MDF staff recently attended the 2017 annual meeting of the American Academy of Neurology, in Boston, MA. Here are highlights from that meeting.

Clinical and histopathological findings in myotonic muscular dystrophy type 2 (DM2): retrospective review of 49 DNA-confirmed cases.
Bhaskar Roy, Qian Wu, Charles Whitaker, and Kevin Felice.

A better understanding of the natural history of DM2 is essential to the design of interventional clinical trials. This poster reviewed clinical profiles of a cohort of 49 confirmed DM2 cases seen over 24-years at Beth Israel. Proximal lower limb weakness was the most predominant symptom, although weakness ranged from absent to severe. Myotonia, grip strength, and FVC also showed considerable variation. Approximately half of study subjects had cataracts.

Evaluation of postural control and falls in individuals with myotonic dystrophy type 1.
Katy Eichinger, Jill R. Quinn, and Shree Pandya.

Clinical trial endpoints that measure parameters meaningful to patients will be necessary for registration trials in myotonic dystrophy (DM1). This poster presented an assessment of postural control and self-reported falls in a cohort of 34 DM1 subjects, studied over a 12-week observational period. Postural sway measurements in DM1 subjects differed significantly from norms and showed good test/re-test reliability. None of the postural measures used were predictive of fall status, although this may be due to the small sample. Further evaluation of postural status may yield reliable, clinically meaningful clinical trial endpoints.

Identification of dysregulated musclin expression and elevated atrial natriuretic peptide levels in adult and congenital myotonic dystrophy.
Donald McCorquodale, Katie Mayne, Brith Otterud, Diane Dunn, Bob Weiss, and Nicholas Johnson.

Understanding tissue-level molecular changes in DM can guide biomarker development as well as identify novel therapeutic targets. This poster addressed two components of a pathway that mediates response to exercise. Musclin expression, an upstream regulator of atrial natriuretic peptide (ANP), increased in skeletal muscle of congenital myotonic dystrophy (CDM) and DM1, accompanied by increases in ANP clearance receptor (NPR3) and ANP. Disregulated musclin/ANP signaling may be linked to weakness and exercise intolerance in CDM and DM1.

Correlation between MRI cerebral white matter changes, muscle structure and/or muscle function in myotonic dystrophy type 1 (DM1).
Cheryl Smith, Peggy Nopoulos, Richard Shields, Dan Thedens, and Laurie Gutmann.

Understanding any linkage between CNS and skeletal muscle changes in DM1 may provide insights into putative biomarkers and clinical trial endpoints. This poster presented pilot data on potential CNS contributions to skeletal muscle structure and function in a DM1 cohort. Data show correlations between an MRI measure (global cerebral fraction anisotrophy—a measure of white matter abnormalities) and both MRI measures of lower limb muscle structure and a lower extremity tracking task (a measure of functional weight bearing movement). The authors concluded that these data suggest that CNS changes in DM1 play a role in neuromuscular functional deficits.

Borderline CNBP CCTG expansions in myotonic dystrophy type 2 in over 16,000 specimens analyzed in a clinical laboratory.
Elise Nedzweckas, Rebecca Moore, Marc Meservey, Tara McNamara, Nicholas Tiebout, Zhenyuan Wang, Sat Dev Batish, and Joseph Higgins.

The frequency of DM2 expansions in the pre-mutation range (CCTG repeat length of approximately 177-372) is unknown. This poster from Quest Diagnostics utilized PCR, PCR repeat-primed, and Southerns to determine CNBP CCTG expansion lengths in 16,253 samples. The frequency of ‘borderline’ repeats was 0.97%, a value larger than in previously published studies. The potential for repeats in this borderline range to expand to pathologic lengths is, as yet, unknown.

Genetic markers of myotonic dystrophy type 1 (DM1) and Duchenne muscular dystrophy (DMD) in human urine.
Layal Antoury, Ningyan Hu, Leonora Balaj, Xandra Breakfield, and Thurman Wheeler.

