Research Strategy & Funding Goals
Research Strategy
Research and development are the pillars to learning and understanding the causes and progression of disease mechanisms that cause the debilitating symptoms of congenital muscular dystrophy. Research and development are also the tools necessary for establishing therapies that will slow and ultimately stop or even cure the progression of CMD.
Yet, all CMD subtypes have many unmet needs, which is why Cure CMD’s approach to funding research is to identify scientists from around the world with a wide variety of expertise. We want to contribute to a growing and adaptable research environment that capitalizes on opportunities as they arise. We also continually monitor the global research community’s activities and breakthroughs, attend conferences and workshops, and our dedicated team reviews all new research papers as they are published. Perhaps most importantly, we maintain a continuous dialogue with affected individuals, families, and caregivers with the overall aim to support the best and most promising scientific research and clinical developments while keeping a patient-centered vision at the forefront of everything we do.
Global Research Priorities
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Natural History Studies (NHS). NHS are a fundamental piece of the clinical trial readiness pipeline that help us understand the expected symptom progression and adverse events associated with CMD. NHS also help us identify reliable outcome measures to be used in clinical trials through discovery and fine-tuning of measurable signs of disease progression to understand whether a treatment is improving that symptom.
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Research Tools. Cure CMD aims to fund the development and discovery of research tools necessary for pre-clinical research, such as patient-derived cell models, donated bio specimens, and animal models.
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Biomarker Discovery Programs. Establishing biomarkers can aid in future clinical trial monitoring.
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Basic Research. We aim to better understand the triggers and pathways that cause CMD.
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Translational Research. Such focus may allow us to transfer lessons learned from basic research, pre-clinical studies, and NHS, into real therapies, through engagement of pharmaceutical companies, researchers, clinicians, regulators and the patient community to advance toward clinical trials and ultimately, treatments.
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Genetic Modifiers as Therapeutic Targets. Strong evidence supports the idea that affected individuals with the same mutation(s) often present with different levels of symptom severity and progression. This may suggest that other genes have an impact on protein production and functionality. Discovery of genes that modify the presentation and evolution of CMD is a new way to find novel targets for therapeutic development.
Global Community Support Initiatives
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Cure CMD Mobile App. Funded in part by the Global Genes RARE Patient Impact Grant, a new mobile app (“Cure CMD”) responds to a need for convenient, comprehensive, searchable information for families, caregivers, affected individuals, and healthcare professionals. Cure CMD will continually update this app to reflect the most up-to-date information.
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Updates and additions to Care Guidelines. Continue dialogue with clinicians and experts to provide information about effective care.
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Educational Webinars. New and existing webinars will provide useful information and research updates in short, digestible sessions. Planned webinars include LMNA Cardiomyopathy, Phase II Omigapil, and Research News for all subtypes.
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Community Blog Initiative. Launch a series of community-built content, written and edited by affected individuals, families, friends, caregivers, and allies - striving to always reflect voices of the community.
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Upgraded Patient Registry Platform. A new database will be more user-friendly for the community and for scientists who seek to utilize de-identified data in their research.
All of these general priorities are necessary and useful for each CMD subtype. However, individual subtypes also have a specific set of characteristics inherent to their genetic cause. This warrants the need to also advance subtype-specific plans.
CMD Subtype Plans
With support from our leading CMD experts, the patient community, and derived from lessons learned from not only CMD-specific research and clinical programs, but also the experiences of those in other neuromuscular diseases, Cure CMD has developed the following subtype-specific research priorities.
αDG (Dystroglycanopathies)
Note: in addition to the symptoms of muscle weakness, most forms of congenital α-dystroglycanopathy involve brain development defects which may express as cognitive impairment, seizures, or visual impairment. For affected individuals and their families, the search for solutions to manage the cognitive and neural complications of αDG is as important, if not more so, than muscle weakness.
αDG Research Priorities
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Disease Model Development. For example, patient-induced pluripotent stem cells (iPSCs) can be converted into neural tissue or 3-D mini-brains, and transgenic mouse models, to help us understand the underlying mechanisms of brain development and allow for testing of potential interventions to boost neuronal plasticity and/or cognitive capacity.
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Ribitol as a Potential Treatment. The addition of ribitol to αDG is necessary for its normal function. Some forms of αDG present a deficit in this step. Dietary administration of ribitol may be a promising therapy for some affected individuals, and we need to study this further.
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Gene Therapy. Most genetic mutations that cause αDG could be amenable to some degree of correction by gene therapy.
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Hinge-Like Project. One of the drivers of symptoms in two CMD subtypes (αDG and LAMA2) is the detachment of the basement membrane (part of the extracellular matrix) and the muscle plasma membrane. This study aims to devise a “molecular hinge” to reconnect those two components bypassing the defect on the α-DG to restore function.
Collagen VI (Ullrich-Intermediate-Bethlem)
COL6 Research Priorities
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Pseudo-Exon Skipping. This type of gene therapy will “skip” the addition of an unwanted part of the gene to restore functionality.
