Gene Editing for DM

Gene editing has garnered considerable publicity as the newest technology with potential for developing therapies for rare diseases. MDF previously published a primer, titled "Using Gene Editing to Correct DM," on the CRISPR/Cas9 technology that has been heavily promoted in the media.

Gene editing technology uses molecular mechanisms that were first developed in bacteria as a shield against invasion from viruses. This approach is rapidly moving into clinical trials for a select group of diseases—those where cells can be isolated from the body, edited, and then returned to patients as a viable treatment for the disease. These diseases are predominantly disorders of the blood and cancers, and several clinical trials are recruiting patients in China (HIV-infected subjects with hematological malignances; CD19+ refractory leukemia/lymphoma; esophageal cancer; metastatic non-small cell lung cancer; EBV-associated malignancies). At least one trial has been approved in the U.S. by the Food and Drug Administration (FDA) and is expected to start soon (this is also for a set of cancers).

For myotonic dystrophy (DM), multiple organ systems are affected and we cannot take the simple path of editing and returning cells to the body—treatment must address simply too much body tissue mass, including the brain, the heart, skeletal muscles, the gastrointestinal system, and other organs that are affected. Thus, for CRISPR/Cas9 to “work” in DM, the gene editing reagents will have to be efficiently delivered to virtually every cell in patients and effectively execute the deletion of CTG and CCTG repeat expansions from the DNA. The delivery of gene editing reagents into patients is an incredibly difficult undertaking and is likely years away from clinical trials in any disease.

Could a Modified CRISPR Technology be Effective in DM?

Investigators at the University of California San Diego, the University of Florida, and the National University of Singapore have recently reported early research that potentially ‘repurposes’ gene editing technology for a set of RNA disorders—myotonic dystrophy type 1 (DM1), myotonic dystrophy type 2 (DM2), a subset of Lou Gehrig’s disease (ALS) patients and Huntington’s disease. They have modified the Cas9 enzyme so it is targeted to toxic RNA, instead of the expanded DNA repeats in these diseases.

The researchers have optimized Cas9 so that it can specifically target and degrade expanded repeat RNA for DMPK and CNBP genes. In many ways, this is similar to the approach that Ionis Pharma is using to target CUG repeats RNA in DM1. 

Their development of an RNA-targeted Cas9 results in the degradation of toxic RNA, an increase in the MBNL protein, and reduction or elimination of the gene splicing defect that characterizes DM. The strategy uses gene therapy vectors to delivery the modified Cas9 enzyme. If this approach were to be effective, it’s likely that patients would only need a single intravenous injection to treat skeletal muscles, the heart, and the gastrointestinal system; because gene therapy does not cross the blood brain barrier, a second injection may be needed, into the fluid around the spinal cord, to treat the brain. To work toward clinical development, the researchers have formed a biotechnology company to raise funding and move the candidate therapy forward.

We Still Have a Considerable Way to Go Before this Novel Strategy is in the Clinic

While this approach shows promise, we should be cautioned that studies thus far have only tried the new experimental therapy in patient cells in tissue culture. Therapy development has to pass through preclinical testing in appropriate mouse models, preclinical safety testing and approval by the FDA before the first clinical trial can be launched. Importantly, this effort represents yet another shot on goal to develop a novel therapeutic for DM1 and DM2. MDF monitors all drug development efforts and will keep the community informed as to their progress.

Accurate assessment of endpoints that are clinically meaningful to the patient is essential for the regulatory approval of a candidate therapeutic. Many of the endpoints used in clinical trials for myotonic dystrophy (DM) type 1 (DM1) thus far do not meet this requirement and thus do not represent adequate registration endpoints. Such registration endpoints are the holy grail for DM. Tools must be validated to assess the diverse factors that contribute to fatigue in order to develop clinical trial endpoints and effective therapies.

Baldanzi and colleagues (University of Pisa) have published an evaluation of several instruments in a cohort of 26 subjects with the genetic and clinical diagnosis of DM1 and proposed a paradigm to assess central and peripheral fatigue. They defined central fatigue as a decrement in voluntary muscle activation during exercise related to cognitive/behavioral function. By contrast, peripheral fatigue was characterized as the consequence of altered transmission at the neuromuscular junction or muscular dysfunction. The authors suggest a protocol for evaluation as an assessment of fatigue in DM1. 

