Sept. 30th is Limb-Girdle Muscular Dystrophy Awareness Day, which celebrates individuals living with the more than 30 different subtypes of Limb-girdle muscular dystrophy (LGMD). MDA has a long-standing commitment to LGMD — we’ve invested more than $59 million in LGMD-specific research since 1950, including more than $2.8 million in current active grants.
MDA Scientific Portfolio Director Lianna Orlando recently sat down to chat about the latest developments in the LGMD research landscape and what to look forward to in the coming years.
What notable LGMD research support is MDA currently funding?
Lianna: MDA recently established the LGMD Clinical Research Network, a geographically-distributed network of investigators and clinics with LGMD expertise. MDA has provided the support needed so they can work together to standardize their efforts and share data. Of particular importance is developing and defining the tools, biomarkers, outcome measures and endpoints that will be most important to utilize in future LGMD clinical trials, and providing the infrastructure for carrying out those trials.
MDA is also supporting genetic testing for LGMD. Since 2015, MDA (in partnership with Sanofi-Genzyme) has been offering a free genetic testing program to individuals who come into the clinic with limb-girdle muscle weakness. In addition to the LGMDs, there are other neuromuscular disorders that can start with limb-girdle weakness, and for some of those diseases (for example Duchenne muscular dystrophy (DMD) and Pompe disease) there are FDA-approved treatments available. But even for the LGMDs, knowing the particular LGMD subtype informs whether individuals need to be closely followed for specific complications, such as cardiopulmonary dysfunction. Therefore, it is important for individuals presenting with limb-girdle weakness to be tested to see if the underlying genetic cause of their disease can be identified.
MDA’s genetic testing program, like other similar gene panel testing programs, is successful in diagnosing approximately one third of cases. That leaves a significant number of “unsolved” cases that require further genetic studies.
To address those unsolved cases, a new partnership between MDA and the Broad Institute of MIT and Harvard has been initiated to allow individuals who have been tested via the MDA gene panel and who did not receive a definitive diagnosis to receive more comprehensive genetic testing at no cost to the individual. This program should be up and running in the coming months.
MDA has also funded other grants aimed at bringing genetic diagnoses to a larger number of individuals by investigating whether newly described gene variants can definitively be attributed as the cause of the disease. And we’re also supporting many other research studies focused on particular LGMD subtypes, looking to better understand the mechanisms of what causes the disease and developing interventions to combat it.
What has MDA supported or funded in the past that is either in the clinic now or about to enter the clinic?
Lianna: Gene therapy clinical trials for several LGMD subtypes are quickly forthcoming, and MDA has a long history of funding the foundational research that underpins these therapies. In particular, MDA was one of the earliest funders of the research underlying the gene therapy soon entering clinical trials for LGMD2D.
How does gene therapy offer hope for those living with LGMD? Are there any other techniques we often hear about in the news, such as gene editing or exon skipping, that might offer therapeutic potential?
Lianna: Many forms of LGMD are a result of gene mutations that don’t allow the gene product to function as it normally would. What gene therapy offers is the opportunity to add back in a copy of that gene without the deleterious mutations so that the muscle cells can now make a functional gene product.
What is exciting about a gene therapy approach is that it targets the root cause of the disease and thus has the potential to be a more transformative therapy than, say, treatments that target the symptoms that develop downstream of the root cause. In the best-case scenario, adding back in a functional gene, if done early and effectively, may prevent further damage to muscle cells, and slow or stop the progression of the disease. There will be a number of important gene therapy clinical trials in different forms of LGMD in the next few years, and the results and learnings from these will be important to advance the entire field.
Beyond gene replacement therapy, some of the gene mutations that cause LGMD are amenable to other gene-targeting approaches such as gene editing or exon skipping. In general, these approaches will be effective for smaller subsets of individuals. While one gene is responsible for causing one subtype of LGMD, there can be several different types of mutations in that one gene that lead to that LGMD subtype. Because gene editing or exon skipping target the specific mutation in that gene, it is unlikely that one gene editing or exon-skipping therapy would work for all individuals with a given LGMD subtype (whereas it is more likely you could use the gene replacement therapy no matter what type of mutation).