Availability of a non-invasive biomarker to track target engagement/modulation of candidate therapeutics would be valuable to any DM clinical trial, and elimination of muscle biopsies would be critical for trials in pediatric CDM subjects. The platform presentation reported analyses of exosomal RNA in blood and urine of DMD, BMD, and DM subjects. Serum showed no differences between DM1 and controls. Several splicing event alterations known to change in skeletal muscle were not detected in urine. But, at least 10 transcripts were differentially spliced in urine that followed patterns seen in skeletal muscle and thus showed potential as non-invasive biomarkers. The source of differentially spliced transcripts in urine was thought to be the kidney or other urinary tract cells.  The group is working to correlate the pattern of splicing events detected in urine with phenotypic changes in DM1 patients.

Receptor and post-receptor abnormalities contribute to insulin resistance in myotonic dystrophy type 1 and type 2 distal and proximal muscles.
Giovanni Meola, Laura Valentina Renna, Francesca Bose, Barbara Fossati, Elisa Brigozi, Michele Cavalli, and Rosana Cardani.

Metabolic dysfunction, including insulin resistance and increased risk of type 2 diabetes mellitus are characteristic of DM1 and DM2. While the insulin receptor (INSR) gene is known to be mis-spliced and links to the DM metabolic phenotype, other insulin signaling pathway components may be involved. This platform presentation presented data on insulin signaling pathway changes in DM1 and DM2 muscle biopsies. DM muscle biopsies showed increased fetal INSR isoform and altered expression and phosphorylation of selected proteins in the IR signaling pathway was seen in DM1 subjects. These effects were more pronounced in proximal versus distal muscles. The authors suggest that profiling of changes in INSR signaling pathways markers might emerge as a biomarker for clinical studies and trials in DM.

Increased EEG theta spectral power in polysomnography of myotonic dystrophy type 1 compared to matched controls.
Chad Ruoff, Joe Cheung, Jennifer Perez, Saranda Sakamuri, Emmanuel Mignot, John Day, and Jacinda Sampson.

Excessive daytime sleepiness and fatigue are hallmarks of DM—development of clinical endpoints to reliably evaluate these symptoms will help drive clinical trials. This poster presented data characterizing EEG spectra from nocturnal polysomnography in DM1 vs. controls. DM1 patients showed increases in wake after sleep onset and increased theta power in stage 2, stage 3, and all sleep stages combined when compared to control. EEG spectral power is being further evaluated as a putative biomarker.

There have been new discoveries in the way that congenital myotonic dystrophy (CDM) is inherited.

How is DM Inherited?

Myotonic dystrophy (DM) is inherited in what geneticists refer to as an autosomal dominant fashion. Let’s break that language down.  

Autosomal refers to the type of chromosome that carries the DM mutation—autosomes versus sex chromosomes. Humans have 23 pairs of chromosomes—pairs 1 through 22 have the same appearance in both males and females, and are referred to as autosomes; but pair 23 differs among the sexes (sex chromosomes), with two X chromosomes in females and one X and one Y in males. 

Autosomal then means that a mutation is carried on one of the chromosomal pairs 1 through 22. In the case of myotonic dystrophy (DM1), chromosome 19 carries the expanded CTG repeat mutation in the DMPK gene; for DM2, it’s chromosome 3 that carries the expanded CCTG repeat in the CNBP gene.

Dominant means that a mutation only has to be on one of the two members of a chromosomal pair to cause the disease. So, in DM1 (myotonic dystrophy type 1) it’s only necessary that the mutation in DMPK be on one member of the chromosome 19 pair, or one member of the chromosome 3 pair for DM2. Recessive disorders have to have the mutation on each member of a chromosomal pair and thus must be inherited from both parents.

Is Congenital DM the Same?