Fatigue is an important contributor to patient-reported burden of disease in DM1. However, across neuromuscular diseases, there has been considerable debate around both defining and measuring fatigue.

Objectively, fatigue is defined as a decrease in power (work performed over time). Fatigue may arise from having to operate at or near one’s maximal motor functional capacity—diminishment of that capacity leads to early onset of fatigue. Yet, another important disease burden in DM2, pain, limits the performance of work and thus the measurement of fatigue is confounded as patients may not want to exert maximal effort due to the discomfort it causes. 

Since patients are able to detect even subtle changes in fatigue, patient reported outcome measures (PROMs) have potential as clinical trial endpoints. Fatigue can have both central and peripheral origins, and its dual origin may impact therapy development strategies. Thus, for a multi-systemic disease like DM, it is particularly important that we have tools to quantitatively evaluate fatigue regardless of origin and, optimally, gain some insights into peripheral and central contributions. A PROM scale such as the Modified Fatigue Impact Scale (MFIS) has three subscales (physical, cognitive, and psychosocial functioning) that may, in part, help understand fatigue. Another commonly used scale, the Multidimensional Assessment of Fatigue (MAF), is valuable in assessing four dimensions of fatigue—degree and severity, distress caused, timing and impact on activities of daily living.

Because fatigue is multifactorial, studies are needed to evaluate and validate measures of fatigue. The Myotonic Dystrophy Health Index (MDHI) is a PROM that has been incorporated into many recent clinical studies and trials and includes separate question banks that assess fatigue, sleep, and cognition. Its fatigue component is thought to focus on muscle fatigue, muscle endurance, and “tiredness” arising from muscle. The sleep and cognitive components have been linked to CNS-based fatigue, including motivation and concentration. 

The complex etiology of fatigue in DM1 makes it difficult for individual instruments to dissect peripheral and central components of fatigue. Given its key role in the burden of DM, it is critical that validated measures of fatigue be incorporated into natural history studies and clinical trials. 

Reference:

The proposal of a clinical protocol to assess central and peripheral fatigue in myotonic dystrophy type 1.
Baldanzi S, Ricci G, Bottari M, Chico L, Simoncini C, Siciliano G.
Arch Ital Biol. 2017 Jul 1;155(1-2):43-54. doi: 10.12871/000398292017125.

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]

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.

When Dr. Thurman Wheeler was a resident in neurology, he remembers a senior physician telling him that myotonic dystrophy would probably be one of the most difficult diseases to treat because it involves so many body systems. But thanks to unprecedented advances in laboratory and clinical research since then, “it looks like it might turn out to be fairly straightforward,” Dr. Wheeler says. Now an assistant professor of neurology at Harvard Medical School and a clinical neurologist at Massachusetts General Hospital, Wheeler has spent more than a decade caring for patients with myotonic dystrophy (DM) and conducting lab-based DM studies using mouse models.

Dr. Wheeler recently received a one-year grant through MDF to develop new serum-based biomarkers in adults and children with type 1 and 2 myotonic dystrophy (DM1 and DM2) for use in therapeutic trials. (For more about MDF grants, see Fellows & Grant Recipients. Additionally, information about the Wyck Foundation and its related grantees is available).

Searching for DM Biomarkers in Body Fluids

Dr. Wheeler’s grant, which runs from November 2016 through October 2017, will allow him and his team to begin initial exploration of the viability of developing DM biomarkers that can be measured in blood and urine, reducing or avoiding the need for muscle biopsies – which are invasive and risky – to support data collection in clinical studies and trials.

Dr. Wheeler will examine differences in extracellular RNA that are associated with DM1 and DM2 compared with healthy controls, and look for possible changes in these RNA forms and levels that correlate with disease activity or treatment response.

"We’re looking for extracellular RNA in blood and urine," Wheeler says. "A few years ago, a colleague here found that blood has extracellular RNAs that can serve as biomarkers for brain tumors," Wheeler says. "We’re going to be adapting the approach of the study that looked for markers of brain tumors and use that for myotonic dystrophy. We’re examining gene expression, splicing, microRNAs, and things like that."

Dr. Wheeler and colleagues will be studying extracellular RNA in adults and children with DM1 and DM2, in collaboration with neurologist Basil Darras at Boston Children’s Hospital.

