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Muscular dystrophies are inherited disorders that cause progressive muscle weakness. There are many types of muscular dystrophies. Current treatments can help improve some symptoms, but none can stop or reverse muscle weakness. We use molecular biology and imaging to study muscular dystrophies with a long term goal of finding new treatments that benefit patients. Together with collaborators, we helped identify and characterize a new class of drugs for treatment of myotonic dystrophy, the most common muscular dystrophy in adults. Based on these findings, a similar drug is being tested in patients with myotonic dystrophy. We continue to look for new treatments, study how muscles become weaker, and develop markers of treatment success.
Layal Antoury, BA, University of PennsylvaniaResearch Technologist, Massachusetts General HospitalNingyan Hu, MS, Nanchang University, China.Research Technologist, Massachusetts General HospitalThurman Wheeler, MD, University of WashingtonAssistant Neurologist, Massachusetts General HospitalAssistant Professor of Neurology, Harvard Medical School
Xandra Breakefield, Mass General HospitalTom Foster, University of RochesterSteve Hauschka, University of WashingtonCasey Maguire, Mass General HospitalSeward Rutkove, Beth Israel Deaconess Medical CenterBakhos Tannous, Mass General HospitalEric Wang, University of Florida
Mass General NeurologyNeuroscience CenterHarvard Medical SchoolNeuromuscular Diagnostic CenterPediatric Neuromuscular Service
We focus on the two most common types of muscular dystrophy: myotonic dystrophy and Duchenne dystrophy.
Muscular dystrophies are caused by changes in the DNA of certain genes that are required for normal muscle function. In some muscular dystrophies, these DNA changes result in a reduction or absence of the gene product, meaning that an important component needed for normal muscle function is present at low levels or missing altogether. This is true in Duchenne muscular dystrophy, where alterations in the DNA of the dystrophin gene lead to absence of dystrophin protein. In some other muscular dystrophies, DNA changes give rise to a gene product that interferes with normal functioning of unrelated genes, similar to the effects of a toxin. This is true in myotonic dystrophy type 1 (abbreviated DM1), where the DMPK gene contains an unusually long CTG segment and produces a DMPK RNA with an unusually long "CUG" segment. The expanded CUG component of the DMPK RNA induces deleterious effects in the muscle, heart, and brain. One of the ways the expanded CUG RNA disrupts muscle function in DM1 is by modifying splicing of pre-messenger RNAs that arise from several unrelated genes. The result is production of RNAs from these other genes that are different sizes than normal. Three examples of genes that are spliced differently in DM1 include chloride channel (Figure, upper), Serca-1 (middle), and Titin (lower). The dark bands represent RNAs of different sizes and demonstrate the very characteristic splicing patterns in DM and non-DM. Modified splicing of chloride channel RNA as shown reduces chloride channel protein levels (red) and leads directly to myotonia in DM.
Progressive weakness in myotonic dystrophy
In DM1, progressive muscle weakness is associated with altered muscle structure. Under a microscope, muscle cells are different shapes, sizes, and disorganized from normal. These structural changes cause weakness by reducing the efficiency of ordinary muscle movements. Recovery of strength in patients will be limited unless muscle structure improves first. We are studying the connection between splicing outcomes, muscle repair, and muscle structure in DM1. A better understanding of this relationship may help the design of new treatments.
New biomarkers for myotonic dystrophy
A biomarker can be defined as a reliable measurement of normal function, dysfunction in disease states, or response to a treatment. Analysis of small piece of muscle tissue called a biopsy can be used to identify biomarkers for muscular dystrophies. In clinical trials of new drugs for DM1, splicing outcomes in patient muscle biopsies may help determine whether the new drugs are effective. However, long-term use of muscle biopsies to follow treatment response may be impractical because they are invasive, painful, expensive, and access is limited. In addition, splicing outcomes in biopsies from some muscles are unreliable as biomarkers. We are interested in finding and developing new biomarkers for DM that will reduce or eliminate the need for a muscle biopsy to follow treatment response.
New treatments for myotonic dystrophy
Together with collaborators, we are investigating new candidate drugs and approaches for treating DM. To determine treatment success, we use splicing outcomes in muscle tissue, an electrophysiology measurement of muscles called myography, molecular imaging, and microscope analysis of muscle structure as biomarkers.
Gene therapy for Duchenne muscular dystrophy
One approach for treatment of Duchenne muscular dystrophy is to increase the level of the missing gene product, dystrophin. This is called gene replacement therapy, or gene therapy for short. Gene therapy has been very effective in pre-clinical (non-human) studies, but several hurdles remain for its use in Duchenne patients. In collaboration with colleagues, we are studying new ways to improve the efficiency of gene therapy for Duchenne muscular dystrophy.
Background in muscle biology, muscle diseases, muscular dystrophies, molecular therapies, RNA metabolism, molecular biology, molecular imaging, translational research, neurogenetic disorders, and/or neuromuscular disorders.