Autosomal dominant inheritance would typically mean that DM could be passed along by either parent. However, for congenital myotonic dystrophy (CDM), inheritance patterns are almost exclusively maternal. This maternal bias has been a mystery, since the “rules of genetics” would indicate that the likelihood of inheriting a DM mutation from either parent should be equal.

Drs. Karen Sermon (Vrije Universiteit Brussel) and Christopher E. Pearson (Hospital for Sick Children) and their colleagues explored the molecular basis for the maternal bias in the inheritance of CDM. They evaluated multiple generations of several families, including 20 individuals with CDM.

While the length of the CTG expansion was clearly greater in CDM than DM1, the investigators confirmed prior findings that the range of repeat lengths partially overlapped, suggesting that CTG repeat length was important, but not the only factor in determining whether someone had DM1 or the more severe CDM.

Genetic changes, such as the expanded CTG in DM1, can cause disease, but there are other changes in DNA that go beyond changes in the sequence of bases (A, T, C, G)—these changes also are heritable and referred to as epigenetic changes. To understand the basis of maternal inheritance bias in CDM, Sermon and Pearson looked for a pattern of epigenetic changes in the vicinity of the DMPK gene on chromosome 19.

The investigators identified specific epigenetic changes adjacent to DMPK in nearly every CDM patient studied, changes that were not observed in DM1 patients. CDM, therefore, appears to require both a long CTG repeat expansion and this epigenetic change. 

CDM and Maternal Bias

So, what causes the maternal bias in CDM inheritance? The investigators speculate that the maternal inheritance bias in CDM may be a consequence of failed survival of sperm that carry the epigenetic change in DMPK. Since sperm without the epigenetic change are at a survival disadvantage, the chances of paternal inheritance are considerably reduced. There are rare cases of paternal inheritance and these cases are sought by and under study by this research group to further advance understanding of CDM. For more information, access the research article.

Many of you have seen posts on social media about treatments they have received in other countries or heard about through friends, that include everything from dietary aids to gene therapy, and want to know how you can assess the possible benefits and risks of these "treatments." In this complicated therapy environment, how can patients make decisions about whether an available treatment or therapy is safe and effective? How can you tell the quacks from the cures?

In Pursuit of a Cure

MDF is committed to the pursuit of improved Care and a Cure for people living with myotonic dystrophy (DM). We’re a non-profit advocacy organization and there is no other reason for our existence. In pursuit of a cure, we fund research, support infrastructure projects for therapy development, recruit investigators to work on DM, educate drug regulatory agencies, and work with companies to help them see the opportunities and potential for investments in a new therapy for myotonic dystrophy.

Patients and their families know well that the search for a cure, or even a treatment that can mitigate symptoms of DM, is a long and arduous process. We have recently seen the development of IONIS-DMPK-2.5Rx ended because the oligonucleotide drug did not reach its target tissue (skeletal muscle) in concentrations adequate to have a meaningful effect. Fortunately, Ionis has reported that it has alternative compounds that appear to have better tissue-targeting and we hope to see these move toward clinical trials.

Sometimes it’s Complicated

More broadly, we have seen significant recent controversy and lack of agreement regarding therapies developed for other rare diseases, with insurance companies refusing to reimburse for drugs they claim do not have enough scientific evidence to demonstrate a clinically-meaningful effect for patients. We also know that the ‘placebo effect’ where patients report significant therapy benefit when actually on a placebo (a non-active substance with no therapeutic effect), can also complicate the discussion, particularly when a given therapy has a relatively small demonstrable impact. 

Stick with What Works

Oligonucleotide drugs can succeed as therapeutics. Biogen and Ionis collaborated on the development of Spinraza for spinal muscular atrophy. The two companies exercised considerable care in development of these drugs and sought FDA approval only after obtaining results from two international, placebo-controlled clinical trials. The key here is that considerable drug effect was demonstrated in a large cohort of patients enrolled in the clinical trials. As a consequence, the drug is now marketed for all types of spinal muscular atrophy and, while the cost of the drug is very high, many families are getting insurance coverage for Spinraza. The evidence had to be there for both therapy approval and insurance company reimbursement.

