Small Molecule Approaches to DM1

A variety of small molecules have been evaluated in models of DM1 as putative therapeutics. Small molecules have the advantage of chemical optimization of drug-like traits, including blood-brain barrier permeability, and thus are attractive for multisystemic disorders like DM1.

Prior studies of the small molecule, pentamidine, and its analogs showed efficacy in restoring splicing defects in DM1 cells and animal models and suggested that the mechanism of action was binding to and inhibition of transcription of the expanded repeat transcript (Coonrod et al., 2013). Chemical modification/analysis of structure-activity relationships of the pentamidine backbone led to identification of the more efficacious and less toxic molecule, furamidine (Siboni et al., 2015).

In evaluation of compounds for marketing approval, FDA and other regulatory agencies regard understanding of the molecular target and mechanism of action as important factors in establishing confidence in the efficacy and safety of candidate therapeutics. Thus, mechanistic studies, using cell and animal models in preclinical studies and molecular markers in clinical trials, represent important steps in evaluation of candidate therapeutics for DM.

Mechanism of Action of Furamidine

Dr. Andy Berglund (University of Florida) and colleagues have built upon their prior work with pentamidine analogs to examine the mechanisms of action (MOA) of furamidine in DM1 models (Jenquin et al., 2018). Dr. Leslie Coonrod, a former MDF Postdoctoral Fellow, was a coauthor on the publication. Information on the structure, properties, vendors, publications, and patents around furamidine is available in the public chemical database, PubChem. Overall the research team reported promiscuous activity for furamidine, potentially impacting multiple pathways in restoring the splicopathy that characterizes DM1.

Furamidine was evaluated in HSA^LR mice for safety and impact upon gene expression and splicing and in DM1 myotubes for safety and impact on splicing. Head to head comparisons were made with another pentamidine analog, heptamidine.

In the HSA^LR model, furamidine (daily, over 7 days) reduced HSA transgene levels and rescued multiple splicing events, suggesting binding of CTG•CAG expanded repeats and transcription inhibition as an important MOA for the drug. In comparison to heptamidine, furamidine rescued more splicing events in the mouse model. Evaluation of furamidine in a patient myoblast line (~2900 repeats) also showed partial rescue of the characteristic mis-splicing pattern. Although dose-limiting toxicity was seen in the cell line studies, efficacy on splicing was obtain at 10x and greater multiples below toxic dose—this was confirmed in follow-up cell toxicity assays. However, in the cell-based assays and in contrast to the HSA^LR data, the impact of the drug on CUG RNA levels was modest.

In additional studies with the human DM1 cell lines, data suggest that furamidine reduces nuclear foci and disrupts the binding of MBNL1 to expanded CUG repeats. Yet, at higher concentrations, furamidine exacerbated mis-splicing while producing a significant reduction in nuclear foci—a finding that the research team first interpreted as drug-induced reduction of MBNL levels; this hypothesis was not confirmed as transcript and protein levels were increased by furamidine treatment.

Assessing a Complex MOA

Taken together, furamidine exhibited a complex MOA, with both similar and discordant findings in cell vs. animal models and across a 100-fold dosing range studied by the research team. They conclude that its primary MOA in the HSA^LR mouse appears to be inhibition of transcription of the expanded repeat, but cannot exclude disruption of MBNL from expanded CUG repeat binding. By contrast, the team posits that increased levels of MBNL proteins and furamidine-induced disruption of the MBNL–CUG complex represent the primary MOA for splicing rescue in patient cell lines. Differences in the pathways engaged by the effective drug concentrations at the target tissues (i.e., tissue bioavailability/exposure) may, at least in part, explain differences in MOA findings in the two models.

Reference:

Reducing levels of toxic RNA with small molecules.
Coonrod LA, Nakamori M, Wang W, Carrell S, Hilton CL, Bodner MJ, Siboni RB, Docter AG, Haley MM, Thornton CA, Berglund JA.
ACS Chem Biol. 2013 Nov 15;8(11):2528-37. doi: 10.1021/cb400431f. Epub 2013 Sep 27.

