MENLO PARK, CA (January 2013): MDF is pleased to announce its most recent round of Fund-A-Fellow postdoctoral fellowship research grant awards. In January 2013, MDF awarded two $100,000 grants to postdoctoral Fellows working in universities and research facilities to encourage basic research in the management, treatment and cure of myotonic dystrophy (DM) for a commitment of $200,000. 

This award cycle brings the total research funding awarded by MDF to over $1.5M since its founding in 2006, and builds on MDF’s commitment to increasing the number of investigators focused on myotonic dystrophy research.  To date, MDF Fellows have attracted additional research funding from larger organizations such as the National Institutes of Health, have helped influence interest in DM research at major pharmaceutical companies, and have risen to senior positions at academic and clinical settings across the United States. MDF Fund-a-Fellows have collaboratively deepened understanding of and commitment to myotonic dystrophy research significantly since the program’s founding in 2009.

Each of the two 2013-2014 FAF recipients will receive $50,000 a year for two years. The applicant pool for this year’s grant awards was extremely competitive and totaled 15, the largest ever for MDF fellowship funding.  Applications were reviewed by a panel of distinguished international researchers and clinicians in the field of myotonic dystrophy. Final selections were determined by the MDF Board of Directors. 

The two 2013-2014 $100,000 postdoctoral fellowship grants have been awarded to: Dr. Suzanne Rzuczek, Ph.D., The Scripps Research Institute – Florida; and Dr. Ayal Hendel, Ph.D., Stanford School of Medicine.  

Research Information

Dr. Ayal Hendel, Ph.D.

CTG/CAG repeat tracts represent the genetic basis for more than a dozen inherited dominant neurological disorders including Myotonic Dystrophy type 1 (DM1) and Huntington’s disease that currently have no cure.  Despite the multitude pathologies underlying these devastating disorders, they all share common etiology: the expansion of CTG/CAG repeats. Interestingly, expanded CTG/CAG repeats have been shown to be prone to double-strand breaks (DSBs).  Moreover, it was shown that the repair of the DSBs leads mainly to repeat contractions. These findings suggest that controlled DSBs might provide a way to induce repeat contractions that will correct disease-causing mutation and reduce disease risk. Dr. Hendel’s research will harness a unique genome editing technology in combination with induced pluripotent stem cells to examine the contribution of DSB repair to the stimulation of repeat contractions in DM1 cells, ultimately exploring new cellular and molecular DM1 pathological mechanisms involved in myotonic dystrophy.

Dr. Suzanne Rzuczek, Ph.D.

Dr. Rzuzcek, in conjunction with the Disney Lab of The Scripps Institute, plans on using small molecules to disrupt the interaction between repeating CUG RNA and MBNL1 (muscleblind-like 1 protein), freeing it to function normally. The Disney Lab, of which Dr. Rzuczek is a member, has designed and synthesized several compounds that specifically bind the expanded CUG RNA and disrupt the interaction with MBNL1 in vitro. These compounds contain CUG-binding small molecules tethered together by a spacer. This approach is called modular assembly. Recently the spacer has been optimized to increase bioactivity and cell uptake. Dr. Rzuczek and her colleagues will improve the activity of the modularly assembled compounds using two approaches. The first will use the repeating DM1 RNA as a template to assemble small compounds with their optimized spacer into large modularly assembled structures within cells. This process is known as in situ click chemistry. The second approach will screen many small molecules that are similar to the known binders of DM1 RNA. Hit compounds will be screened in cells using a method that detects low levels of bioactivity. Compounds that are active in cells will be modularly assembled on the Disney-optimized spacer to enhance the interaction with DM1 RNA and improve bioactivity. If successful, these compounds could become a treatment for myotonic dystrophy. 