The collaboration with Dr. Darras, who sees more pediatric patients than does Dr. Wheeler, is important, Wheeler says, “because this enables us to expand the study in children. Muscle biopsies in children require general anesthesia, he notes, “and that’s something you want to avoid in myotonic dystrophy, because patients can have a difficult time coming out of it. So, if we’re successful, we may be able to include children [in clinical trials] much earlier than originally thought.”

Early Years in the Clinic and Lab

Wheeler, who graduated from the University of Washington School of Medicine in 1995 and then completed a neurology residency at that institution, first became interested in muscular dystrophy research during a fellowship in neuromuscular medicine at Johns Hopkins University.

He then moved to Stanford University to work with Tom Rando, M.D., Ph.D., on developing nonviral gene therapy for Duchenne muscular dystrophy. Then, as now, the potential for unwanted effects associated with using viral vectors as gene delivery vehicles was well understood, and the Rando lab was looking to reduce this downside.

"We were doing plasmid and oligo work," Wheeler recalls. "[Dr. Rando] was using a type of non-viral gene therapy called antisense for gene correction of point mutations in a mouse model of Duchenne muscular dystrophy.  It involves using an oligo that’s complementary to the region across the point mutation except it has the correct base."

After three years at Stanford, Wheeler took advantage of an opening at the University of Rochester (N.Y.) to switch gears and study DM. “I knew what myotonic dystrophy was," he says, “but I had never done any research on it. I moved to Rochester, took what I learned about nonviral gene therapy from Tom, and applied it to myotonic dystrophy.”

"We ended up getting antisense to work for exon skipping to eliminate myotonia [in a DM mouse model]. The chloride channel RNA is misspliced in myotonic dystrophy. There’s an exon included aberrantly in the disease state. So if you use antisense to induce skipping of that exon, that can potentially rescue the myotonia, because you’d be restoring the normal chloride channel RNA, and that leads to a normal chloride channel protein. We did that in mice, and it worked beautifully.”

Correction of chloride channel splicing wasn’t taken forward into drug development, Wheeler says, "because there’s much more to myotonic dystrophy than myotonia. You’d eliminate the myotonia, but ultimately you’d be doing nothing for the rest of the symptoms."

It did, however, provide evidence that antisense could be an effective therapy, setting the stage for therapy development to target the fundamental DM1 RNA defect – expanded CUG repeats in the DMPK gene. “In parallel, we were working on CUG targeting,” Wheeler says of his Rochester work. “We were doing them both at the same time, and we finished the chloride channel work first. But we knew that the CUG targeting was working in the mice and that that could be a long-term answer.”

Developing Antisense for DM1 Treatment 

At first, the Rochester team’s goal was to develop antisense against the CUG repeat expansion in the DMPK gene. "We originally were using antisense that was targeting the repeat expansion directly," Wheeler recalls, "and the concern was that there are other genes that have shorter CUG repeats where that could interfere. We didn’t really find that in mice, but it was a theoretical concern."

Then came involvement with Ionis Pharmaceuticals, a Carlsbad, CA-based biotechnology company specializing in RNA-targeted drug discovery and development. 

"We tried some of the Ionis drugs that they developed earlier, but they didn’t really work very well," Wheeler says. "Then Ionis suggested we try their gapmer approach, and that worked incredibly well." A gapmer, he explains, refers to the design of the antisense. “The antisense has modified RNA at the 3-prime and 5-prime ends, separated by a central gap of DNA. When the oligo binds to the target RNA, you get a DNA-RNA heteroduplex that is recognized by RNAse H, which cleaves it. When the cleavage happens, the rest of the transcript is degraded by exonucleases." Non-gapmer antisense compounds, he explains, "just bind to the target and kind of sit there."

Unlike earlier antisense approaches for DM1, the Ionis gapmer approach did not directly target the CUG repeat expansion. "It targets outside the repeats," Wheeler says, thus removing the risk of inadvertent binding to CUG repeats in other genes. And, since RNAse H is located in the nucleus, the strategy preferentially targets aberrant DMPK RNA transcripts, which get stuck in that location, while normal DMPK RNA quickly leaves the area. "Transcripts that have a prolonged dwell time in the nucleus appear to be more susceptible,” he notes, although “potentially, the gapmer still could target the pre-messenger RNA of DMPK alleles with non-expanded repeats [normal alleles], so that is one of the things we’ll be watching in the clinical trials."

