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.

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.

Gene Editing

The basic science discovery of an adaptive immunity system that evolved in bacteria as a DNA-targeting viral defense mechanism was so revolutionary that early manuscripts from three independent labs were rejected by multiple journals. From that inauspicious beginning, CRISPR/Cas9 technology is rapidly advancing toward clinical trials in multiple disease indications. 

Even that renowned purveyor of scientific knowledge, The New Yorker, has touted the therapeutic potential of CRISPR/Cas9 gene editing (see "The Gene Hackers").

Gene editing is rapidly moving toward clinical trials, indeed ex vivo editing of T-cells in order to target tumors was approved by the National Institutes of Health’s (NIH) Recombinant DNA Advisory Committee (RAC) and trials are anticipated to start in early 2017. By design, the oncology clinical trial largely avoids many potential barriers to CRISPR/Cas9-based therapies—efficiency of gene editing, safety, delivery and ethics. It is not surprising that a disease where ex vivo gene editing is a plausible therapeutic strategy is the first to reach clinical trials.

Possibilities for DM

For myotonic dystrophy (DM), gene editing is an attractive, but currently theoretical strategy for directly addressing the primary genetic defect by excising pathogenic expanded CTG or CTTG repeats. Recognizing that expanded repeats are present in every cell, thereby requiring in vivo gene editing, the DM field must address all of the barriers noted above if clinical trials are to become a reality.

A recent publication from Dr. Bé Wieringa and colleagues takes an important step in assessing the feasibility of CRISPR/Cas9-mediated somatic gene editing for DM. In studies of myoblasts from normal subjects, DM1 patients, and immortalized mouse myoblasts (DM500), the research team explored ways of modulating efficacy of expanded repeat excision. They evaluated both unilateral (from one side of the repeat tract) and dual CRISPR cleavage strategies. 

The group’s findings show specificity in removal of normal and expanded CTG repeats from the DMPK locus. Their dual CRISPR editing approach resulted in unusually large deletions (kilobase size, encompassing the entire expanded repeat) with no adverse biologic consequences for gene expression, DMPK mRNA localization, MBNL distribution or myogenesis. Unilateral cleavage of an unstable genomic repeat was viewed as unadvised, since the ensuing recombination repair may produce unpredictable genomic changes.

The promise of gene editing lies in its objective of stopping downstream pathogenic mechanisms via correction of the primary DNA defect. The challenges lie in establishing safety (putative off-target editing), further optimization of editing efficacy/efficiency, and ensuring bioavailability of CRISPR/Cas9 reagents to tissues impacted by DM. These are not trivial barriers, but the latest findings by Dr. Wieringa and colleagues provide important in vitro proof of concept and thereby represent an important step.

Reference:

CRISPR/Cas9-Induced (CTG⋅CAG)n Repeat Instability in the Myotonic Dystrophy Type 1 Locus: Implications for Therapeutic Genome Editing
van Agtmaal EL, André LM, Willemse M, Cumming SA, van Kessel ID, van den Broek WJ, Gourdon G, Furling D, Mouly V, Monckton DG, Wansink DG, Wieringa B.
Mol Ther. 2017 Jan 4;25(1):24-43. doi: 10.1016/j.ymthe. 2016.10.014.

Biomarkers are a major interest for myotonic dystrophy (DM), but understanding of their utility (Context of Use) in clinical trials can be elusive. The ‘flavors’ of biomarkers relate to the ways they are utilized: diagnostic, prognostic, predictive, pharmacodynamics (PD) and pharmacokinetic (PK). The right biomarkers are invaluable in selecting/stratifying patients, determining on-target activity, and dosing and assessing efficacy and safety of candidate therapies. Arriving at the “right” biomarkers to minimize uncertainty and aid decision-making is essential, but nontrivial, as experiences in Duchenne have so clearly shown.

A simplistic view is that a molecular endpoint identified in a laboratory study can be a panacea in accelerating drug approval. The reality is that, in moving beyond the discovery phase, a range of questions, from methodological to interpretive, must be answered before a biomarker has validity.