Achieving a drug that is proven to have a considerable level of effect on measures that are clinically-meaningful to DM patients is a central requirement for both drug approval and reimbursement. 

The therapies that we hope to achieve for DM will come only from this evidence-based drug development and approval process. MDF regularly meets with biotechnology and pharmaceutical companies—including ten companies in the last two months—providing information and making the case that DM represents a good investment with a clear pathway to drug approval. Any legitimate clinical trial will be listed in ClinicalTrials.gov, and information about legitimate DM studies and trials will always be circulated by MDF.

Dangers lie in the pursuit of quack “therapies.” A brief Google search will reveal fabulous claims of cures for just about any disease, if the patient will only travel to a developing country, with less regulatory oversight, for the ‘breakthrough’ therapy. Most often, the claims of effectiveness lack substantiation. These “therapies” have certainly not gone through any drug regulatory agency for approval, and often supportive data has not even been published in a reputable scientific or medical journal. They are, to put it bluntly, quack “therapies” that are potentially harmful because safety data is often not there.

To the safety point, even in the U.S., unproven “therapies” that bypass FDA regulations have caused harm. Three women were recently blinded in Florida after receiving stem cell “therapy” injections for macular degeneration.

Do Your Homework

So, to steal from an old saying, ya can’t tell the quacks from the cures without a scorecard. If a DM therapy sounds too good to be true, the people behind it are probably just after your money. The reliable scorecard here is the physician who is knowledgeable of DM. If your doctor or any other reputable physician with an understanding of DM won’t prescribe the treatment, you probably should not be taking it. 

MDF is also happy to help you understand whether something is in a legitimate clinical trial, an approved therapy…or not. Browse the resources and tools available on the MDF website or call the MDF Warmline at 415-800-7777.

The June issue of Current Opinion in Genetics and Development is focused on the topic "Molecular and Genetic Bases of Disease." Four outstanding review articles in the issue have direct relevance to myotonic dystrophy (DM) and are currently available online.

The first article (by Drs. Nan Zhang and Tetsuo Ashizawa) reviews the formation of RNA foci in microsatellite expansion disorders, how RNA binding proteins participate in toxic RNA gain of function, and how transcriptional and RNA processing/transport may ensue.

The second article (by Drs. Kevin Yum, Eric Wang, and Auinash Kalsotra) discusses mechanisms underlying repeat expansion, diagnostic approaches to determining repeat length, and how DM repeat length relates to disease onset, progression and severity.

The third article (by Drs. John Cleary and Laura Ranum) reviews basic mechanisms of repeat-associated non-ATG (RAN) translation and how RAN proteins may enter into the pathogenesis of microsatellite expansion disorders, including DM.

The fourth article (by Drs. Charles Thornton, Eric Wang and Ellie Carrell) focuses on the latest molecular strategies being used in the development of candidate therapies for DM, reviewing approaches targeted at transcriptional silencing, post-transcriptional silencing, inhibition of interactions between MBNL and toxic RNA, and pathways downstream of RNA toxicity.

Taken together, this is a compelling series of review articles, of benefit to basic, translational, and clinical scientists of all levels working on DM.

References:

RNA Toxicity and Foci Formation in Microsatellite Expansion Diseases
Zhang N, Ashizawa T.
Curr Opin Genet Dev. 2017 Feb 13;44:17-29. doi: 10.1016/j.gde.2017.01.005. [Epub ahead of print]

Myotonic Dystrophy: Disease Repeat Range, Penetrance, Age of Onset, and Relationship between Repeat Size and Phenotypes
Yum K, Wang ET, Kalsotra A.
Curr Opin Genet Dev. 2017 Feb 14;44:30-37. doi: 10.1016/j.gde.2017.01.007. [Epub ahead of print]