Biological Efficacy and Toxicity of Diamidines in Myotonic Dystrophy Type 1 Models.
Siboni RB, Bodner MJ, Khalifa MM, Docter AG, Choi JY, Nakamori M, Haley MM, Berglund JA.
J Med Chem. 2015 Aug 13;58(15):5770-80. doi: 10.1021/acs.jmedchem.5b00356. Epub 2015 Jul 21.

Furamidine rescues myotonic dystrophy type I associated mis-splicing through multiple mechanisms.
Jenquin JR, Coonrod LA, Silverglate QA, Pellitier NA, Hale MA, Xia G, Nakamori M, Berglund JA.
ACS Chem Biol. 2018 Aug 17. doi: 10.1021/acschembio.8b00646. [Epub ahead of print]

Respiratory dysfunction is a major contributor to morbidity and mortality in DM. An evidence-based approach is essential to understanding the underlying risk factors and appropriate actions in management of respiratory status in DM patients. Such an understanding of the natural history and relative value of interventions for respiratory dysfunction is also essential in the design of interventional clinical trials. Careful natural history studies are the path forward to improved clinical care and informed clinical trials.

Understanding the Risk Factors Behind Respiratory Function in DM1

Dr. Ghilas Boussaïd (Hôpital Raymond Poincaré, Garches, France) and colleagues have evaluated the relationship of DM1 genotype and other respiratory function determinants in the progression of respiratory dysfunction. Their prospective observational study provided data on 283 subjects, followed for five years or until loss to follow-up, for regression modeling of functional changes over time.

Respiratory function parameters associated with CTG repeat length were determined via a multivariate linear regression analysis. Higher peak cough impairment and lower vital capacity and maximum inspiratory pressure were associated with longer CTG repeats. Observed decline over time in vital capacity was associated with longer CTG repeats, older baseline age, and higher baseline BMI values. Longer CTG repeats also correlated with larger decreases in maximum inspiratory pressure, maximum expiratory pressure, and increased risk of death. Very long repeats (>1000) were associated with annual vital capacity declines as high as 36%--these rapid declines flag adult CDM patients for very close respiratory monitoring.

Impact of Respiratory Care

Non-invasive ventilation was in use for 13% of study subjects at baseline and was initiated in 41% of the remaining subjects during follow-up. Decision to initiate non-invasive ventilation was associated with lower peak cough flow after accounting for age and arterial CO₂ tension. Non-invasive ventilation improved vital capacity. The authors posit that closer respiratory follow-up is warranted for patients with long CTG repeats and/or high BMI. They also noted the compliance issues with non-invasive ventilation in DM1 patients and highlighted the importance of considering sociological and psychological variables in future studies of respiratory function and non-invasive ventilation.

Taken together, the authors established that long CTG repeats are associated with a more severe respiratory phenotype and faster functional decline. Obesity was also identified as an important risk factor for respiratory status. They did not identify an association between non-invasive ventilation and many measure of improvements in respiratory status, but concede limitations in this study. Overall, starting early with regular peak cough flow assessments and following patients closely, particularly in adults with CDM, were seen as an effective means of reducing risks of respiratory dysfunction.

References:

Genotype and other determinants of respiratory function in myotonic dystrophy type 1.
Boussaïd G, Wahbi K, Laforet P, Eymard B, Stojkovic T, Behin A, Djillali A, Orlikowski D, Prigent H, Lofaso F.
Neuromuscul Disord. 2017 Dec 26. pii: S0960-8966(17)30524-2. doi: 10.1016/j.nmd.2017.12.011. [Epub ahead of print]

Request for Applications - Development of a Genome Editing Strategy for Myotonic Dystrophy Type 1

MDF is pleased to announce a Request for Applications (RFA) for the Development of a Genome Editing Strategy for Myotonic Dystrophy Type 1. MDF intends to issue two 2-year awards of up to $250,000 total cost each for projects that address the evaluation of genome editing strategies for DM1 that target the DMPK gene.