Given the high bar for regulatory qualification, biomarker studies ultimately must reside within collaborative networks that recognize that no one gets to the solution alone. A key barrier to overcome is that biomarker qualification is uncharted territory for most academic researchers.

Two recent initiatives, the BEST Resource (Biomarkers, EndpointS, and other Tools) and the Framework for Defining Evidentiary Criteria for Biomarker Qualification, are aimed at clarifying terminology and process with all stakeholders, and thereby accelerating qualification and use of biomarkers in therapy development programs.

The FDA-NIH Joint Leadership Council, dedicated to improving regulatory science, developed the BEST Resource. BEST initially focused on harmonizing the terminology of translational science and biomedical project development. The intent is to provide clarity and consistency in communications among all stakeholders. The BEST glossary is an invaluable resource, going well beyond biomarker and endpoint terminology to provide a wealth of examples and informational links.

The Framework for Defining Evidentiary Criteria for Biomarker Qualification, a partnership led by the Foundation for the NIH that includes NIH, FDA, PhRMA, the Critical Path Institute and pharmaceutical companies, provides “a general framework to assist the development of biomarkers for qualification, to improve upon the quality of submissions to the FDA and to clarify the evidentiary criteria needed to support the biomarker’s "Context Of Use" (pdf). The ready availability of these criteria increases transparency of the qualification process and thereby facilitates interactions between biomarker developers and FDA.

What opportunities exist to exploit these new tools in biomarker development for DM? In a recent DM Research News, MDF highlighted the potential for FDA biomarker qualification of a panel of splicing events identified with the Myotonic Dystrophy Clinical Research Network (DMCRN). The recent clarification of evidentiary standards will markedly aid this effort. In addition, the Wyck Foundation and MDF recently funded Dr. Thurman Wheeler (Massachusetts General Hospital) to explore miRNAs in serum and urine as DM1 biomarkers. While this is a discovery-phase project, it’s important that the new qualification guidance is taken into account even by studies at such an early stage.

A recent publication by Ms. Alessandra Perfetti, Dr. Fabio Martelli and colleagues (IRCCS Policlinico San Donato) piloted circulating miRNAs as putative biomarkers for DM1. Dysregulated miRNAs included miR-1, miR-27b, miR-133a/-133b, miR-140-3p, miR-206, miR-454 and miR-574. Elevated miRNAs correlated with impaired muscle strength and elevated MCK, and could readily distinguish DM1 (103 subjects) from controls (111). Some of the miRNAs identified in DM1 patient samples are non-specific in that they also are dysregulated in Duchenne (miR-1, mIR-206 and miR-133a/-133b), but that does not preclude their potential value as prognostic, predictive, PD or PK biomarkers in DM1. Before a biomarker can be qualified, more extensive studies must assess how this miRNA profile links to pathogenic or regenerative processes across multiple organ systems, and show if these miRNAs are suitable in tracking disease progression and/or drug efficacy.

To achieve qualified DM biomarkers, we all must speak the same “BEST” language and assimilate, rather than silo, lessons learned from each study. But most of all, the DM research community must adopt a highly collaborative culture (valuing community needs over individual publications), since validated, quantitative assays, well-powered and phenotypically rich data sets and inter-site validation are essential in navigating the pathway to effective drug development tools.

Reference:

BEST (Biomarkers, EndpointS, and other Tools) Resource
FDA-NIH Biomarker Working Group.

Framework for Defining Evidentiary Criteria for Biomarker Qualification: Final Version. Evidentiary Criteria Writing Group

Validation of Plasma MicroRNAs as Biomarkers for Myotonic Dystrophy Type 1.
Perfetti A, Greco S, Cardani R, Fossati B, Cuomo G, Valaperta R, Ambrogi F, Cortese A, Botta A, Mignarri A, Santoro M, Gaetano C, Costa E, Dotti MT, Silvestri G, Massa R, Meola G, Martelli F.
Sci Rep. 2016 Dec 1;6:38174. doi: 10.1038/srep38174.