01/23/2013

A generic cardiovascular drug called mexiletine, initially developed to treat heart rhythm abnormalities, appears to hold some potential for treating muscle stiffness and other symptoms of non-dystrophic myotonias (NDMs), a rare group of disorders without progressive muscle wasting and weakness, that have abnormalities in the function of ion channels in the muscle cells (chloride or sodium channels).  The abnormal ion channel function leads to stiffness and delayed relaxation of muscle following grip or tight closing of the eyes (myotonia).  Myotonic dystrophy (DM) has as one of its alterations abnormal function of the chloride channel.  This causes myotonia and stiffness, and, like the patients with non-dystrophic myotonia, DM patients show a beneficial response to treatment with mexiletine.

10/23/2012

Circular RNA Primer

Cells contain a striking diversity of RNA types, many of which have been implicated in the pathogenesis of neuromuscular disease. Unlike most RNAs, circular RNAs (circRNAs) are single-stranded, covalently closed loops. CircRNAs arise via one of three mechanisms: (a) direct ligation of 5′ and 3′ ends of linear RNAs, (b) as intermediates in RNA processing reactions, or (c) via “back splicing,” when a downstream 5′ splice site (donor) is joined to an upstream 3′ splice site (acceptor). A variety of biologic roles for circRNAs have been identified.

Presence of circRNA in DM1 Skeletal Muscle

While aberrant RNA splicing represents a central disease mechanism in DM1, virtually nothing is known regarding the potential for dysregulation of circRNAs. Dr. Fabio Martelli (IRCCS Policlinico San Donato) and colleagues have recently published an analysis of dysregulation of circRNAs in DM1 patient skeletal muscle biopsies (Voellenkle et al., 2019). The authors show that specific myogenesis-associated circRNAs are altered in DM1 biopsies and in DM1 patient myogenic cell cultures.

The research team identified specific circRNAs through review of 30 published DM1 RNAseq databases—relative abundance of a circRNA to its linear counterpart was used as an initial filter, followed by comparison to a list of circRNAs that were previously identified in human or murine myoblasts. Thus, the analysis was not comprehensive, but geared toward identification of transcripts most likely to be dysregulated in skeletal muscle tissue. Candidate circRNAs meeting the investigators’ criteria then were validated using qPCR of skeletal muscles from DM1 subjects and age-/sex-matched controls. Primer specificity was confirmed and the possibility that results were due to a general increase in transcription in DM1 was excluded, and results were confirmed in independent muscle biopsies.

Taken together, four circRNAs—circCDYL, circHIPK3, circRTN4_03, and circZNF609—exhibited significantly increased circular-to-linear RNA ratio in DM1 muscles versus controls. The research team subsequently used receiver operating characteristic curve analysis and confirmed that a transcript’s circular-to-linear ratio could discriminate between DM1 and healthy controls. Finally, the increase in circular fraction for the four circRNAs correlated with a variety of clinical and molecular characteristics of study subjects. Circular fraction ratios correlated with both skeletal muscle strength and splicing biomarkers of disease severity.  Moreover, circular fraction was higher in the more severely affected DM1 patients. Induction of two of the dysregulated circRNAs (circCDYL and circRTN4) was also detected in plasma. Finally, analyses of DM1 myogenic cell lines identified a pattern of circRNA dysregulation that was, in part, similar to data obtained in patient muscle biopsies.

Potential Utility of Dysregulated circRNAs in DM1

The research team self-identified caveats and described these findings as pilot data. Any putative contributing role that dysregulated circRNAs may have in the pathogenesis of DM1 is currently unknown. Yet the discovery of specific, dysregulated circRNAs in DM1 skeletal muscle, if confirmed, may offer advantages for drug development efforts—circRNAs are exceptionally stable in that they are resistant to exonuclease degradation and their dysregulation was detectable in plasma and myogenic cell lines from DM1 patients. These traits make them amenable to use as pharmacodynamic biomarkers for clinical studies and trials in DM1.