A phase 1-2 trial of IONIS-DMPKRx-2.5 in adults with DM1, testing the gapmer antisense against DMPK RNA at multiple U.S. centers, opened in 2014. It ended in late 2016, with results reported in January 2017. “I know that Ionis has taken great steps to test the safety ahead of time, and it’s been very effective in mice and other preclinical models of DM1,” Wheeler says. While the Ionis clinical trial did not achieve sufficient drug levels in skeletal muscle, they are exploring two other antisense oligonucleotide molecules that show promise of greater potency.

Move to Harvard

As fruitful and exciting as his time at the University of Rochester was, Wheeler was eager to expand his lab-based research and begin clinical work in DM and other muscular dystrophies. With that in mind, in 2013, he relocated to Massachusetts General Hospital and Harvard Medical School.  “It was just a great professional opportunity,” he says. “It was a natural step. In Rochester, I was doing no clinical work. Here I have a research lab that focuses on developing new biomarkers, including this new clinical project [for biomarker identification], as well as studying the factors that make muscles weaker and identifying new treatments for myotonic dystrophy. I also have an all-ages clinic every week and a pediatric clinic twice a month where I see patients with both types of myotonic dystrophy and all other forms of muscular dystrophy.”

Improving and Expanding Clinical Trials

“I’m optimistic that [antisense oligonucleotide therapies] will be safe and have some therapeutic effects,” Wheeler says. “I guess the question is to what extent the knockdown of the expanded repeat RNA will reverse the symptoms. In someone with mild symptoms, the drug may have a tremendous effect and slow progression.  But how will it work for patients who have a greater degree of weakness, more muscle atrophy, or problems walking?  Will the drug be able to improve their function at all? Or will we need to develop second-line therapies, the way the Duchenne dystrophy field is doing?”

Downstream effects of the expanded CUG repeats that appear to contribute significantly to disease symptoms include functionally low levels of the MBNL proteins and abnormally high levels of the CELF1 protein. Increasing MBNL activity and reducing total CELF1, preferably with small molecules, might add a lot to antisense therapy, Wheeler notes. “A small molecule that you could take by mouth would be ideal,” he says. “Until we have something that is proven to be highly effective, I think we should continue developing new therapies that target the disease from different angles.”

Continuing clinical trials of new DM therapies, including those for children, will require reliable biomarkers of disease activity, preferably markers accessible in blood or urine rather than muscle markers that require biopsies. 

“The plan is to begin the process of identifying biomarkers,” Wheeler says of his new grant. “That was one of the goals described by MDF. They want to find a project that is working toward biomarkers that will be on track to get qualified by the Food and Drug Administration (FDA).  

“The goal that I have is to try and reduce the need for muscle biopsies by looking at biofluids, so that there’s no anesthesia, no incision, no scarring, and no bleeding risk. This would allow monitoring during the treatment trial instead of waiting until the end.

“We had our first contact with the FDA back when the grant was submitted, which was in June [2016]. I think that no one expects that we’re going to have a biomarker or a group of biomarkers by the end of the year, but we’re going to be working toward that goal.”

For more about Dr. Wheeler’s MGH-based research, see Wheeler Muscular Dystrophy Research Lab. For information about muscular dystrophy clinics for adults, call (617) 726-3642; for children, call (617) 643-4645. Recruitment for the biomarker study is being done through the clinics.

Construction of a conceptual framework that integrates phenotypic, cellular and molecular data in DM is a critical step in developing a robust and diverse pipeline of candidate therapies. Although basic science has mechanistically linked the inherited repeat expansions to DM1 and DM2 phenotypes, there are critical gaps in understanding of disease mechanisms. A recent publication extends our understanding.

Dr. Perrine Castets, Prof. Michael Sinnreich and colleagues at the University of Basel recently studied the notion that perturbation of skeletal muscle metabolic pathways, including those responsible for protein degradation (ubiquitin-proteasome system and autophagy), plays an important role in DM. Their results, published in the Journal of Clinical Investigation, establish that (a) DM1 muscle is characterized by an altered response to energy/nutrient deprivation and that (b) dysregulation of AMPK/mTORC1 signaling, at least in part, underlies the altered metabolic state and its role in the pathogenesis of DM1 skeletal muscle. Importantly, these findings suggest new targets for drug discovery and development.