New Developments in RAN Translation: Insights from Multiple Diseases
Cleary JD, Ranum LP.
Curr Opin Genet Dev. 2017 Mar 30;44:125-134. doi: 10.1016/j.gde.2017.03.006. [Epub ahead of print]

Myotonic Dystrophy: Approach to Therapy
Thornton CA, Wang E, Carrell EM.
Curr Opin Genet Dev. 2017 Apr 1;44:135-140. doi: 10.1016/j.gde.2017.03.007. [Epub ahead of print]

MDF’s Patient-Focused Drug Development (PFDD) meeting, held in 2016 in conjunction with the U.S. Food and Drug Administration (FDA), highlighted the critical role of patients in developing clinically-meaningful outcome measures to facilitate drug development and approval. Identification of the symptoms regarded as most important to patients and caregivers, and the benefits they would most hope to derive from a therapy, provides critical guidance that must be included from the earliest stages of drug development.

Patient registries, like MDF’s Myotonic Dystrophy Family Registry, the National Registry for Myotonic Dystrophy & Facioscapulohumeral Dystrophy at the University of Rochester, the DM-Scope Registry in France, and the UK Myotonic Dystrophy Patient Registry, represent critically important data repositories to facilitate studies of the burden of disease for those living with myotonic dystrophy (DM).

The UK DM Patient Registry published a cross-sectional analysis of self-reported data from 556 myotonic dystrophy type 1 (DM1) patients with a confirmed diagnosis, representing approximately 8.5% of the estimated affected population in the United Kingdom (UK). Registered patients were also able to nominate healthcare specialists to enter their genetic and clinical data; these data augmented patient profiles and served to validate the patient-reported registry format.

Registrant gender was equally distributed (51% female) and a positive family history of DM was reported by 89% of registrants. Mean age of onset was 33 years. Fatigue/daytime sleepiness (79%) and myotonia (78%) were the most frequently reported symptoms—the occurrence of myotonia positively correlated with fatigue, dysphagia and ambulatory status. As in a prior report by the DM-Scope Registry, the UK cohort showed a higher frequency of severe myotonia in males, although fatigue did not show gender bias. Men also reported a higher frequency of cardiac abnormalities, non-invasive ventilation, and mobility impairments, while cataract surgery was more common in women. Most patients (65%) did not require assistive devices to walk. Severity of symptoms did not correlate with CTG repeat length obtained at the time of genetic testing.

While only one-third of patients reported having EKG, 48% of those were diagnosed with a cardiac conduction system abnormality and 36% had received an implanted cardiac device. Non-invasive ventilation was used regularly by 15% of patients. Of the patients with data available, 26% reported cataract surgery.

The UK group reported that the delays in receiving a genetic diagnosis of DM1 remain substantial and do not seem to have improved since the advent of genetic testing in 1996. They stress the importance of reducing the genetic diagnostic odyssey, not only to improve patient care and quality of life, but also to facilitate community readiness for interventional trials and approved therapies.

Taken together, knowledge of the symptoms that are most important to DM1 patients provides guidance not only for improved care, but also for the development of novel therapeutics. Studies such as that reported here, from the UK registry, provide an evidence-based underpinning that is essential for progress. An improved collaborative environment, whereby registry data is more readily shared, is a goal that will not only improve the science, but is in the best interests of those living with DM.

Reference:

The UK Myotonic Dystrophy Patient Registry: Facilitating and Accelerating Clinical Research
Wood L, Cordts I, Atalaia A, Marini-Bettolo C, Maddison P, Phillips M, Roberts M, Rogers M, Hammans S, Straub V, Petty R, Orrell R, Monckton DG, Nikolenko N, Jimenez-Moreno AC, Thompson R, Hilton-Jones D, Turner C, Lochmüller H.
J Neurol. 2017 Apr 10. doi: 10.1007/s00415-017-8483-2. [Epub ahead of print]

The burden of disease for myotonic dystrophy (DM) is multi-systemic, including skeletal muscle weakness, fatigue, cardiac arrhythmias, respiratory insufficiency and intellectual disability. Modeling of this constellation of symptoms is important for mechanistic studies and preclinical therapy development. Yet, what is arguably the most widely available mouse model, the HSA-LR, is designed to model the skeletal muscle molecular, structural and functional deficits of skeletal muscle.