The focus of this RFA is early stage discovery and development of in vivo genome editing technologies in academic laboratories or other nonprofit research institutions, utilizing state-of-the-art knowledge. The goal is to establish a proof of concept for a therapeutic that is not incremental, but has a substantial level of effect across the multiple body systems impacted by the DM1 disease.

Collaborations between experts in genome editing technologies and those with strong track records in myotonic dystrophy research are strongly encouraged.

Application Details

Applications are due November 30, 2018. Applicants are encouraged to contact Chief Executive Officer, Molly White, with any questions about this RFA or the scientific content of their proposals. Technical issues should be directed to MDF Grants Manager Elizabeth Habeeb-Louks.

Click here to read the full Request for Applications; access the RFA Cover Sheet. Read summary report from the 2018 MDF Gene Editing Workshop.

We’ve all been there. A truly innovative idea falls out of a routine experiment and you seek funding for this high risk/high reward project that could represent a paradigm shift for the field. Then the reality sets in—innovation without a strong basis in an existing conceptual framework or without sufficient preliminary data is not often valued by study section members.

Program Announcement with special review

Over the years, NIH has tried a variety of grant mechanisms to encourage non-incremental research that is truly innovative. NIAMS has just re-issued their Program Announcement with special review (PAR) to support disease-focused translational studies based upon “innovative ideas of high potential value, especially those in their early stage of development that may not fare well otherwise in peer review.” These announcements focus on musculoskeletal diseases and thus represent an excellent opportunity to push the research envelope in myotonic dystrophy. The PARs give clear examples of the type of work that can be supported through these grant mechanisms—potential applicants are strongly encouraged to consult that section of the PAR. See the links to the PARs below.

Mechanisms of PAR

One of these NIAMS PARs uses the X02 mechanism—this solicits what are essentially pre-applications, to determine if your idea is a fit for both the funding opportunity and NIAMS’ mission. It is not necessary to first submit an X02 before applying for funding, but this mechanism is a means of getting formal feedback before preparing a full application.

The primary solicitation in this program uses the two-phase R61/R33 mechanism. The R61 phase can extend up to two years and is intended to rigorously test the proposed concept or hypothesis. Transition to the R33 phase is based upon achievement of milestones based on unambiguous confirmation of the central hypothesis. The R33 then extends the work for an additional year, to further validate the innovative concept. Funding level is up to $250,000 total direct costs/year.

Although identified as “translational” research, there are two important points. First, translation appears to be broadly defined as exploration of disease mechanisms is included, as is development/testing of diagnostics, therapeutic agents, or preventive interventions (preclinical work only). Second, the caution is that innovation must be the central component, so, for example, routine testing of a candidate therapeutic may or may not fit the intent of the PAR. Consult the Program Director.

DM Grant Applications Strongly Encouraged

NIAMS program staff strongly encouraged the notion of grant applications from the myotonic dystrophy field. Staff emphasized that ideas must be high risk/high reward to meet the bar of the PAR. Proposals should test novel hypotheses. X02 pre-applications receive a mail review and significance and innovation are key factors in the review. The R61/R33 full applications are reviewed by a Special Emphasis Panel (SEP) convened by NIAMS. Here the review emphasis is on innovation and applications should be designed to establish proof of concept in the R61 phase as a milestone for transition to the R33. SEP review helps ensure that study section members understand the intent and ground rules of this grant mechanism. Applications that are not sufficiently innovative or do not have a grounding premise are unlikely to score well.

Investigators interested in this grant program are strongly encouraged to contact Dr. Tom Cheever (thomas.cheever@nih.gov), the NIAMS Program Director responsible for funding in myotonic dystrophy. Some of you may also know Dr. Amanda Boyce (boycea@mail.nih.gov), since she is NIAMS’ Program Director for muscle biology grants—Dr. Boyce is the primary contact on the PARs. This is a very non-traditional and nuanced program and their feedback will be essential for applications to be successful.

