13]  Krzysztof Sobczak,et al.  Reversal of RNA Dominance by Displacement of Protein Sequestered on Triplet Repeat RNA , 2009, Science.

[14]  Radim Mazanec,et al.  Highly unstable sequence interruptions of the CTG repeat in the myotonic dystrophy gene , 2009, American journal of medical genetics. Part A.

[15]  D. Mittelman,et al.  Zinc-finger directed double-strand breaks within CAG repeat tracts promote repeat instability in human cells , 2009, Proceedings of the National Academy of Sciences.

[16]  William A Banks,et al.  Characteristics of compounds that cross the blood-brain barrier , 2009, BMC neurology.

[17]  M. Disney,et al.  Rational and modular design of potent ligands targeting the RNA that causes myotonic dystrophy 2. , 2009, ACS chemical biology.

[18]  R. Juliano,et al.  Biological barriers to therapy with antisense and siRNA oligonucleotides. , 2009, Molecular pharmaceutics.

[19]  D. Corey,et al.  Allele-specific silencing of mutant huntingtin and ataxin-3 genes by targeting expanded CAG repeats in mRNAs , 2009, Nature Biotechnology.

[20]  M. Swanson,et al.  Transcriptional and post-transcriptional impact of toxic RNA in myotonic dystrophy. , 2009, Human molecular genetics.

[21]  A. Bigot,et al.  Large CTG repeats trigger p16-dependent premature senescence in myotonic dystrophy type 1 muscle precursor cells. , 2009, The American journal of pathology.

[22]  P. Hanawalt,et al.  Peptide nucleic acid (PNA) binding and its effect on in vitro transcription in friedreich's ataxia triplet repeats , 2009, Molecular carcinogenesis.

[23]  P. White,et al.  Overcoming biological barriers to in vivo efficacy of antisense oligonucleotides , 2009, Expert Reviews in Molecular Medicine.

[24]  S. Krauss,et al.  Cellular responses to targeted genomic sequence modification using single-stranded oligonucleotides and zinc-finger nucleases. , 2009, DNA repair.

[25]  R. Kole,et al.  Therapeutic potential of splice-switching oligonucleotides. , 2009, Oligonucleotides.

[26]  P. Lai,et al.  Correction of dystrophia myotonica type 1 pre-mRNA transcripts by artificial trans-splicing , 2009, Gene Therapy.

[27]  P. Zamore,et al.  Small silencing RNAs: an expanding universe , 2009, Nature Reviews Genetics.

[28]  R. Junghans.  Dystrophia myotonia: why focus on foci? , 2009, European Journal of Human Genetics.

[29]  J. Castle,et al.  A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart , 2008, Proceedings of the National Academy of Sciences.

[30]  C. Berul,et al.  Cytoplasmic CUG RNA Foci Are Insufficient to Elicit Key DM1 Features , 2008, PloS one.

[31]  J. Uney,et al.  The effect of myotonic dystrophy transcript levels and location on muscle differentiation. , 2008, Biochemical and biophysical research communications.

[32]  Benjamin L Miller,et al.  Dynamic combinatorial selection of molecules capable of inhibiting the (CUG) repeat RNA-MBNL1 interaction in vitro: discovery of lead compounds targeting myotonic dystrophy (DM1). , 2008, Journal of the American Chemical Society.

[33]  S. Liebhaber,et al.  Effects of local mRNA structure on posttranscriptional gene silencing , 2008, Proceedings of the National Academy of Sciences.

[34]  J. Wilusz,et al.  The RNA-binding Protein CUGBP1 Regulates Stability of Tumor Necrosis Factor mRNA in Muscle Cells , 2008, Journal of Biological Chemistry.

[35]  J. Albrecht,et al.  Ectopic expression of cyclin D3 corrects differentiation of DM1 myoblasts through activation of RNA CUG-binding protein, CUGBP1. , 2008, Experimental cell research.

[36]  R. Artero,et al.  Genetic and Chemical Modifiers of a CUG Toxicity Model in Drosophila , 2008, PloS one.

[37]  J. Lueck,et al.  Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy. , 2007, Journal of Clinical Investigation.

[38]  Roy Parker,et al.  RNA Quality Control in Eukaryotes , 2007, Cell.

[39]  Guey-Shin Wang,et al.  Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation. , 2007, Molecular cell.

[40]  T. M. Wheeler,et al.  Myotonic dystrophy: RNA-mediated muscle disease , 2007, Current opinion in neurology.

[41]  M. Cairns,et al.  Brothers in arms: DNA enzymes, short interfering RNA, and the emerging wave of small-molecule nucleic acid-based gene-silencing strategies. , 2007, The American journal of pathology.

[42]  Guey-Shin Wang,et al.  Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy. , 2007, The Journal of clinical investigation.

[43]  E. Roeder,et al.  Homozygous myotonic dystrophy: Clinical findings in two patients and review of the literature , 2007, American journal of medical genetics. Part A.