Dr. Guey-Shin Wang and colleagues at Academia Sinica (Taiwan) developed an EpA960/CaMKII-Cre mouse that carries an inducible human DMPK with 960 CTG repeats in the 3’ UTR. Cre expression occurs in the forebrain (cortex and hippocampus) after two weeks of age, preserving earlier neurodevelopmental events from toxic RNA exposure and MBNL depletion.

Atrophy of the cortex and corpus callosum, features of the myotonic dystrophy type 1 (DM1) patient central nervous system (CNS), were observed in the adult EpA960/CaMKII-Cre mice. The mice showed progressive neuropathological findings: reduced MBNL1 in dendrites of cortical layer V neurons at six months of age, brain atrophy (axon and dendrite pathology) by nine months, and loss of MBNL2 and MBNL-directed splicopathy were later events, at 12 months.

Functionally, EpA960/CaMKII-Cre mice were evaluated at six months for hippocampus-dependent spatial learning and memory using the Morris water maze—escape latencies were greater for mutants compared with controls, suggestive of slower learning. Evaluation of long-term potentiation (LTP) in hippocampal slices at six months of age also was consistent with synaptic dysfunction and the functional learning disabilities seen in these mice.

The EpA960/CaMKII-Cre mouse model recapitulates some features, including disease progression, seen in DM1 patient CNS. Moreover, the authors suggest that depletion of MBNL1 and MBNL2 in the CNS are distinct events with differing roles in disease progression. Early synaptic dysfunction may be triggered by MBNL1 depletion, and is a precursor to dendritic and axonal pathology. Since splicing changes were detected only later, commensurate with MBNL2 depletion, the early synaptic dysfunction likely is mediated by MBNL1-related, but alternative splicing-independent events.

Reference:

Reduced Cytoplasmic MBNL1 is an Early Event in a Brain-specific Mouse Model of Myotonic Dystrophy.
Wang PY, Lin YM, Wang LH, Kuo TY, Cheng SJ, Wang GS.
Hum Mol Genet. 2017 Mar 24. doi: 10.1093/hmg/ddx115.

Inheritance of congenital myotonic dystrophy (CDM) is almost exclusively maternal and, while typically associated with large CTG expansions, is not always genetically differentiated from myotonic dystrophy type 1 (DM1) by repeat tract length. Correlations between CDM/DM1 genotype and phenotype can be improved through evaluation of somatic expansions. Yet it is clear that factors other than germ line repeat length underlie the bias toward maternal inheritance and the heterogeneity of CDM.

The laboratories of Drs. Karen Sermon (Vrije Universiteit Brussel) and Chris Pearson (Hospital for Sick Children) recently collaborated on an epigenetic analysis of the DM1 genetic locus in a cohort of DM1 and CDM patients. Prior reports showed that the DM1 locus resides in a 3.5 kB CpG island with putative CTCF sites, suggesting an epigenetic mechanism for DM1 regulation and disease phenotypes that diverge from CTG length assessments. Earlier reports also established variability in methylation status at that locus in both DM1 patients and DM1 transgenic mice. Drs. Sermon and Pearson hypothesized that CTG expansion might alter CpG methylation status and that a consequent regulatory dysfunction contributes to the severity of the CDM phenotype.

Drs. Sermon and Pearson and team evaluated multiple generations of several families, including 20 individuals with CDM. Results showed nearly an absolute correlation between the methylation status upstream of the expanded CTG repeat and the occurrence of CDM (19/20 cases). By contrast, this pattern of methylation was rarely found among DM1 patients (2/59 cases). The authors suggest that CpG site methylation is an important contributing factor, with the development of CDM not being determined by CTG repeat length alone.