For More Information:

NIAMS: Pre-Application: Research Innovation for Scientific Knowledge (RISK) for Musculoskeletal Diseases (X02 Clinical Trial Not Allowed)
https://grants.nih.gov/grants/guide/pa-files/PAR-18-865.html
Deadlines: October 4, 2018; July 3, 2019 (required letters of intent deadlines: September 4, 2018; June 3, 2019)

NIAMS: Research Innovations for Scientific Knowledge (RISK) for Musculoskeletal Diseases (R61/R33 Clinical Trial Not Allowed)
https://grants.nih.gov/grants/guide/rfa-files/RFA-AR-19-013.html
Deadlines: April 9, 2019; January 9, 2020

A Core Issue for Understanding DM—How MBNL Interacts with RNA

Given the disease mechanisms that are operative in DM, an understanding of how the RNA-binding protein, Muscleblind (MBNL), interacts with pre-mRNA to regulate alternative splicing is essential. Recent studies have shown that MBNL exhibits differential dose-response relationships across the various gene translation events that it regulates in health and disease. It is as yet unclear precisely how the structure of the pre-mRNA itself contributes to patterning of MBNL-dependent alternative splicing.

RNA Structural Properties May Impact MBNL Binding and Functionality

MBNL’s normal function in alternative splicing, and perturbations of those functions in DM, is governed in part by the tissue-specific distribution and expression levels of its three isoforms (MBNL1, MBNL2, and MBNL3) during pre- and post-natal development. Yet, the structural properties of the pre-mRNAs that MBNL regulates may, themselves, play critical roles in the binding affinity and efficiency of MBNL-directed alternative splicing. A new publication looks at the MBNL—pre-mRNA interactions with the goal of understanding how transcript properties influence alternative splicing.

While the nature of MBNL-binding motifs has been well-characterized previously, Dr. Krzysztof Sobczak’s group (Adam Mickiewicz University—Poland) and their colleagues at the University of Florida show here the structural organization of the RNA regulatory elements in target pre-mRNA may play a more important role. An MDF fellow, Lukasz Sznajder, contributed to this work.

The team demonstrated the importance of target RNA structure in showing that both MBNL binding and splicing activity are regulated by the number and structural arrangement of UGCU motifs, but, while splicing regulation is affected by the distance between UGCU motifs, that outcome is not a function of differences in binding efficiency. MBNL binding patterns are altered, however, when the MBNL binding sites are included in an RNA hairpin. Furthermore, modifications of target RNA secondary structure showed that structuring the same RNA binding site differently leads to altered MBNL1 binding and splicing regulation activity. In tissues expressing multiple MBNL paralogs, the team detected competitive interactions that influenced splicing events.

Modeling Regulation of Alternative Splicing by MBNL

The modeling of MBNL regulation of alternative splicing now has at least two components. Component 1—it has already been clear that the spectrum of MBNL-modulated alternative splicing events are differentially sensitive to free MBNL levels. Component 2—these latest findings extend understanding of regulatory control by showing that structural properties of the pre-mRNA targets also represent a key determinant of splicing event sensitivity to free MBNL. Moreover, tissue specificity in alternative splicing is now seen to derive from the MBNL paralogs that are expressed and interactions among those paralogs. An understanding of MBNL protein interactions and of how pre-mRNA structure impacts binding and functional activity of the MBNL paralogs may be critical in efforts to design effective therapeutic strategies for DM.

Reference:

MBNL splicing activity depends on RNA binding site structural context.
Taylor K, Sznajder LJ, Cywoniuk P, Thomas JD, Swanson MS, Sobczak K.
Nucleic Acids Res. 2018 Jun 28. doi: 10.1093/nar/gky565. [Epub ahead of print]

An Ophthalmological Perspective on DM1

When considering the spectrum of organ system involvement in DM1, the list of ophthalmological considerations is usually short—cataracts being the major concern, but also ophthalmoplegia (including ptosis) and extraocular muscle myotonia (see MDF’s website for a review of ocular issues in DM). Some reports have suggested the co-occurrence of DM1 and Fuchs’ endothelial corneal dystrophy (FECD), a disease, like DM1, that is linked to an expanded CTG repeat (in TCF4 rather than DMPK) and MBNL sequestration along with expanded CUG RNA in nuclear foci. Identification of this pathophysiologic mechanism link between the two diseases suggests that the RNA gain-of-function in DMPK that produces DM1 may also put these patients at risk for FECD.