The myotonic dystrophy (DM) community has a strong champion in singer-songwriter Eric Hutchinson. As part of his long-time efforts to support Care and a Cure for myotonic dystrophy, Eric is offering one-of-a-kind fan activities and memorabilia in a new pledge campaign, and a portion of the proceeds will be donated to MDF. Eric is offering private concerts for you and your guests as part of the pledge campaign, a deluxe edition of his album Easy Street, a signed and personalized acoustic guitar, framed lyrics and the opportunity to have a private tour of New York City with him, among other items. The pledge campaign ends on December 31, 2016.

"I’m thrilled to announce the Deluxe Edition of my latest album, Easy Street!" said Eric. "I recently learned about PledgeMusic.com and thought it sounded like a fantastic way to share some of my time, new music and some special memorabilia with all of you. Plus, for the first time ever, ‘Easy Street’ is available on VINYL, the first time ANY of my albums has been on wax. I’ve spent a lot of 2016 educating people about myotonic dystrophy, a condition that has affected my dad and my family for a long time. Part of the proceeds from this PledgeMusic campaign will go to support MDF and myotonic dystrophy research.

"I know firsthand what living with myotonic dystrophy looks like for a loved one and his or her caregivers. I'm committed to helping to find care and a cure for DM and I hope you'll join me. I want to thank MDF for helping my family better understand myotonic dystrophy and letting us know that we’re not alone in living with this disease. I’m donating to MDF because it’s important to provide resources and support to families, and accelerate efforts to find a therapy."

Eric’s commitment to support the DM community is driven by his own personal connection to the disease: His father has DM, and for years Eric lived with fear and uncertainty about his own status. Eric wrote about his family connection to myotonic dystrophy this year in a heartfelt personal essay.

The multi-system involvement and heterogeneity that characterize myotonic dystrophy (DM) have fostered several efforts to design patient-reported outcome measures (PROMs) for clinical studies and trials. The intent of PROMs is to use patient feedback in design and implementation of validated questionnaires that can simultaneously capture changes across the challenging symptomology of DM while obtaining clinically meaningful information to support regulatory approval. While PROMs can prove insightful as an analytic tool for complex disorders, the potential barriers to PROM design, development, and interpretation are such that the Food and Drug Administration (FDA) developed a Guidance for Industry document (pdf) to aid in development of PROMs. Choice of PROMs for use in interventional trials must then be carefully informed.

Dr. Tara Symonds and her colleagues at Clinical Outcomes Solutions (COS) recently reported out a literature review of available PROMs that focus on type 1 myotonic dystrophy (DM1). COS a is health economics and outcomes research consulting group with considerable experience in understanding PROM design and implementation in clinical studies. Disclosure: The COS project was funded by Biogen, a company engaged in therapy development in DM1.

Dr. Symonds and her group evaluated a health status measure (MDHI), three activities of daily living scales (DM1-Activ, DM-Activc, and Life-H), two health related quality of life measures (INQoL & INQoL Serbian), and five sleep and fatigue measures (ESS, DSS, CFS, FSS, and FDSS) comparing their validity, reliability, and ability to detect change of each to guide choice of PROMs for use in DM1 studies.

MDHI was viewed as the only measure that attempted to capture all aspects of a DM1 patient's life that were impacted. Design of MDHI specifically for DM, internal consistency of the tool across domains assessed, test-retest reliability, and design in compliance with FDA’s Guidance for Industry were viewed as favorable traits. It was also noted that construct validity had been established for MDHI via comparison with a variety of existing functional measures (e.g., MMT, grip testing, and timed function tests).

DM1-Activ also was considered to have good validity and reliability and showed construct validity when compared to various manual testing measures and the Muscular Impairment Rating Scale (MIRS).