Analysis of human embryonic stem cells (hESC) and chorionic villus samples from the study cohort identified upstream CpG site methylation only in maternally-derived samples; paternal samples never showed methylation upstream of expanded DMPK alleles.

Generational increases in both methylation and CTG expansion length were seen in each CDM family studied. Yet since CTG repeat lengths overlapped in DM1 and CDM, while upstream methylation was almost exclusive to CDM, the authors concluded that methylation status is a stronger indicator of CDM than absolute repeat length. Moreover, they speculate that the maternal inheritance bias of CDM may be a consequence of a failed survival of spermatogonia carrying the pathogenic methylation upstream of DMPK. Importantly, while their data suggests that it is rare, the authors do not exclude paternal inheritance for CDM.

Reference:

CpG Methylation, a Parent-of-Origin Effect for Maternal-Biased Transmission of Congenital Myotonic Dystrophy.
Barbé L, Lanni S, López-Castel A, Franck S, Spits C, Keymolen K, Seneca S, Tomé S, Miron I, Letourneau J, Liang M, Choufani S, Weksberg R, Wilson MD, Sedlacek Z, Gagnon C, Musova Z, Chitayat D, Shannon P, Mathieu J, Sermon K, Pearson CE.
Am J Hum Genet. 2017 Mar 2;100(3):488-505. doi: 10.1016/j.ajhg.2017.01.033.

Cardiac troponin-I, a sarcomeric regulatory protein integral to skeletal and cardiac muscle contraction, has long been utilized as a diagnostic and prognostic biomarker of heart disease. For muscular dystrophies, elevated serum creatine kinase and troponin are associated with myopathic changes in muscle. Understanding the sensitivity of the analytical tools, as well as the types of cardiac issues that may result in elevated cardiac markers in serum, is critical to use of these assays in monitoring myotonic dystrophy type 1 (DM1) patients.

The constellation of cardiac involvement in DM1 includes atrioventricular block, prolonged QT interval, prolonged QRS interval, increased ventricular premature contractions, atrial fibrillation/flutter, right/left bundle branch block, non-sustained ventricular tachycardia and left ventricular systolic dysfunction (Petri et al., Int. J. Cardiol. 160: 82-88, 2012). Prior reports identified a correlation between CTG repeat length and cardiac dysfunction and linked the degree of neuromuscular and cardiac involvement in patients.

A large multi-center study in Scotland recently reported out an analysis of serum levels of cardiac troponin-I (cTnI) in a cohort of 117 well-characterized DM1 patients recruited from outpatient clinics. Nine subjects had cTnI levels that exceeded the 99th percentile of the general population. One-third of subjects with elevated cTnI also had left ventricular systolic dysfunction. The authors noted that elevations in cTnI did not correlate with CTG length, were not predictive of severe conduction abnormalities and did not correlate with muscle strength (by MIRS score). There also was no association between cTnI level and the presence of an implanted cardiac device.

Overall, the authors suggest that cTnI levels represent a potential biomarker to assess risks in the management of DM1 patients and for stratification of subjects in clinical trials. Although the lack of correlation of cTnI levels and MIRS score suggests a cardiac origin for elevated serum cTnI, the underlying responsible pathology in the context of known cardiac phenotype of DM1 is currently unclear. Finally, the authors suggest that the overall sample of patients with elevated cTnI is small and propose these findings as exploratory, requiring follow-up of this and other putative cardiac biomarkers in larger cohorts.