Interest in muscle biology, muscle diseases, muscular dystrophies, molecular therapies, RNA metabolism, molecular biology, molecular imaging, translational research, neurogenetic disorders, and/or neuromuscular disorders.
Wheeler TM, Baker JN, Chad DA, Zilinski JL, Verzosa S, and Mordes DA, Case records of the Massachusetts General Hospital. Case 30-2015: A 50 year-old man with cardiogenic shock, N Engl J Med, 373(13):1251-61, 2015.Pandey SK, Wheeler TM, Justice SL, Kim A, Younis H, Gattis D, Jouvin D, Puymirat J, Swayze EE, Freier SM, Bennett CF, Thornton CA, and MacLeod RA. Identification and characterization of modified antisense oligonucleotides targeting DMPK in mice and nonhuman primates for the treatment of myotonic dystrophy type 1, J Pharmacol Exp Ther, 2015 Sep 1. pii: jpet.115.226969. [Epub ahead of print].Nakamori M, Sobczak K, Puwanant A, Welle S, Eichinger K, Pandya S, Dekdebrun J, Cline M, Heatwole CR, Tawil R, Osborne RJ, Wheeler TM, Swanson MS, Moxley III RT, and Thornton CA. Splicing biomarkers of disease severity in myotonic dystrophy, Ann Neurol, 74(6): 862-872, 2013 doi: 10.1002/ana.23992.Sobczak K, Wheeler TM, Wang W, and Thornton CA. RNA interference targeting CUG repeats in a mouse model of myotonic dystrophy, Mol Ther, 21(2): 380-87, 2013. doi: 10.1038/mt.2012.222. Epub 2012 Nov 27.Wheeler TM, Leger AL, Pandey SK, MacLeod AR, Nakamori M, Cheng SH, Wentworth BM, Bennett CF, and Thornton CA. Targeting nuclear RNA for in vivo correction of myotonic dystrophy, Nature 488(7409): 111-115, 2012. “News & Views” comment in Nature, 488(7409): 36-38, 2012. Research Highlights in Mol Ther, Nat Rev Genet, and Nat Rev Drug Discovery.Mankodi A, Wheeler TM, Shetty R, Salceies KM, Becher MW, and Thornton CA. Progressive myopathy in an inducible mouse model of oculopharyngeal muscular dystrophy, Neurobiol Dis 45(1): 539-546, 2012.Mulders SAM, van den Broek JAAW, Wheeler TM, Croes HJE, van Kuik-Romeijn P, de Kimpe SJ, Platenburg GJ, Gourdon G, Thornton CA, Wieringa B, and Wansink DG. Triplet repeat oligonucleotide mediated reversal of RNA toxicity in myotonic dystrophy, Proc Natl Acad Sci, U S A, 106(33): 13915-13920, 2009.Wheeler TM, Sobczak K, Lueck JD, Osborne RJ, Lin X, Dirksen RT, and Thornton CA. Reversal of RNA-dominance by displacement of protein sequestered on triplet repeat RNA, Science, 325: 336-339, 2009. Comment in Science, 325: 272-273, 2009. Research Highlights in Nature Biotechnology, Nature Medicine, and Nature Reviews Genetics. Featured in Chemical and Engineering News, Neurology Today, Toronto Star, Reuters, and The Wall Street Journal.Wheeler TM. Myotonic dystrophy: therapeutic strategies for the future, Neurotherapeutics, 5(4): 592-600, 2008. (invited review).Wheeler TM, Lueck JD, Swanson MS, Dirksen RT, and Thornton CA. Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy, J Clin Invest, 117(12): 3952-3957, 2007. Featured in US News and World Report, BBC News, Forbes, WebMD, and The Washington Post.Wheeler TM and Thornton CA. Myotonic Dystrophy: RNA-mediated muscle disease, Curr Opin Neurol, 20(5): 572-576, 2007.Wheeler TM, Krym MC, and Thornton CA. Ribonuclear foci at the neuromuscular junction in myotonic dystrophy type 1, Neuromuscul Disord, 17(3): 242-247, 2007.Kanadia RN, Shin J, Yuan Y, Beattie SG, Wheeler TM, Thornton CA, and Swanson MS. Reversal of RNA mis-splicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy, Proc Natl Acad Sci U S A, 103(31): 11748-11753, 2006.Bertoni C, Jarrahian S, Wheeler TM, Li Y, Olivares EC, Calos MP, and Rando TA. Enhancement of plasmid-mediated gene therapy for muscular dystrophy by directed plasmid integration, Proc Natl Acad Sci U S A, 103(2): 419-424, 2006.
Massachusetts General Hospital149 13th St.Boston, MA 02129Tel: 617-726-7506
MGH Muscular Dystrophy Clinic
Tel (adult): 617-726-3642 Tel (pediatric): 617-643-4645
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