A Prospective Study of DM1 Patients for FECD

Due to the mechanistic similarities between DM1 and FECD—that both are RNA gain-of-function diseases resulting from MBNL sequestration by expanded trinucleotide repeats—Dr. Keith Baratz (Mayo Clinic) and colleagues prospectively evaluated 26 subjects from 14 DM1 families for phenotypic FECD and expanded repeats in DMPK and TCF4.

The research team identified five genotypically and phenotypically DM1 probands with phenotypic FECD (36%), a prevalence that greatly exceeded the prevalence of FECD in the at-risk age group in the general population (5%). Genotypic evaluation of samples available from 4 probands failed to show expanded CTG repeats in TCF4—thus each was phenotypically FECD without the normally associated genotype—but each had repeat expansions in DMPK. Co-segregation of DM1 and FECD was found in 12 additional family members; none of the affected individuals had expanded repeats in TCF4. Finally, RNASeq evaluation of RNA samples from the corneal epithelia of a FECD-affected and an unaffected subject confirmed target tissue expression of both DMPK and TCF4.

Monitor DM1 Patients for Development of FECD

These data suggest that DM1 patients are at risk for phenotypic FECD even though they lack the disease-causing expanded repeat in TCF4. Sequestration of MBNL and disruptions to alternative splicing patterns appear to be the commonality to the two diseases. Chromsomal location of the MBNL-sequestering pathogenic expanded repeat sequence then may not be essential in causation of either disease. The research group did not find an association between clinical/genetic traits of DM1 and the presence/severity of FECD—but they acknowledge that such analyses would likely require a considerably larger cohort. Finally, since TCF4 is broadly expressed (including a putative role in CNS development and linkage to the neurodevelopmental disorder, Pitt-Hopkins Syndrome), the converse might be true—that FECD patients are at risk for DM1—but there does not appear to be any available information addressing that hypothesis, perhaps due to tissue expression levels of TCF4.

Reference:

Fuchs' Endothelial Corneal Dystrophy in Patients With Myotonic Dystrophy, Type 1.
Winkler NS, Milone M, Martinez-Thompson JM, Raja H, Aleff RA, Patel SV, Fautsch MP, Wieben ED, Baratz KH.
Invest Ophthalmol Vis Sci. 2018 Jun 1;59(7):3053-3057. doi: 10.1167/iovs.17-23160.

Impact of “Pure” versus Variant Expanded Repeats in DM1

A key driving factor behind DM1 is the instability of expanded CTG repeats in DMPK, resulting in both germline and somatic expansions in repeat length that, in turn, reduce age of symptom onset and increase disease severity. Prior studies have noted that 3-5% of DM1 patients have their expanded CTG repeats interrupted by short runs of CCG, CTC or GGC repeats. Such allelic variants may impact genetics-based diagnostic methodologies, repeat stability, and DM1 phenotype.

Analysis of Variant Repeats in a Scottish Cohort

Drs. Sarah Cumming and Mark Hamilton (University of Glasgow and Queen Elizabeth University Hospital--Glasgow) and colleagues recruited and evaluated 251 adult DM1 subjects from four major clinical genetics centers to assess for the presence and impact of variant-containing CTG expansions that exceeded the normally pathogenic length threshold. Since they found that more common technologies were inadequate to detect allelic variants, research subject allelic structures were determined using the PacBio RS II sequencing platform.

The research team identified three DM1 families each with one individual with prior genetic diagnosis of DM1 that was then subjected to variant screening. Phenotypically, each had either no muscle signs or only mild signs of the disease (note: each had their genetic evaluation based upon familial history, not symptoms). Each was found to have paternally-transmitted, de novo CCG repeats near the 3’ end of their expanded CTG tracts. When comparing these three subjects to symptomatic DM1 subjects with similar estimated progenitor allele lengths, the team observed less somatic expansion in blood samples from those with variants. Returning to the full Scottish cohort for variant repeat sequencing, 18 total subjects were identified with variant-containing CTG expansions in DMPK.