[44]  S. Sakoda,et al.  Endoplasmic reticulum stress in myotonic dystrophy type 1 muscle , 2007, Acta Neuropathologica.

[45]  S. Mirkin.  Expandable DNA repeats and human disease , 2007, Nature.

[46]  J. Krol,et al.  Ribonuclease dicer cleaves triplet repeat hairpins into shorter repeats that silence specific targets. , 2007, Molecular cell.

[47]  Jeffrey Wilusz,et al.  The highways and byways of mRNA decay , 2007, Nature Reviews Molecular Cell Biology.

[48]  D. Corey,et al.  Activating gene expression in mammalian cells with promoter-targeted duplex RNAs. , 2007, Nature chemical biology.

[49]  M. Napierala,et al.  Structural characteristics of trinucleotide repeats in transcripts , 2006 .

[50]  J. Rossi,et al.  Interaction of musleblind, CUG‐BP1 and hnRNP H proteins in DM1‐associated aberrant IR splicing , 2006, The EMBO journal.

[51]  M. Swanson,et al.  Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[52]  M. Mahadevan,et al.  Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy , 2006, Nature Genetics.

[53]  T. Cooper,et al.  MBNL1 and CUGBP1 modify expanded CUG-induced toxicity in a Drosophila model of myotonic dystrophy type 1. , 2006, Human molecular genetics.

[54]  D. Monckton,et al.  CHAPTER 35 – Somatic Mosaicism of Expanded CAG·CTG Repeats in Humans and Mice: Dynamics, Mechanisms, and Consequences , 2006 .

[55]  D. Monckton,et al.  Chemical modifiers of unstable expanded simple sequence repeats: what goes up, could come down. , 2006, Mutation research.

[56]  T. Cooper,et al.  RNA-mediated neuromuscular disorders. , 2006, Annual review of neuroscience.

[57]  B. Schoser,et al.  DM2 intronic expansions: evidence for CCUG accumulation without flanking sequence or effects on ZNF9 mRNA processing or protein expression. , 2006, Human molecular genetics.

[58]  L. Malinina.  Possible Involvement of the RNAi Pathway in Trinucleotide Repeat Expansion Diseases , 2005, Journal of Biomolecular Structure and Dynamics.

[59]  Jeremy S Logue,et al.  The structural basis of myotonic dystrophy from the crystal structure of CUG repeats. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[60]  S. Tapscott,et al.  Antisense transcription and heterochromatin at the DM1 CTG repeats are constrained by CTCF. , 2005, Molecular cell.

[61]  Tien Hsu,et al.  RNA-dependent integrin α3 protein localization regulated by the Muscleblind-like protein MLP1 , 2005, Nature Cell Biology.

[62]  Christopher J. Wilkinson,et al.  The Polo kinase Plk4 functions in centriole duplication , 2005, Nature Cell Biology.

[63]  C. E. Pearson,et al.  Repeat instability: mechanisms of dynamic mutations , 2005, Nature Reviews Genetics.

[64]  D. Corey,et al.  Inhibiting gene expression at transcription start sites in chromosomal DNA with antigene RNAs , 2005, Nature chemical biology.

[65]  Tadeusz Kulinski,et al.  Thermodynamic stability of RNA structures formed by CNG trinucleotide repeats. Implication for prediction of RNA structure. , 2005, Biochemistry.

[66]  T. Cooper,et al.  Transgenic mice expressing CUG-BP1 reproduce splicing mis-regulation observed in myotonic dystrophy. , 2005, Human molecular genetics.

[67]  J. Uney,et al.  Woodchuck post‐transcriptional element induces nuclear export of myotonic dystrophy 3′ untranslated region transcripts , 2005, EMBO reports.

[68]  G. Wang,et al.  Cytoplasmic and Nuclear Retained DMPK mRNAs Are Targets for RNA Interference in Myotonic Dystrophy Cells* , 2005, Journal of Biological Chemistry.

[69]  L. Ranum,et al.  RNA pathogenesis of the myotonic dystrophies , 2005, Neuromuscular Disorders.

[70]  T. Rana,et al.  Specific and potent RNAi in the nucleus of human cells , 2005, Nature Structural &Molecular Biology.

[71]  K. Jellinger.  Myotonic Dystrophy: Present Management, Future Therapy , 2004 .

[72]  T. Cooper,et al.  Muscleblind proteins regulate alternative splicing , 2004, The EMBO journal.

[73]  S. Mansfield,et al.  RNA repair using spliceosome-mediated RNA trans-splicing. , 2004, Trends in molecular medicine.

[74]  David R Corey,et al.  Recognition of chromosomal DNA by PNAs. , 2004, Chemistry & biology.

[75]  Roma H. Patel,et al.  Overexpression of CUG Triplet Repeat-binding Protein, CUGBP1, in Mice Inhibits Myogenesis* , 2004, Journal of Biological Chemistry.

[76]  R. P. Junghans,et al.  RNA Leaching of Transcription Factors Disrupts Transcription in Myotonic Dystrophy , 2004, Science.