However, gene editing or other gene-targeting approaches may have other advantages over gene replacement therapy, in terms of ultimate effectiveness. So, exploring these possibilities in the LGMDs are active areas of research. In general, though, for most of the LGMDs, gene therapy is further along than other approaches.
Let’s circle back and talk a little bit more about the LGMD Clinical Research Network, especially as it pertains to accelerating the arrival of the types of therapies you just discussed to the clinic.
Lianna: With gene therapy trials starting in the LGMDs and other approaches in earlier stages of clinical development, there is pressing need for the LGMD field to be “clinical trial ready.” MDA believes that one of the best ways to help a field achieve this level of readiness is to create and support a coordinated network of sites that are working together on this common goal. In short, clinical research networks collect the data necessary to inform the feasibility and design of future clinical trials, and provide the infrastructure to carry out those trials.
For example, clinical research networks:
- Standardize protocols, training and sharing of information across sites, which results in more uniform practices and reduces some of the “noise” in the data.
- Observe the natural history of disease, which increases our understanding of how these diseases manifest and helps to inform clinical trial design.
- Determine the tools to effectively measure disease progression and the endpoint measures that can be used to demonstrate whether a treatment is having a significant benefit.
All of these goals are critically important for any company who is considering developing therapies and conducting trials in LGMD.
We envision this LGMD Clinical Research Network to be the starting point for a growing network that will include additional sites as time and future resources allow.
How will LGMD research be affected by MOVR?
Note: MOVR is MDA’s data hub, an expansion of our previous neuromuscular disease data registry, that captures clinician-entered, patient-reported and genetic data. MOVR will be rolled out at 25 MDA Care Centers throughout the country this fall, focusing on amyotrophic lateral sclerosis (ALS), Becker muscular dystrophy (BMD), spinal muscular atrophy (SMA) and DMD, with LGMD added shortly thereafter. Click here to learn more about MOVR.
Lianna: LGMD is one of the first new diseases that will be added to MOVR in 2019. We are in the process of working with LGMD specialists to define the clinical data points we will collect at each participant’s clinic visits. There are a few natural-history studies already in existence that have been following individuals with a particular subtype of LGMD over the course of many years, and some single-subtype LGMD registries where individuals with the appropriate subtype can enter their own information. However, the addition of LGMD to MOVR will represent the first central repository for clinician-entered data across all LGMD subtypes, and will include data such as demographics, genetic testing results, natural history of disease, clinical milestones, use of medications, functional mobility tests and much more.
While each of the subtypes of LGMD is rare, MOVR represents a unique opportunity for individuals with all LGMD subtypes to have the opportunity to contribute to a better understanding of their disease. By leveraging MDA’s distributed network of Care Centers and aggregating real world evidence across all MOVR sites, we will be able to develop a richer and more complete picture of the clinical description of each of the diseases. We will also be able to use this data to inform the feasibility and design of future clinical trials in LGMD, as well as help matching the right individuals with the right trials.
What is your opinion on the overall state of LGMD research today compared to the recent past?
Lianna: LGMD research has long been a priority for MDA, but in the last decade or so we’ve seen tremendous momentum in the field. Some of this can be attributed to the improvement in genetic and molecular techniques, which have increased the number of LGMD genes that have been identified and expanded our ability to develop the research models by which to better study these diseases.
Another major accelerant for LGMD research has been the recent drug approvals in DMD and SMA. These approvals have helped pharma realize that there is real opportunity working on neuromuscular diseases, which has the dual effect of bringing new companies into the field and encouraging companies that have previously focused on DMD and SMA to take the expertise they’ve developed in those diseases and extend it to LGMDs. All of this is good for the LGMD field and driving more interest and innovation into LGMD research.
Lastly, it is also worth noting that the establishment and activities of other patient advocacy organizations that focus on a single LGMD subtype are also contributing to robust interest and support of research efforts. As much as possible, MDA would like to work with these organizations on shared endeavors.
With all the advances in LGMD research, the establishment of the LGMD clinical research network and the launch of MOVR, it is really an exciting time for the LGMD field. Our hope is that with all these advances, we will see therapeutic breakthroughs for patients in the not-too-distant future.