Reference:

Elevated Plasma Levels of Cardiac Troponin-I Predict Left Ventricular Systolic Dysfunction in Patients with Myotonic Dystrophy Type 1: A Multicentre Cohort Follow-up Study.
Hamilton MJ, Robb Y, Cumming S, Gregory H, Duncan A, Rahman M, McKeown A, McWilliam C, Dean J, Wilcox A, Farrugia ME, Cooper A, McGhie J, Adam B, Petty R; Scottish Myotonic Dystrophy Consortium., Longman C, Findlay I, Japp A, Monckton DG, Denvir MA.
PLoS One. 2017 Mar 21;12(3):e0174166. doi: 10.1371/journal.pone.0174166.

A potentially revolutionary technology may allow development of a drug for DM that can correct a patient’s DNA by selectively removing the expanded CTG and CCTG repeats in DM1 and DM2, respectively.

This new gene editing technology has emerged from the discovery of how bacteria protect themselves from invading viruses. There very likely will be a Nobel Prize awarded to scientists who discovered how this bacterial defense mechanism could be used to edit human gene defects. There certainly has been a rather public fight over the patent rights that are potentially worth billions of dollars among the research groups at the University of California, Berkeley and the Eli and Edythe L. Broad Institute of MIT and Harvard.

CRISPR is an acronym for short, repetitive DNA sequences that function to immunize bacteria from viruses. CRISPR DNA works together with a family of proteins, known as Cas proteins, which cut and thereby inactivate the invading virus’ DNA. Working together, CRISPR and Cas can recognize viral DNA as foreign and then inactivate it via the DNA-cutting Cas protein.

Researchers Jennifer Doudna (U.C. Berkeley) and Feng Zhang (Broad) have shown that the CRISPR/Cas system can be adapted to cut human DNA at highly specified locations to either remove existing genes or to insert new genes. The potential value for DM is that known mutation-containing DNA sequences, specifically the expanded repeats in DMPK or CNBP, could be cut to remove the disease-causing expanded repeats. Doudna and Zhang are likely to share a Nobel Prize for this discovery, while it appears that Zhang and the Broad Institute have won the patent rights battle.

Is gene editing using the CRISPR/Cas system going to be available soon for DM? The direct answer is, no. Several issues need to be resolved before any clinical application of gene editing is realized. The specificity and efficiency of gene editing will need to improve. Delivery of the gene editing reagents also must be optimized—these are large molecules that will have to be delivered by intravenous injections and must then gain access to cells throughout the body of DM patients in order to correct the multiple symptoms of the disease. Lastly, there is the issue of safety—studies need to show not only that the CRISPR/Cas system is designed to edit the DMPK or CNBP genes, but that it does not cause harm by editing unintended genes. MDF is working with researchers and biotechnology companies to help advance CRISPR/Cas gene editing for DM.

Gene editing is entering clinical trials this year for some types of cancer. The strategy is to edit the patient’s immune cells, outside of their body (thereby circumventing some barriers to the technology), and the cells that are put back into the body have gene edits so they attack the tumor. This human study is an important proof of concept, and a step that will be critical as we move toward the application of gene editing for DM.

Reports over the last decade have challenged the quality and strength of preclinical evidence, the scientific rationale that’s behind the launch of clinical trials. The U.S. National Institutes of Health (NIH) now requires applicants to address scientific rationale, rigor, biological variables, and the authenticity of biological and chemical reagents. Applying such considerations in developing the case for clinical testing of an experimental therapeutic can help ensure that trials do not fail for avoidable reasons.

The European Neuromuscular Consortium (ENMC) recently held a workshop entitled "Finalizing a Plan to Guarantee Quality in Translational Research for Neuromuscular Diseases." MDF staff participated in the workshop that emphasized “choke points” in ensuring rigorous research—the funders and publishers. The proceedings of the workshop are to be published in Neuromuscular Disorders.

All stakeholders are responsible for adequacy of the rationale for clinical trials. DM investigators are encouraged to observe established standards for preclinical efficacy studies, such as the National Institute of Neurological Disorders and Stroke (NINDS) rigor guidelines (pdf). The path to an approved therapy for DM is an arduous one and should not be complicated by clinical trials of candidate therapeutics that do not have a solid scientific basis.