Most other PROMs assessed by the authors were viewed as more limited in capability and performance, and all PROMs were thought to require further assessment of responsiveness and meaningful change thresholds in interventional clinical trials. Dr. Symonds and team concluded that MDHI is arguably the best measure for use in clinical studies and trials provided that the critical areas of responsiveness and definition of meaningful change to patient are addressed. DM1-Activ also was deemed to have potential as a PROM in interventional trials, as long as content validity is explored further and the issues of responsiveness and meaningful change prove acceptable. Other measures were considered acceptable in evaluation of specific domains of the symptomatology of DM1.

FDA’s Guidance for Industry supports the use of well-designed and implemented PROMs as putative primary endpoint measures for clinical trials. Even as a secondary measure, a carefully selected PROM can bring considerable value to clinical trials, not the least is insight into meaningful benefit to the patient. The publication by Dr. Symonds and colleagues provides an evaluation of currently available tools by experts outside of the DM community. While current drug discovery and development efforts have focused on skeletal muscle function, desired treatments for DM will have to address a much wider disease burden. Validated and reliable PROMs with an ability to capture changes in multiple symptoms important to DM1 patients may prove to be a valuable tool in natural history studies and definitive clinical trials.

Reference:

A Review of Patient Reported Outcome Measures for Use in DM1 Patients
Symonds T, Randall JA, Campbell P.
Muscle Nerve. 2016 Nov 11. doi: 10.1002/mus.25469.

To date, technological hurdles have been a barrier to creating a mouse model for type 2 myotonic dystrophy (DM2), hindering understanding and treatment development for this disorder. But that’s about to change, thanks in part to the work of Łukasz Sznajder, Ph.D., a recipient of a 2016-2017 research fellowship grant from MDF.

"Currently, there are only cellular and fruit fly models available," says Dr. Sznajder, "and they’re not sufficient to understand the complex nature of DM2. A mouse model is urgently necessary to break this barrier."

Without mouse models it would have been impossible to develop the drugs now being tested to treat most neuromuscular disorders, including type 1 myotonic dystrophy (DM1).

A DM2 mouse model “will provide an excellent platform to evaluate DM2 phenotypes,” Dr. Sznajder says.

It would also allow researchers to study tissues that are hard to obtain from patients, such as those from the cardiac muscle and brain, and it would shed light on the differences between DM1 and DM2.

"My proposed model represents a unique opportunity to distinguish the differences between DM1 and DM2," Sznajder says. "We expect to answer puzzling questions, such as why there is no congenital-onset form of DM2," which is caused by several thousand CCTG repeats in the first intron of the CNBP gene.

"It is worth mentioning that the size of this mutation is several times that of the expansion that leads to DM1," Sznajder says. That, he notes, poses some challenges in developing a DM2 mouse model. "First, the amplification of even a few hundred repeats is not possible using conventional strategies. Second, the precise insertion of these repeats into the mouse CNBP gene is a highly inefficient process," he says.

"New technologies have remarkably improved the efficiency of genome engineering, and we hope to use these technologies to overcome the current challenges in DM2 modeling," he says.

Moving Toward DM2 Therapies

A mouse model will also allow Dr. Sznajder and his team to test therapeutic strategies for DM2 like antisense oligonucleotides and small molecules.

The antisense oligonucleotide-based drug IONIS-DMPKRx, designed to block harmful interactions between expanded RNA repeats and cellular proteins in DM1, is now in a phase 1-2 trial. Dr. Sznajder and his colleagues hope to develop a similar molecule to treat DM2.

"It is scientifically possible to adjust the oligonucleotide sequence to make it useful for DM2," Sznajder says. "However, a good mouse model of the disease is needed to test the efficiency of this or other approaches." His new DM2 mouse is expected to provide this vital tool.

A Passion for DM Research

Dr. Sznajder recently moved from his native Poland to realize his dream of working with a renowned DM researcher in the United States.

Coming of age in Poland in the 2000s, Sznajder decided to become a biomedical scientist, ultimately earning his doctorate in biotechnology and molecular biology from the Adam Mickiewicz University in Poznań in December 2015.

"For some time," he says, "I had dreamed about working at a prestigious university in the United States under the supervision of someone who would enable me to develop my scientific career while following my passion for research in myotonic dystrophy."