Reference:

Dysregulation of Circular RNAs in Myotonic Dystrophy Type 1.
Voellenkle C, Perfetti A, Carrara M, Fuschi P, Renna LV, Longo M, Sain SB, Cardani R, Valaperta R, Silvestri G, Legnini I, Bozzoni I, Furling D, Gaetano C, Falcone G, Meola G, Martelli F.
Int J Mol Sci. 2019 Apr 19;20(8). pii: E1938. doi: 10.3390/ijms20081938.

The Elusive Quantification of Repeat Length

In a disease that exhibits somatic mosaicism, somatic cell instability, and the consequent tissue-to-tissue variability in expanded repeat length, assigning an “actual progenitor repeat length” value to individual DM1 patients has been problematic. The connotations here are obvious—how do we use repeat length for essential drug development functions from molecular biomarkers to genotype-phenotype analyses to stratification of patients in interventional clinical trials, if the parameter is hard to pin down? A recent paper from a multi-site team (Universidad de Costa Rica, University of Texas MD Anderson Cancer Center, and University of Glasgow) attempts to determine the optimal body fluid/tissue to sample and thereby yield insight into the best path forward for clinical studies and interventional clinical trials (Corrales et al., 2019).

Saliva as an Accessible and Reliable Source for DM1 Mutation Testing

Dr. Fernando Morales and colleagues sought to build on their prior findings (Morales et al., 2012 & 2016) that used small pool-PCR (SP-PCR) to control for somatic instability in estimations of progenitor allele length measured in blood. The goal was to improve upon allele length correlations with age of DM1 onset. In their latest work, the research team reports out on comparison of saliva vs. blood as the analyte source for progenitor allele length determinations.

This report was based upon analysis of progenitor allele length in saliva and blood from 40 DM1 patients that had been characterized for age of onset; screening also assessed for presence of variant repeats and methylation of CTCF binding sites adjacent to the DMPK locus, as these may be modifiers of somatic instability. Modal allele length was slightly larger in saliva (529 repeats) than concurrently collected blood samples (486 repeats). Progenitor allele length then was estimated as the lower boundary of allele distribution from SP-PCR—values from the two sample sources were highly correlated and, again, were higher in saliva than blood (414 vs. 310).

Analyses showed that progenitor allele length estimated from blood samples explained 75% of the variation in DM1 age of onset, while that from saliva explained 66% of the variation. The authors suggest that the “true progenitor allele length” needed for genotype-phenotype studies and other preclinical and clinical development purposes is more likely reflected by the values obtained from blood samples.

Additional single molecule SP-PCR studies, excluding two CDM cases, revealed greater somatic instability in blood than in saliva. The research team also showed that the lower boundary of allele distribution was slightly higher in saliva than in blood, while the overall degree of somatic variation was typically lower in saliva than in blood. Finally, analyses of repeat variants and methylation levels as putative modifiers of somatic instability showed that neither were significant factors.

Blood or Saliva?

The authors of this paper summarize the compelling literature case against use of skeletal muscle samples (essentially the confounding effect of tissue-specific rate of somatic expansion) to estimate progenitor allele size, bringing the choice down to blood or saliva. These data show that somatic mosaicism is comparable in blood and saliva DNA from DM1 patients, while saliva is obtained by considerably less invasive means—a feature that is potentially vital for interventional clinical trials in CDM or repeated sampling to assess efficacy of a candidate therapeutic in either CDM or DM1.

References:

Analysis of mutational dynamics at the DMPK (CTG)n locus identifies saliva as a suitable DNA sample source for genetic analysis in myotonic dystrophy type 1.
Corrales E, Vásquez M, Zhang B, Santamaría-Ulloa C, Cuenca P, Krahe R, Monckton DG, Morales F.
PLoS One. 2019 May 2;14(5):e0216407. doi: 10.1371/journal.pone.0216407. eCollection 2019.

Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity.
Morales F, Couto JM, Higham CF, Hogg G, Cuenca P, Braida C, Wilson RH, Adam B, del Valle G, Brian R, Sittenfeld M, Ashizawa T, Wilcox A, Wilcox DE, Monckton DG.
Hum Mol Genet. 2012 Aug 15;21(16):3558-67. doi: 10.1093/hmg/dds185. Epub 2012 May 16.