In studies of the HSALR mouse model of DM1, the investigators showed that a normal molecular response to fasting, AMPK activation and mTORC1 inhibition, is compromised in HSALR mice. Consistent with these findings and the interrelated role of AMPK and mTORC1 in autophagy, experimentally induced autophagy was disrupted in HSALR muscle. Deprivation of energy and nutrient supply in DM1 patient myotubes also produced data consistent with dysregulated autophagy. Finally, targeting either AMPK (with AICAR) or mTORC1 (with rapamycin) signaling improved muscle strength, splicing and/or myotonia in HSALR mice.

While the AMPK agonist, AICAR, disrupted nuclear foci and reduced myotonia, along with partial normalization of splicing (correction of Clcn1, but not Atp2a1 and Camk2b) in HSALR mice, rapamycin’s, an mTORC1 inhibitor, normalization of muscle function was not accompanied by correction of mis-splicing.

Many of the therapeutic strategies under development for DM are based on restoration of dysregulated alternative splicing. The study by the University of Basel group further supports those strategies, but also characterizes a key metabolic defect in DM1 muscle and identifies the mTORC1 pathway as an alternative, splicing-independent target for therapy development.

Thus far, nearly all of the therapy development programs in DM address the muscle phenotype. Recent studies show that the mTOR pathway may be an important target in developmental intellectual disorders, and two mTOR inhibitors have regulatory approval for other indications (Novartis' Everolimus and Wyeth's Sirolimus (rapamycin)). Drugs targeting mTORC1 then may have efficacy for both the skeletal muscle and cognitive symptoms of DM1 and thus their potential should be explored via rigorous efficacy studies in appropriate preclinical models.

Reference:

Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I.
Brockhoff M, Rion N, Chojnowska K, Wiktorowicz T, Eickhorst C, Erne B, Frank S, Angelini C, Furling D, Rüegg MA, Sinnreich M, Castets P.
J Clin Invest. 2017 Jan 9. pii: 89616. doi: 10.1172/JCI89616. [Epub ahead of print

In November, MDF staff met with the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the National Institute of Neurological Disorders and Stroke (NINDS) senior leadership and program/policy staff to discuss research opportunities and federal support for myotonic dystrophy (DM). Discussions focused on two areas: the scientific workforce and biomarker and registration endpoint development.

MDF reviewed efforts to support the scientific workforce through the MDF Postdoctoral Research Fellowship program and expressed support for NIAMS and NINDS efforts to extend their R01 paylines for new investigators. Dr. Steve Katz, Director, NIAMS, noted that 58% of K award recipients successfully transition to R type awards and encouraged clinical researchers in DM to utilize the K award mechanism. Dr. Walter Koroshetz, Director, NINDS, noted that 22 academic medical centers currently held NINDS R25 awards to support resident’s research in neurology; he encouraged faculty working on DM at these medical centers to take full advantage of the R25 awards.

MDF also encouraged NIAMS and NINDS to consider mechanisms to support young faculty seeking to renew their initial R01 awards. This is often a critical stage for young investigators (and NIH data bear that out), as they have had to set up their lab, produce on proposed projects, and gather preliminary data for specific aims of the renewal within the initial five or fewer years of funding. The NIAMS and NINDS directors indicated that they were sensitive to the issue. Dr. Katz noted the NIAMS STAR Program (Supplements to Advance Research from Projects to Programs). This program provides up to $150,000 per award in administrative supplements to young faculty on their initial R01 who need additional time and data to obtain either a renewal or a new R01 award. Young faculty with an initial R01 from NIAMS should review the program announcement.

MDF staff also reviewed the Foundation’s role in addressing opportunities and challenges along the entire therapeutic development pipeline. The potential for development and qualification of biomarkers for use in early phase clinical development was highlighted as a timely opportunity in DM. Likewise, overcoming the challenges in developing registration endpoints for drugs and biologics under development for DM were identified as a critical need.