During his graduate studies, Sznajder was fortunate enough to work under Dr. Krzysztof Sobczak, who had been a postdoc in the laboratory of Dr. Charles Thornton, a DM researcher at the University of Rochester in New York state and a colleague of Dr. Maurice Swanson.

Under the mentorship of Dr. Sobczak, Sznajder started working on RNA toxicity and MBNL proteins, which he describes as "critical players in the molecular cascade of DM."

Dr. Sznajder is continuing his vital DM research under Dr. Maurice Swanson at the University of Florida.

As a consequence of the retention of mutant DMPK transcripts in the nucleus in DM1, patients express baseline levels of DMPK protein that are already half those of unaffected individuals. Since a key therapeutic strategy relies upon degradation of DMPK transcripts using antisense oligonucleotides (ASO), there are concerns as to whether essential functions of DMPK may be comprised and thereby contribute to the pathogenesis in DM1.

A University of Rochester team led by Dr. Charles Thornton has addressed this issue using mouse models with constitutive (genetic deletion) or acquired (ASO reduction) reductions in Dmpk. The function of DMPK is currently unknown. Prior reports in genetic models have shown that mice with heterozygous deletion of Dmpk exhibit cardiac conduction system defects, while those with homozygous deletion show skeletal muscle myopathy and weakness. Thus optimization of the ability of ASOs to target and degrade DMPK transcripts could exacerbate cardiac and skeletal muscle dysfunction in DM1.

Dr. Thornton and colleagues reevaluated the impact of genetic and ASO-induced reductions in Dmpk in two mouse models. They saw no effect of genetic deletion or ASO knockdown on cardiac (heart rate, PR interval, QRS duration, left ventricular contractile parameters) or skeletal (grip strength) functional measures, despite the substantial reductions that were achieved in Dmpk protein levels. Current strategies for ASO knockdown in DM1 utilize an allele-selective approach by targeting and degrading the mutant DMPK transcripts that are retained in the nucleus. However, there is the possibility that wild-type DMPK transcripts that traffic to the cytoplasm may also be degraded, as the next generation ASO chemistries result in more effective delivery to skeletal and cardiac muscles.

Yet despite the concern that substantial reductions in Dmpk protein may impact these muscles, Dr. Thornton’s team did not uncover any pathophysiology associated with Dmpk knockdown, even when genetic and ASO strategies were combined to yield as much as 90% reduction. Differences between the results of the Thornton team and prior investigations may relate to technical differences in the studies, mouse background strain differences, or features of the genetic knockout alleles.

The levels of Dmpk silencing seen in this study most likely would exceed those that could be obtained in DM1 patients, even with a highly effective ASO drug. The level of reduction of Dmpk in the mouse models also would likely exceed the reductions that are necessary to effectively restore the DM1-linked changes in mRNA splicing, and thereby mitigate DM1 signs and symptoms.

Hence these findings support the notion that strategies to increase the effectiveness of ASO candidate therapies can be effective in DM1 without increasing the risk of cardiac and skeletal muscle events.

Reference:

Dmpk gene deletion or antisense knockdown does not compromise cardiac or skeletal muscle function in mice.
Carrell ST, Carrell EM, Auerbach D, Pandey SK, Bennett CF, Dirksen RT, Thornton CA.
Hum Mol Genet. 2016 Aug 13. pii: ddw266.

Endpoint Award

Dr. Donovan Lott, of the University of Florida, has successfully competed for support of his project, “Development of Magnetic Resonance Imaging as an Endpoint in Myotonic Dystrophy Type 1.” The award is for one year, at $150,000. 

Dr. Lott’s group has extensive experience in developing skeletal muscle MRI as an endpoint measure in neuromuscular disease, including their ongoing interactions with FDA to obtain biomarker qualification. There have been very few imaging studies of myotonic dystrophy skeletal muscle. Given the considerable potential of MRI, an assessment of the feasibility of the approach in DM is essential.