A polymorphism in the MSH3 mismatch repair gene is associated with the levels of somatic instability of the expanded CTG repeat in the blood DNA of myotonic dystrophy type 1 patients.
Morales F, Vásquez M, Santamaría C, Cuenca P, Corrales E, Monckton DG.
DNA Repair (Amst). 2016 Apr;40:57-66. doi: 10.1016/j.dnarep.2016.01.001. Epub 2016 Mar 8.

RNA: A Popular Target in DM1

Given the novel disease mechanisms that are operative for myotonic dystrophy (DM), “drugging the RNA World” is a very popular theme in drug discovery and development for this disease. Small and large molecule approaches based on this strategy are in preclinical development for DM. Companies such as Expansion Therapeutics are moving toward interventional clinical trials to test the strategy. Dr. Steven Zimmerman (University of Illinois at Urbana–Champaign) and colleagues have recently published data in a model organism in support of a multivalent candidate therapeutic targeting both expanded repeat DNA and RNA in addressing the RNA gain-of-function in DM1 (Lee et al., 2019).

Multivalent Targeting of DM1 Expanded Repeats in DNA and RNA

Dr. Zimmerman and his colleagues have exploited their expertise in bioorganic, synthetic organic, and physical organic chemistry to design and evaluate multivalent ligands targeted to expanded CTG DNA and expanded CUG RNA in a preclinical discovery and development effort for DM1 therapeutics. The Zimmerman team describes the approach as exploiting “smart molecules designed to enter the cell nucleus, bind the target DNA or RNA specifically and operate to reverse the deleterious effects of the expanded repeats.” The efficacy of this strategy lies in the use of a single ligand that targets both transcription of expanded CTG repeat DNA and interactions of expanded CUG repeat RNA with Muscleblind to mitigate the consequences of DM1.

The research team first focused on rational optimization of their existing small molecule inhibitor that targets DM1 expanded repeat RNA. Dimerization of the inhibitor markedly improved its efficacy, but vastly reduced cell permeability—thus necessitating a strategy change to ensure drug-like properties of the candidate therapeutic. Utilization of a linker sequence improved cell permeability and allowed oligomerization of the original monomer to further enhance binding to CUG expansions. Moreover, optimization of their synthetic and purification procedures provided a means to move forward with further testing of the molecule.

Studies in HeLa cells transfected with 960 CTG-repeat DMPK showed the ability of the multivalent compound to disrupt the nuclear foci and rescue the mis-splicing characteristic of DM1 in a dose-dependent manner. Activity in suppressing nuclear foci in the HeLa cell model was 1000-fold greater than with the original monomeric compound. The oligomer also showed promising activity in DM1 patient-derived myoblasts.

A surprising finding with the oligomeric compound tested here was that it also targeted expanded CTG DNA—this dual mechanism capability in targeting both transcription of the expanded repeat DMPK gene and its toxic transcript could potentiate the activity of the compound. Finally, in initial model organism efficacy testing, the oligomer showed activity in a DM1 Drosophila climbing assay and in a liver-specific DM1 mouse model—supporting both the bioavailability and activity of the compound. Preliminary toxicity studies showed no liabilities.

Synthesis and Next Steps

Taken together, a multivalent, cell-penetrating compound with potential to knock down both production of toxic DMPK RNA transcript and its interactions with MBNL represents an attractive opportunity for therapy development in DM1. The model organisms that this compound has been tested in thus far, a DM1 fly and liver-specific DM1 mouse, are not ‘traditional’ models for therapy development in the disease, but establish an initial level of proof of concept. The strength of the Zimmerman group lies in bioorganic chemistry expertise and partnership with groups with strengths in DM1 disease mechanisms and preclinical models should help ascertain the value in moving forward with the novel compounds developed here.