NIAMS Staff pointed to RFA-AR-17-009, Research Innovations for Scientific Knowledge (RISK) for Musculoskeletal Diseases (R61/R33), a program designed for high-risk projects, as a potential means of funding biomarkers and clinical endpoints in DM. NINDS has a continuing program targeted at clinical trial readiness (including biomarker and endpoint development): PAR-16-020, Clinical Trial Readiness for Rare Neurological and Neuromuscular Diseases (U01).

Since the NIAMS initiative has only one application date, and the NINDS initiative is intended for mature projects, such as biomarker qualification efforts, MDF staff strongly encouraged both institutes to consider an initiative to facilitate early discovery and development of biomarkers and endpoint measures for DM. MDF believes the existing funding opportunities are important, and should be considered by investigators, but noted that early stage discovery projects in these areas may not compete well with hypothesis-driven applications and that a targeted initiative is a critical need for the DM field.

Taken together, MDF will remain engaged with the NIH, meeting on a regular basis to ensure that opportunities and critical needs in the DM field receive attention. DM researchers are encouraged to make opportunities and needs known to MDF staff so they can be incorporated into discussions with NIH leadership and program staff.

There has been relatively little research on quality of life for DM2 patients, and DM2 is often considered “less severe” than DM1. However, a new study identified a subset of DM2 patients who are impacted as severely as those with DM1.

Dr. Dusanka Savic-Pavicevic and colleagues recently published a comparison of genetically confirmed DM2 and DM1 patients using a variety of quality of life measures.

The research team found no differences between DM2 and DM1 in the overall and physical composite scores of the survey.

Emotional and mental composite scores were typically better in DM2 patients, as were independence and body image scores. Disease impact on cognition, strength, heart function, breathing and cataracts were also less severe in DM2.

The DM2 patients who reported worse scores were typically older, weaker, and had higher fatigue levels than the DM2 patients who scored better on certain segments of the surveys. Lower quality of life scores were also associated with lower cognitive achievement, memory impairment and lower educational levels.

A deeper understanding of the correlation of age, strength, and fatigue with quality of life in DM2 is needed to facilitate better patient outcomes. More DM2 studies like this will pave the way for higher quality care.

Reference:

Quality of life in patients with myotonic dystrophy type 2.
Rakocevic Stojanovic V, Peric S, Paunic T, Pesovic J, Vujnic M, Peric M, Nikolic A, Lavrnic D, Savic Pavicevic D.
J Neurol Sci. 2016 Jun 15. 

A panel of physical therapy professionals and people living with DM discuss ways to stay physically fit.

Panel discussion by Dr. Katy Eichinger, PT, DPT, University of Rochester; Mike Hamlin, DM Community Member; Dr. Leslie Krongold, EdD, Myotonic.

Researchers at the University of Virginia recently published a paper describing a biological pathway they believe is affected in people with myotonic dystrophy (DM). Previous studies have identified the DNA mutations causing both types of DM, and determined that the RNA molecule made from the DNA is the culprit in causing toxicity in the cell and leading to symptoms of DM.

Though DM symptoms such as myotonia have been linked to the toxic RNA molecule, other symptoms such as muscle weakness and muscle wasting have not been fully explained. This study identifies a possible pathway, the TWEAK/Fn14 pathway, which appears to be activated in DM mouse models and in muscles of people with DM1. The authors suggest this pathway may be responsible for muscle degeneration in DM1, and that blocking the pathway might prove beneficial. A drug blocking this pathway, known as the anti-TWEAK antibody, is currently in trials for other diseases.

When the anti-TWEAK antibody was tested on a very small sample of DM mouse models, there were improvements in muscle appearance and function. However, the treatment was not sufficient to reverse myotonia or cardiac conduction defects in the mouse models. The authors concluded that the treatment will likely not cure myotonic dystrophy, but instead may be better suited for a therapeutic approach involving a combination of experimental treatments.

Further analysis is necessary to determine whether the TWEAK/Fn14 pathway and targeting it in individuals with DM1 provides a worthwhile therapeutic strategy. The pharmaceutical company Biogen Idec and the Mahadevan Lab at the University of Virginia have been conducting an investigative collaboration for several years studying the pathway and the anti-TWEAK molecule. Anti-TWEAK may be used at some point in the future to target specific diseases that may or may not include DM, but plans and dates have not been formulated. MDF will keep the community apprised if developments become available.

05/21/2015