Criticality of Understanding DM1 Allelic Variants

Since estimated progenitor allele length was similar between those with CCG repeat variants and patients with earlier onset/more severe DM1, these data lend further support for the argument that somatic expansion plays a vital role in the pathogenesis of DM1.

Genotypic modifiers have been implicated in phenotypic variations in neuromuscular diseases. Their impact can alter dramatically alter disease progression—e.g., LTBP4 and SPP1 variants alter muscle strength and ambulation in DMD—and thus is critical to understand for genetic counseling and clinical trials design. In the case of these findings from the Glasgow team, it is a sequence disruption in the disease-causing CTG repeat expansion that acts as the modifier, serving to mechanistically interfere with somatic cell repeat expansion. Although definitive conclusions are not provided by their data set, the investigators noted that germline transmission also may be significantly different in subjects with variant-containing CTG repeat expansions.

Finally, with the advent of new genomic technologies (including genome editing), knowledge of mechanisms underlying phenotypic differences between patients with “pure” versus variant expanded repeats may yield insights into novel drug discovery and development strategies for DM1.

Reference:

De novo repeat interruptions are associated with reduced somatic instability and mild or absent clinical features in myotonic dystrophy type 1.
Cumming SA, Hamilton MJ, Robb Y, Gregory H, McWilliam C, Cooper A, Adam B, McGhie J, Hamilton G, Herzyk P, Tschannen MR, Worthey E, Petty R, Ballantyne B; Scottish Myotonic Dystrophy Consortium, Warner J, Farrugia ME, Longman C, Monckton DG.
Eur J Hum Genet. 2018 Jul 2. doi: 10.1038/s41431-018-0156-9. [Epub ahead of print]

One of the challenges faced by doctors treating patients with myotonic dystrophy type 1 (DM1)—and drug developers designing clinical trials—is the broad difference in the way the disease manifests itself and progresses from patient to patient. Dr. Guillaume Bassez, a neurologist, member of the MDF Scientific Advisory Committee and head of the Translational Myotonic Dystrophy Research Group at the Institut de Myologie in Paris, has worked to find ways to break the DM1 population into subgroups that might guide treatment decisions and bring more precision to care.

Some patients may be in the grips of the disease at birth, while others may not experience the onset of symptoms until their teens, as young adults, or older. While patients have long been characterized by the severity of their symptoms and the time of onset, doctors still do not have an agreed-upon ways of categorizing patients and using that to tailor care or design clinical trials.

Though Dr. Bassez described DM1 as a continuum, he said the question is whether there are meaningful ways to recognize differences between subgroups of patients within that continuum to better guide treatments and research. Using a national registry of 3,000 DM1 patients in France that he established, he and his colleagues conducted research to inform segmenting the population into two sub-groups, then three, then four. In the end, the team found statistical support for using five subgroups with distinct disease symptom differences based on the age of onset. They are: congenital (birth), infantile (up to 10), juvenile (10 to 20), adult (20-40), and late-onset adult (over 40).

“DM1 is not just a sequence of the same pattern. It’s a complex matrix or patterning,” he said. “Thanks to this registry, this kind of review could be conducted. Because of the large amounts of data, we are now able to refine the clinical phenotype of the diseases.”

It’s not the first time Dr. Bassez has sought ways to determine differences in the way disease the manifests itself and progresses in different portions of the DM1 population. Previous work showed to the surprise of many that the clinical manifestations of myotonic dystrophy (DM) in men and women were different. “We think that stratifying the disease is important for clinical studies and clinical trials,” he said.

The Power of a Registry

During last year’s 11th meeting of the International Myotonic Dystrophy Consortium (IDMC-11) in San Francisco, Dr. Bassez discussed both the case for using these subgroupings as a way to tailor care and develop new approaches to research, and also the patient registry he has developed and efforts to expand it beyond France.