Reference:

Intrinsically cell-penetrating multivalent and multitargeting ligands for myotonic dystrophy type 1.
Lee J, Bai Y, Chembazhi UV, Peng S, Yum K, Luu LM, Hagler LD, Serrano JF, Chan HYE, Kalsotra A, Zimmerman SC.
Proc Natl Acad Sci U S A. 2019 Apr 11. pii: 201820827. doi: 10.1073/pnas.1820827116. [Epub ahead of print]

Antisense oligonucleotides – short segments of genetic material designed to target specific areas of a gene or chromosome – that activate an enzyme to “chew up” toxic RNA (ribonucleic acid) could point the way to a treatment for a degenerative muscle disease called myotonic dystrophy, said researchers from Baylor College of Medicine and Isis Pharmaceuticals, Inc., in a report in the journal Proceedings of the National Academy of Sciences (www.pnas.org) .

“This is a proof-of-principle therapy that is very effective in cell culture and mice,” said Dr. Thomas A. Cooper, professor of pathology and immunology and molecular and cellular biology at BCM and the report’s corresponding author. “The treatment will have to be refined to deliver systemically in people with myotonic dystrophy.”

Myotonic dystrophy is the most common muscular disease in adults, affecting mainly the skeletal muscles, heart and central nervous system. It occurs because of a mutation that causes numerous repeats of three letters of the genetic code (CTG) in a gene called DMPK. RNA is made as a step in the cell’s production of the protein associated with the gene. The messenger RNA (the chemical blueprint for making a protein) that is produced from the mutated gene also contains the abnormal long repeats that cause the RNA to accumulate in the cell’s nucleus. There it sequesters and blocks the function of a protein called Muscleblind-like 1 and activates another protein called CELF1. These proteins antagonize one another and the result is abnormal expression of proteins from many other genes in adult tissues, resulting in disease.

To counteract this, Cooper and his colleagues created antisense oligonucleotides called gapmers, which are simply strands of genetic material that seek out portions of the abnormal RNA repeats and target an enzyme called RNase H to the toxic RNA causing its degradation. They also showed that combining the gapmers with other antisense oligonucleotides that help released the sequestered Muscleblind-like1 can enhance the effect.

“It worked in cultures of cells with the expanded repeats and in mice that model myotonic dystrophy,” said Cooper. “We did it in skeletal muscle first because we can inject the material directly into the muscle.”

Later, he plans to determine if the material also works in the animals’ hearts.

Using the treatment in people will require more fine-tuning, said Cooper. He would like to be able to give the therapy systemically rather than directly into the muscle. They saw some muscle damage and inflammation in the animals they treated.

Antisense oligonucleotide treatments are being tested in Duchenne muscular dystrophy and another disease called spinal muscular atrophy, said Cooper.

Others who took part in this research include Johanna E. Lee of BCM and C. Frank Bennett of Isis.

Funding for this work came from the National Institutes of Health, the Muscular Dystrophy Association and the Shanna and Andrew Linbeck Family Charitable Fund.

Reposted with permission from Baylor College of Medicine

05/16/2012

The new approach could have implications for many genetic diseases

While RNA is an appealing drug target, small molecules that can actually affect its function have rarely been found. But now scientists from the Florida campus of The Scripps Research Institute have for the first time designed a series of small molecules that act against an RNA defect directly responsible for the most common form of adult-onset muscular dystrophy.

In two related studies published recently in online-before-print editions of Journal of the American Chemical Society and ACS Chemical Biology, the scientists show that these novel compounds significantly improve a number of biological defects associated with myotonic dystrophy type 1 in both cell culture and animal models.

“Our compounds attack the root cause of the disease and they improve defects in animal models,” said Scripps Research Associate Professor Matthew Disney, PhD. “This represents a significant advance in rational design of compounds targeting RNA. The work not only opens up potential therapies for this type of muscular dystrophy, but also paves the way for RNA-targeted therapeutics in general.”