Drug development in myotonic dystrophy (DM) enjoys an important advantage—having the tools in hand to show that a drug candidate gains access to and modifies the primary cause of the disease. Since expanded repeats in DMPK (in DM1) and CNBP (DM2) sequester MBNL1 protein and cause easily assessable molecular (mis-splicing of a large set of genes) and physiological (myotonia) changes, we can get an early signal in Phase 1/2 trials that a candidate therapy engages and modulates a key drug discovery and development target.

The existence of clear endpoints for early stage clinical trials helps de-risk DM for investments by pharmaceutical and biotechnology companies. By contrast, the development of endpoint measures that either establish, or are surrogates for, a clinically meaningful benefit is a clear need for Phase 3 trials in DM, in order to gain regulatory approval for a drug or biologic.

With the objective of meeting this critical need, MDF issued a Request for Applications to identify and support a project with the objective of developing new, clinically meaningful endpoint measures or refining endpoint measures already in development. Dr. Donovan’s project received the highest rating from the MDF peer review panel and was selected for funding.

Dr. Donovan’s team will complete a project in 25 DM1 patients. In these studies, they will quantitatively assess upper and lower limb muscle status by MRI and relate findings to a battery of functional measures, thereby taking the first steps toward development and qualification of MRI as a sensitive and non-invasive biomarker for clinical trials in DM. A qualified endpoint measure, with established linkage to clinically meaningful outcomes for patients, will make each of our clinical trials considerably more efficient and informative.

UK Natural History Grant 

Professor Hanns Lochmuller and Newcastle University are being awarded a $125,000 grant to extend a natural history study of 200-400 adult DM1 patients. 

The Newcastle group is currently funded by the UK National Institute for Health Research to recruit and collect natural history data on the DM1 cohort for one year, through March 31, 2017. MDF funding will leverage this existing funding to allow Professor Lochmuller and colleagues to reach the upper end of their recruitment target and to extend the duration of data collection from this valuable cohort for an additional year. Data collection involves a wide variety of endpoints, with the aggregate data assisting in the planning, design, and recruitment of future clinical trials, as well as supporting identification of putative biomarkers of DM1.

Robust natural history studies are critical to the development of endpoint measures that reflect clinically meaningful benefit for use in registration trials. MDF and MDF UK are pleased to be able to leverage other grant funding to increase the value and impact of this study.

Dr. Yao Yao, a former MDF Fellow, has brought us a step closer to effective muscle stem cell therapies for muscular dystrophy.

Dr. Yao identified a cell signaling mechanism by which muscle stem cells are directed to aid muscle regeneration. His work was recently published in the prestigious research journal, Nature Communications.

Muscle stem cells are responsible for the growth and regeneration of skeletal muscles. They are located immediately adjacent to muscle fibers and divide and fuse with the muscle fiber to increase its size and strength, for example, when you exercise.

These stem cells are also the means by which damaged and weakened muscles are strengthened and repaired. The process is very similar, whether the muscle damage is due to an injury or a muscle wasting disease, like DM.

Because of their vital role in muscle regeneration, muscle stem cells are a potentially important target for developing therapies. Increasing their activity should improve muscle repair.

The development of cell therapies has been difficult, however, because we don’t sufficiently understand stem cell biology. Muscle stem cells participate in both muscle regeneration and the fatty deterioration of muscle. Understanding the regulation of muscle stem cell fate is a critical, early step in therapy development.

A better understanding of the properties of muscle stem cells (and the molecular and cellular mechanisms that control their fate) will be essential to using them in therapies. MDF is pleased to have supported Dr. Yao’s advances in the therapeutic potential for muscle stem cells.

Dr. Yao currently holds a faculty position in the College of Pharmacy at the University of Minnesota, Duluth. For more details on Dr. Yao’s lab, click here.

Reference:

Laminin regulates PDGFRβ(+) cell stemness and muscle development.
Yao Y, Norris EH, E Mason C, Strickland S. 
Nat Commun. 2016 May 3.