[77]  W. Hauswirth,et al.  A Muscleblind Knockout Model for Myotonic Dystrophy , 2003, Science.

[78]  B. Wieringa,et al.  Transgenic mouse models for myotonic dystrophy type 1 (DM1) , 2003, Cytogenetic and Genome Research.

[79]  Haibin Xia,et al.  Allele-specific silencing of dominant disease genes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[80]  G. Doucet,et al.  Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions , 2003, Gene Therapy.

[81]  J. Rossi,et al.  Hammerhead ribozyme-mediated destruction of nuclear foci in myotonic dystrophy myoblasts. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[82]  Jens Kurreck,et al.  Antisense technologies. Improvement through novel chemical modifications. , 2003, European journal of biochemistry.

[83]  P. Harper,et al.  Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells. , 2002, Human molecular genetics.

[84]  A. Fire,et al.  Rescue of polyglutamine-mediated cytotoxicity by double-stranded RNA-mediated RNA interference. , 2002, Human molecular genetics.

[85]  M. Swanson,et al.  Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2. , 2001, Human molecular genetics.

[86]  M. Mahadevan,et al.  The myotonic dystrophy expanded CUG repeat tract is necessary but not sufficient to disrupt C2C12 myoblast differentiation. , 2001, Human molecular genetics.

[87]  T. Cooper,et al.  Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy , 2001, Nature Genetics.

[88]  S. Naylor,et al.  Myotonic Dystrophy Type 2 Caused by a CCTG Expansion in Intron 1 of ZNF9 , 2001, Science.

[89]  T. Ashizawa,et al.  RNA CUG Repeats Sequester CUGBP1 and Alter Protein Levels and Activity of CUGBP1* , 2001, The Journal of Biological Chemistry.

[90]  R. J. White,et al.  Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. , 2000, Science.

[91]  B. Byrne,et al.  Recruitment of human muscleblind proteins to (CUG)n expansions associated with myotonic dystrophy , 2000, The EMBO journal.

[92]  G. Tiscornia,et al.  Myotonic dystrophy: the role of the CUG triplet repeats in splicing of a novel DMPK exon and altered cytoplasmic DMPK mRNA isoform ratios. , 2000, Molecular cell.

[93]  C. Junien,et al.  Transgenic mice carrying large human genomic sequences with expanded CTG repeat mimic closely the DM CTG repeat intergenerational and somatic instability. , 2000, Human molecular genetics.

[94]  B. Wieringa,et al.  Constitutive and regulated modes of splicing produce six major myotonic dystrophy protein kinase (DMPK) isoforms with distinct properties. , 2000, Human molecular genetics.

[95]  J. Summerton.  Morpholino antisense oligomers: the case for an RNase H-independent structural type. , 1999, Biochimica et biophysica acta.

[96]  M. Mahadevan,et al.  Cis and trans effects of the myotonic dystrophy (DM) mutation in a cell culture model. , 1999, Human molecular genetics.

[97]  R. Kalb,et al.  Sequence‐specific cleavage of Huntingtin mRNA by catalytic DNA , 1999, Annals of neurology.

[98]  B. Wieringa,et al.  Expanding complexity in myotonic dystrophy , 1998, BioEssays : news and reviews in molecular, cellular and developmental biology.

[99]  T. Cooper,et al.  Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. , 1998, Science.

[100]  M. Wood,et al.  Ribozyme-mediated trans-splicing of a trinucleotide repeat , 1998, Nature Genetics.

[101]  M. Napierala,et al.  CUG Repeats Present in Myotonin Kinase RNA Form Metastable “Slippery” Hairpins* , 1997, The Journal of Biological Chemistry.

[102]  D. Housman,et al.  Mice lacking the myotonic dystrophy protein kinase develop a late onset progressive myopathy , 1996, Nature Genetics.

[103]  A. Berns,et al.  Abnormal myotonic dystrophy protein kinase levels produce only mild myopathy in mice , 1996, Nature Genetics.

[104]  V. Allfrey,et al.  Invasion of the CAG Triplet Repeats by a Complementary Peptide Nucleic Acid Inhibits Transcription of the Androgen Receptor and TATA-binding Protein Genes and Correlates with Refolding of an Active Nucleosome Containing a Unique AR Gene Sequence* , 1996, The Journal of Biological Chemistry.

[105]  C. Amemiya,et al.  Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene. , 1992, Science.

[106]  David E. Housman,et al.  Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member , 1992, Cell.

[107]  H. Riele,et al.  Gene modification in embryonic stem cells by single-stranded DNA oligonucleotides. , 2009, Methods in molecular biology.

[108]  A. Tucker,et al.  RNA toxicity in myotonic muscular dystrophy induces NKX2-5 expression , 2008, Nature Genetics.

[109]  E. Nanba,et al.  [Myotonic dystrophy]. , 2005, Nihon rinsho. Japanese journal of clinical medicine.

[110]  J. Kurreck.  Improvement through novel chemical modifications , 2003 .