Myotonic dystrophy type 1 involves a type of RNA defect known as a “triplet repeat,” a series of three nucleotides repeated more times than normal in an individual’s genetic code. In this case, the repetition of the cytosine-uracil-guanine (CUG) in RNA sequence leads to disease by binding to a particular protein, MBNL1, rendering it inactive. This results in a number of protein splicing abnormalities. Symptoms of this variable disease can include wasting of the muscles and other muscle problems, cataracts, heart defects, and hormone changes.

To find compounds that acted against the problematic RNA in the disease, Disney and his colleagues used information contained in an RNA motif-small molecule database that the group has been developing.  By querying the database against the secondary structure of the triplet repeat that causes myotonic dystrophy type 1, a lead compound targeting this RNA was quickly identified.  The lead compounds were then custom-assembled to target the expanded repeat or further optimized using computational chemistry. In animal models, one of these compounds improved protein-splicing defects by more than 40 percent.

“There are limitless RNA targets involved in disease; the question is how to find small molecules that bind to them,” Disney said. “We’ve answered that question by rationally designing these compounds that target this RNA. There’s no reason that other bioactive small molecules targeting other RNAs couldn’t be developed using a similar approach.”

The first authors of the JACS study, “Design of a Bioactive Small Molecule that Targets the Myotonic Dystrophy Type 1 RNA via an RNA Motif-Ligand Database & Chemical Similarity Searching” (http://pubs.acs.org/doi/abs/10.1021/ja210088v), are Raman Parkesh and Jessica Childs-Disney of Scripps Research. Other authors include Amit Kumar and Tuan Tran also of Scripps Research; Masayuki Nakamori, Jason Hoskins and Charles A. Thornton of the University of Rochester; and Eric Wang, Thomas Wang and David Housman of the Massachusetts Institute of Technology. This study was supported by the National Institutes of Health, Scripps Research, the Camille & Henry Dreyfus Foundation, and the Research Corporation for Science Advancement.

The first author of the ACS Chemical Biology study, “Rationally Designed Small Molecules Targeting the RNA That Causes Myotonic Dystrophy Type 1 Are Potently Bioactive” (http://pubs.acs.org/doi/abs/10.1021/cb200408a) is Jessica L. Childs-Disney of Scripps Research. Other authors include Suzanne G. Rzuczek of Scripps Research and Jason Hoskins and Charles A. Thornton of the University of Rochester. This study was supported by the National Institutes of Health, the Muscular Dystrophy Association, Scripps Research, the Camille & Henry Dreyfus Foundation, and the Research Corporation for Science Advancement.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neuroscience, and vaccine development, as well as for its insights into autoimmune, cardiovascular, and infectious disease. Headquartered in La Jolla, California, the institute also includes a campus in Jupiter, Florida, where scientists focus on drug discovery and technology development in addition to basic biomedical science. Scripps Research currently employs about 3,000 scientists, staff, postdoctoral fellows, and graduate students on its two campuses. The institute's graduate program, which awards Ph.D. degrees in biology and chemistry, is ranked among the top ten such programs in the nation. For more information, see www.scripps.edu.

Reposted with permission from The Scripps Research Institute
Source: http://www.scripps.edu/news/press/2012/20120222disney.html

05/16/2012

ROSEVILLE, CA (January 25, 2012): MDF is pleased to announce its largest-ever round of Fund-A-Fellow postdoctoral fellowship research grant awards. In January 2012, MDF awarded four-$100,000 awards to postdoctoral Fellows working in universities and research facilities to encourage basic research in the management, treatment and cure of myotonic dystrophy (DM). This award cycle nearly doubles the number of fellowship grants awarded since the program was launched in 2009, and brings the total research funding awarded by the MDF to over $1M since its founding in 2006.

MDF will supoprt four new postdoctoral fellows in the 2012-2013 grant cycle for a total of $400,000. “Our goal in establishing this postdoctoral fellowship program was to attract and support researchers in the beginning stages of their careers, seeding research that could lead to larger grants from other entities such as the National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC), the Muscular Dystrophy Association (MDA) and other governmental and philanthropic agencies. I believe that the ever increasing interest in the number of applications for this round of fellowships confirms that we are achieving our goal,” said Lisa Harvey, Education and Research Director for MDF.