Known as the International DM Standardized Registry, or DM Scope, it is being used to help researchers select and enroll patients in clinical trials. It is also used to create natural histories, validate outcome measures for use in clinical trials, and tease out correlations between patients’ genotype and phenotype.

For now, the registry is a collaboration between French and Canadian researchers who have been focusing on harmonizing their separate databases and standardizing the way data is gathered and recorded. They expect to include the participation of DM researchers in other countries to expand the reach of the registry in the future.

“It’s a powerful tool and an active project. Based on the success of the French-Canadian pilot, we will extend it internationally. We are doing a proof of concept with Canada to show it would be useful for designing clinical studies,” said Dr. Bassez. “We’ve received some interest from European colleagues, but we have to make it a success between France and Canada first.”

Treating Fatigue Without Drugs

At IDMC-11, Dr. Bassez discussed another area of work: He contributed to a four-country study, titled “OPTOMISTIC,” that looked at non-drug approaches to treating DM. This involved the use of cognitive behavior therapy and aerobic exercise as a way to address fatigue and related problems such as sleepiness and inactivity that DM patients experience. Today there is no approved drug for these symptoms.

The study, which took place in France, Germany, the Netherlands, and the United Kingdom, included 255 adult DM1 patients suffering from severe fatigue. In addition to tracking improvements in patients, the researchers sought to identify the most appropriate outcome measures and potential biomarkers that can serve as surrogate measures that correlate with observed clinical variations.

Dr. Bassez presented baseline outcome measures data from the study, which ran for ten months with a six-month follow up without therapy to see if the results are durable or if patients return to baseline over time. An article reporting the results of the OPTOMISTIC study was published in Lancet Neurology in June 2018.

Dr. Bassez, who co-organized IDMC-10 in Paris, said the growth of the IDMC conference reflects the progress that’s been made to understand DM and develop therapies. “There is a growing number of researchers, groups, and labs worldwide fighting the disease and increasing the hope of patients,” he said. “The first one in Paris had 80 people in a single room. There was nothing about therapy during IDMC-1. Now, 30 percent of the content is focused on therapies.”

For the last 15 years, the NIH has funded centers of excellence program mandated in the MD-CARE Act, the Senator Paul D. Wellstone Muscular Dystrophy Research Centers Program. The University of Rochester was the recipient of one of the first, and is the longest continuously funded Wellstone Center. It has taken a flagship role in its focus upon myotonic dystrophy, serving as the hub of the Myotonic Dystrophy Clinical Research Network.

Wellstone Center Primer

The Wellstone Centers Program currently includes six centers of excellence, focusing on the various types of muscular dystrophy. Only one current Wellstone Center, that at Rochester, has a focus on myotonic dystrophy. The Wellstone Centers Program was recently re-competed, with three existing Centers competing with new applicants for awards to start in September 2018.

Wellstone Centers are required to “promote collaborative basic, translational and clinical research and provide important resources that can be used by the national muscular dystrophy research communities.” Each is currently required to be led by an accomplished Director and Co-Director and to include: two or more collaborative projects (at least one focused on clinical research), an administrative core, a scientific research resource core, and a training core. Renewing Centers and new applicants compete in two cycles, with three Centers awarded in each cycle. Awards are made for up to $1M total direct costs/year, for 5 years.

Opportunity for Feedback on Future Course of the Wellstone Centers Program

One outcome of a National Academy of Sciences study is that NIH is required to seek input from stakeholders on large centers of excellence programs, such as the Wellstone Centers. To this end, the NIH has released a Request for Information (RFI) to solicit feedback from all stakeholders on how the Wellstone Program can be enhanced.

The RFI asks for input on the following areas:

1. The Wellstone Centers program’s key accomplishments.
2. The Wellstone Centers greatest challenges.
3. Research and training resources shared by the Wellstone Centers. If you have utilized Wellstone Center resources, please share how you became aware of these resources and your experience with obtaining and using them.
4. Involvement of research participants, their families, health care providers, and other muscular dystrophy community members in Wellstone Center activities.
5. The most compelling research needs in the muscular dystrophy field and the Centers’ potential role in addressing them.
6. Additional opportunities for advancing research in muscular dystrophy within the Wellstone Centers.