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Antisense. We all have two copies of each gene, often only one is affected (dominant mutations). This project aims to inhibit the faulty gene from expressing itself and allowing the unaffected gene to take over, restoring functionality.
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Gene Replacement Therapy. Classical gene therapy approaches for recessive mutations.
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Stop Codon Read-Through. A molecular intervention that uses compounds with the specific ability to mask the stop signal for protein synthesis as a consequence of a nonsense mutation (Ataluren in DMD is an example of this type of intervention).
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Vectors Targeting COL6-Producing Cells. The main source of Collagen VI production are the fibroblast cells located in the muscle interstitial tissue, and gene therapy will need to target these cells. This project aims to discover, improve and/or “tune-up” this tool.
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Understanding Contractures. The COL6 patient community has identified contractures as one of the progressive, incapacitating symptoms that most impact quality of life. We are focused on supporting research on contractures and identifying potential therapies to slow or even reverse this symptom.
LAMA2 (Merosin Deficient)
LAMA2 Research Priorities
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LINKR Project. One of the drivers of symptoms in two CMD subtypes (LAMA2 and αDG) is the detachment of the basement membrane (part of the extracellular matrix) and the muscle plasma membrane. This study aims to reconnect those two components bypassing the absence or defect of the LAMA2 protein to restore function.
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LAMININ 111 Protein Replacement Therapy. LAMA111 is the predominant laminin isoform in embryonic skeletal muscle but is replaced by LAMA211 after birth. LAMA111 and LAMA211 are structurally and functionally similar. This study aims to replace the affected LAMA211 production by reintroducing LAMA111. Researchers have successfully rescued the disease phenotype in mouse models, and the biotech company, Prothelia, in partnership with Cure CMD and LAMA2 experts, plans to move this potential therapy into human clinical trials.
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Endogenous LAMA111 Overexpression. Similar to the previous priority, protein replacement of faulty LAMA211 by normal LAMA111 could be achieved by overexpressing the affected individual’s own production of LAMA111 by the use of a specific type of CRISPR approach.
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LAMA2 Natural History Study (NHS) in Children Ages 0-5 Years. Support the design and execution a two-part NHS to develop additional outcome measures and clinical trial endpoints in affected children ages 0-5 years.
LMNA (Laminopathy/LGMD1B)
LMNA Research Priorities
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Gene Therapy. LMNA-CMD is an autosomal dominant disorder, meaning that only one copy of the altered gene is enough to cause symptoms. The dominant-negative effect of the mutation makes gene therapy approaches a little more difficult, and therefore, support for studies to identify the best gene therapy tools for LMNA-CMD are critical.
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Targeting LINC. Linkers of the Nucleoskeleton to Cytoskeleton, or “LINC” is a protein complex providing a structural link between the nucleus and the cytoplasm of muscle cells. Studies aimed at manipulating this complex have potential as a therapeutic target.
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Drug Profiling in DCM. A few small molecule drugs are currently in clinical trials for adults with LMNA-related dilated cardiomyopathy (DCM). Support for pre-clinical studies that move us closer to clinical trials for these interventions in the pediatric community will be pursued once proven safe and effective in adults.
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Natural History Study (NHS). Design and execute a prospective NHS based on data recently collected and published in a global retrospective study.
SELENON
SELENON Research Priorities
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Calcium Homeostasis Recovery and Oxidative Stress Reduction. The SELENON protein is likely involved in protecting muscle cells against oxidative stress, as well as playing a key role in the tight regulation of calcium storage and release needed for muscle contractions. As a result, mutations alter calcium homeostasis and triggers maladaptive cellular stress responses involving other proteins of the sarcoplasmic reticulum. Using cells from affected individuals and animal models, we aim to dissect this pathway with the potential to uncover novel therapeutic targets.
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Gene Therapy. The size of the components needed to deliver gene therapy treatments using classical AAV vectors may be larger than their cargo capacity. Moreover, function is mostly expressed during development, so it is an open question as to how effective gene therapy would be in affected adults. Therefore, additional support for studies aimed to overcome these roadblocks, and to find the most effective gene therapy approach are critical.
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Disease-in-a-Dish Studies. This research aims to collect patient specimens such as fibroblasts (skin cells) to make patient-induced pluripotent stem cells (iPSCs) and then convert these cells into 3D muscle cells that can be used to screen thousands of potential interventions, as well as test gene therapy approaches.
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Respiratory Natural History Data Collection. Collect data in a formal clinical study on respiratory function to both standardize respiratory care and identify outcome measures and clinical trial endpoints.
Questions?
Cure CMD continues to leverage these and past activities to canalize the power of experience and expertise to elevate the status of CMD, from a low interest, low awareness, ultra-rare disease, to a conspicuous group of disorders, driving pharmaceutical interest and improved care guidelines - all to fulfill our mission of finding treatments and improving the lives of those living with congenital muscular dystrophy.
Have questions about Cure CMD’s Research Priority Pipeline?