Each recipient will receive $50,000 a year for two years. Applications were reviewed by a panel of distinguished international researchers and clinicians in the field of myotonic dystrophy. Final selections were determined by the MDF Board of Directors.

The four $100,000 postdoctoral fellowship grants have been awarded to Dr. Micah Bodner, Ph.D., at University of Oregon; Dr. Nicholas Johnson, M.D., at University of Rochester Medical Center; Dr. Zhihua (Tina) Gao, Ph.D., at Baylor College of Medicine; and Dr. Eric Wang, Ph.D., at Harvard-MIT Division of Health Sciences and Technology (HST).

Research Information

Micah Bodner, Ph.D.

Dr. Bodner’s research, “Therapeutic Agents for Myotonic Dystrophy; Defining the Pharmacophore of Pentamidine,” under the guidance of Dr. John Andrew Berglund, Ph.D. and Dr. Michael Haley, Ph.D., at the University of Oregon, will continue the study of a potential therapeutic drug, pentamidine, which was recently identified by the University of Oregon. Pentamidine is a promising lead compound for treatment of DM. Pentamidine and compounds like it have been used to reverse symptoms of DM in cell and mouse models of the disease and even alleviate myotonia in mice. However, some obstacles must be overcome before a pentamidine-based compound can be used clinically. The obstacles include: a lack of evidence for how pentamidine elicits the therapeutic effect; lack of oral availability; lack of central nervous system (CNS) activity; and toxicity. The experiments proposed in Dr. Bodner’s research plan are designed to increase understanding of how pentamidine functions and how to manipulate it in order to make a useful DM therapeutic that is orally available, CNS active and non-toxic.

The information gained from these experiments will also be used to design other compounds similar to pentamidine to better understand what portions of the compound promote binding to the RNA fragment. These compounds will then be used in DM cell and mouse model testing to understand how they perform in tests and whether they are tolerated by the cells and animals.

Nicholas Johnson, M.D.

Dr. Johnson’s research, “Characterization of Symptoms and Development of a Disease Specific Instrument for Congenital and Juvenile Myotonic Dystrophy,” under the guidance of Dr. Chad Heatwole, M.D. at the University of Rochester Medical Center in Rochester, New York, will study the severe congenital and juvenile onset forms of myotonic dystrophy.

Currently, there is very little information about the most critical symptoms associated with these forms of the disease. There are anecdotal reports that indicate that the issues important to patients with early onset myotonic dystrophy are different from those experienced by adult onset myotonic dystrophy patients. To date no significant research has been conducted to study the impacts of promising adult-onset DM therapies in congenital and juvenile-onset populations. This project will collect survey data from children and their parents describing and prioritizing the effects of the disease on the children’s cognitive, physical, and emotional health. This data will be used to create instruments measuring quality of life for these populations. These instruments will address the most critical and prevalent issues to congenital and juvenile-onset DM patients and their family members and will be designed for use in the upcoming clinical trials.

Zhihua (Tina) Gao, Ph.D.

Dr. Gao’s research, “Development of Therapeutic Approaches to Silence CUG Expansion RNA in Myotonic Dystrophy Mouse Models Using Recombinant Adeno-associated Virus,” under the guidance of Dr. Thomas Cooper, M.D., at Baylor College of Medicine in Houston, Texas, will use a virus that has been modified for therapies of other muscular dystrophies to carry elements that can remove the toxic RNA in myotonic dystrophy mouse models. The effective therapeutic approach developed in the mouse model holds a potential for future clinical trials in DM1 patients.