Responding to the Wellstone Center RFI

The Wellstone Program represents a major investment in muscular dystrophy research and will optimally serve the myotonic dystrophy community if shaped by the best ideas. MDF strongly encourages those living with muscular dystrophy, their families, clinicians, researchers, advocacy organizations, and other individuals and organizations to review information on the site and respond to the RFI via the link in the announcement below.

Responses are due by August 10, 2018.

NIH Announcement:

Request for Information (RFI): Evaluation of the NIH Senator Paul D. Wellstone Muscular Dystrophy Research Centers Program
(NOT-AR-18-021)
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Heart, Lung, and Blood Institute
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Institute of Neurological Disorders and Stroke

Participants are often frustrated to find that they have limited to no access to their own data from a clinical study or interventional clinical trial. The operative phrase for the participant here is “their own data,” that results from the time, effort, and risks the patient undertakes to participate in clinical research. While their data may collectively contribute toward improving future clinical trials or provide the basis for regulatory decisions for a candidate therapeutic, the study participant views the data as having personal value.

The frustration for participants in learning little of study outcomes lies in feeling abandoned just as the study punch line becomes evident. Yet, potential patient confusion that any “research results” may automatically have reliable clinical value is a confounder to full transparency. To address this controversial issue, the NAS was asked by the Centers for Medicare and Medicaid Services (CMS), the Food and Drug Administration (FDA), and the National Institutes of Health (NIH) to develop a roadmap toward balancing the expectations of participants in clinical research with a careful risk-benefit assessment of the practice of releasing individual results to study participants.

NAS Report Advocates for Better Communication

The NAS put together a committee, bringing together experts in clinical research, informatics, stakeholder engagement, and biomedical ethics (patient representatives were included as reviewers of the report), that worked for a year to produce a 380-page report entitled: “Returning Individual Research Results to Participants: Guidance for a New Research Paradigm.” The report PDF is available at no charge on the NAS website (see link below).

Overall, the NAS report states: “The responsible return of individual research results requires careful forethought and preparation. Thus, the committee recommends that investigators include plans in study protocols that describe whether results will be returned and, if so, when and how and that research sponsors and funding agencies require that applications for funding consistently address the issue. Additionally, institutions and IRBs should develop policies to support the review of plans to return individual research results.” The decision about communicating research results to the patient was conceptualized by the committee as balancing the perceived value of the data to the participant with the feasibility of returning individual data in an understandable fashion. The demands that increased communication will place on the research enterprise are not inconsequential, but the potential benefits for clinical research through improved engagement and trust are considerable.

The NAS report highlights 12 specific recommendations to: facilitate evaluation of the risks and benefits of return individual research results to patients, establish biospecimen management procedures to ensure quality management, establish a decision making process for return of individual research results, ascertain patients preferences and values, guide planning for return of individual research results, effectively communicate individual research results to participants, and help reshape the regulatory environment.

Toward Better Clinical Studies

Taken together, the report seeks to implement changes that will improve collaboration and transparency between clinical investigators and research participants in order to improve the quality and effectiveness of clinical research. The benefits of improved engagement of stakeholders in the clinical research enterprise (e.g., patient-centered research) are already evident in improved study recruitment and retention, evolution of clinically meaningful study endpoints, and, ultimately, more effective care and novel therapeutics. With this report, NAS has broached the next logical step in committing to stakeholder communication. MDF encourages clinical researchers working on DM to read and carefully consider the NAS report.

References:

Returning Individual Research Results to Participants: Guidance for a New Research Paradigm: https://www.nap.edu/catalog/25094/returning-individual-research-results-to-participants-guidance-for-a-new

A series of additional NAS reports under the topic of “Exploring the Treatment of Research Participants” can be found at: https://notes.nap.edu/2018/07/12/treatment-research-participants/.