Myotonic dystrophy is caused by an unusual genetic mutation in which a small DNA segment of the mutated gene is repeated hundreds of times. DNA, in the form of chromosomes, is in the nucleus of a cell. When there is a need, DNA is copied into RNA. RNA then moves from the nucleus to the cytoplasm of the cell to deliver the genetic message. In myotonic dystrophy, the mutated gene is copied into RNA, but the RNA is trapped in the nucleus because of the repeated segments. The RNA then builds up in the nucleus and creates problems that disrupt the functions of many other genes. The RNA with repeated segments therefore becomes very toxic.

By forcing the expression of the mutated gene with hundreds of repeated segments in mouse skeletal muscle and heart, researchers have mimicked the DM1 (type 1) disease in mice. The goal of Dr. Gao’s proposal is to develop a recombinant adeno-associated virus (rAAV) vector-based strategy to clear away the toxic RNA in the DM1 mice. Dr. Gao’s sponsoring facility, the lab of Dr. Thomas Cooper, M.D., at Baylor College of Medicine, recently established a collaboration with Dr. Reed Clark, Ph.D., at the Center for Gene Therapy at Nationwide Children's Hospital/Ohio State University in Columbus, Ohio, led by Dr. Jerry R. Mendell, M.D.  A major effort of the Center is to develop rAAV vectors for therapeutic approaches for DMD, LGMD, FSHD, and DM1. Once established and optimized in mice, Dr. Gao and her team will work with collaborators to develop rAAV as a therapeutic approach for human trials. This strategy will be developed for DM1, the more common form of DM, but can also be used for DM2 (type 2).

Eric Wang, Ph.D.

Dr. Wang’s research, “Identification of RNA Processing Changes in the Myotonic Dystrophy Transcriptome,” under the guidance of Dr. Christopher Burge, Ph.D., and Dr. David E. Housman, Ph.D., at Harvard-MIT Division of Health Sciences and Technology (HST), Cambridge, Massachusetts, will help to improve the understanding of DM pathogenesis.

Various events associated with the expanded RNA repeat sequences that cause DM have been well established, but there are other hypotheses for what happens during DM pathogenesis. To date there have been no studies globally surveying all the RNA changes in DM, making it challenging for the DM research community to conclude whether it has identified all the major cellular pathways disturbed in DM. Identifying all these changes will provide a research road map, as well as specific readouts that can be used for diagnostics and therapeutic studies. Using a type of high throughput sequencing technology that has been recently developed, Dr. Wang proposes to identify RNA level changes that occur in various mouse models of DM, assess the extent to which current models for DM pathogenesis can explain what is happening in human DM, and develop potential therapeutic interventions using the insights gained from these analyses. The successful completion of these studies will augment the DM community’s understanding of DM pathogenesis, and provide a set of biomarkers that can be used immediately for diagnostics and therapeutic development.

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About Myotonic Dystrophy

Described as “the most variable of all diseases found in medicine”, myotonic dystrophy is an inherited disorder that can appear at any age and that manifests differently in each individual.  Considered by some researchers to be the most common form of muscular dystrophy, DM affects approximately 1:8,000 people worldwide and can cause not only muscle weakness, atrophy and myotonia (the delayed relaxation of a muscle), but also problems in the heart, brain, GI tract, endocrine, skeletal and respiratory systems. The variability of this disease often makes it difficult to diagnose. Since the gene was identified in the early 1990’s, researchers have discovered that the genetic flaw generally enlarges and causes more severe symptoms in subsequent generations, rendering it a genetic time bomb.

About MDF

MDF is a patient advocacy organization dedicated to leading and mobilizing resources toward effective management, treatment and ultimately a cure for myotonic dystrophy.  The Foundation provides invaluable medical information, empowering families and medical providers as they navigate the disease process. The website, www.myotonic.org, and medical information provided by the Foundation, is approved by members of the MDF Scientific Advisory Committee, comprised of experts in the field of myotonic dystrophy and muscle research who together have devoted more than ninety years to the research and treatment of myotonic dystrophy.  In addition, MDF has a community website where families and caregivers meet others living with similar challenges and share information.

Questions?

For more information about MDF , contact us at info@myotonic.org or 86-MYOTONIC.

05/16/2012