Explore our narrated poster session below for information on research related to Duchenne.
Explore our narrated poster session below for information on research related to Duchenne.
The DMD onset is still unknown and the current treatments are not efficient enough with adverse effects. Thanks to a newly available cell model, we are able to modeled the disease in a petri dish. With it, we have two projects: 1/ better understand DMD onset to define earlier markers for diagnostic and therapeutic targets; 2/ find new treatments or optimize current ones.
First of all, our data argue for an early developmental manifestation of DMD whose onset is triggered before the entry into the skeletal muscle compartment, data leading to a necessary reconsideration of dystrophin roles during muscle development. Secondly, this cell model is used to find small molecules to mitigate DMD phenotypes and then provide new combined therapies for Duchenne patients.
Because of the increased vulnerability to health problems, boys with DMD who were born preterm may be at risk of unwanted health outcomes, such as use of assisted ventilation, at a younger age. It is recommended that boys with DMD receive breathing support with mechanical insufflation-exsufflation devices (MI-E, “cough machines”). We observed that the median age for cough machines use was 4 year younger among preterm than full-term born males with DMD. We found that preterm-born boys with DMD were 87% more likely than full term-born boys to undergo medical interventions related to respiratory function. Families of boys with DMD and clinicians caring for them may need to be particularly alert to the potential need for respiratory support in males born preterm.
Duchenne muscular dystrophy (DMD) is the most common genetic disorder, affecting 1 in 3500 male births. DMD is characterized by progressive damage, oxidative stress, inflammation, and weakness of limb muscles, respiratory muscles, and the heart. Mutation of dystrophin gene leads to a cascade of biochemical events that causes DMD pathology. Over the last decade our laboratory, colleagues, and other scientists have discovered that oxidative stress produced by the NADPH oxidase-2 cluster of proteins (Nox2) triggers the domino effect that causes DMD. Indeed, targeting Nox2 has relieved pathology in dystrophic mice. In this study, we identify important proteins that could activate or feedback into the Nox2 complex and thus drive DMD pathology. By targeting the redox chain of events that causes DMD, we propose to rapidly develop new medicines and therapeutics that will “short circuit” the disease and relieve patients suffering from DMD. Block Nox Now!
Recent advances in the treatment of Duchenne Muscular Dystrophy (DMD) children have sparked significant interest in finding reliable clinical and imaging assessment tools to monitor responsiveness to current and emerging therapeutic modalities. In this presentation, we aimed to establish correlations between validated clinical/functional assessment tools as motor function measure (MFM) and 6-minute walk test (6MWT) and quantitative US (as an indicator of muscle fat content) in regard to their potential diagnostic and prognostic role in DMD children. Our results revealed that the higher the fat replacement in muscles, the lower the scores of MFM and the lower meters achieved by patients in 6MWT. Our results suggest that quantitative muscle US correlates significantly with functional assessment tools as MFM and 6MWT, and augments their promising role in disease tracking of DMD children. In that regard quantitative muscle US has the potential to act as a supplement to functional assessment tools.
We are creating a natural history immune profile of the canine model for DMD. This profile will be used to evaluate different gene therapy approaches. The evaluation of the immune responses is critical to validate the safety of the different approaches. Using this profile, we will be able to evaluate the dogs’ immune responses to gene therapy. In our lab, we develop AAV-mediated gene therapy, but this profile will evaluate other techniques that our lab is currently in development.
Clinical evaluation of mobility is often limited to the laboratory setting. Common evaluations such as timed motor performance tests give us valuable information, but do not provide us with information about how children walk and move in their communities and daily life. Use of low-cost consumer level mobile device software applications to remotely measure gait represents an opportunity to expand studies into the community setting, and may aid in early diagnosis, clinical monitoring and clinical trials.
Interactions between muscle strength, heart function, and respiratory health all impact a person’s wellness and ability to function. Abnormalities with any one of these systems affects the others. Most testing for DMD evaluates each system independently such as: timed physical activity tests, pulmonary function tests, and echocardiograms, but none reflect overall impact of the disease which increases over time. We created a multiorgan system score, Major Adverse Dystrophinopathy Events (MADE), that tracks progressive health problems that occur with DMD. We used patient data previously collected by the CINRG Duchenne Natural History Study to show how the MADE score could be used. It was higher in those who died during the study compared to those who lived. The first step to decrease death related to heart and breathing complications of DMD is to identify a high-risk person before severe illness occurs. This is the goal of the MADE score.
Families affected by DMD report that speech-language concerns alter family dynamics, hinder bonding during infancy, and can be a barrier to effective learning. We identify that this is an area of unmet need that has long been neglected in DMD. By addressing this knowledge gap and spreading awareness of the different manifestations of speech delay, we can better tailor treatment approaches and resources to patients. Speech delay is often one of the first signs of Duchenne, so educating primary care physicians and neurologists will raise awareness of necessary steps for timely diagnosis and early intervention.
The TREAT-NMD DMD Dataset poster offers insight to the DMD community of the development process for the application and the importance attached to harmonising and standardising of patient data collection. It notes the contribution to the project of key opinion leaders in the field of DMD research from clinical, academic and patient led organisations in developing the dataset to meet the changing needs of stakeholders. The poster also describes the collaboration underpinning the development process; a close partnership with a range, clinical, patient and dual-reported DMD registries from around the world to ensure that patient needs drive the project and its outcomes.
Duchenne muscular dystrophy (DMD) is characterized by a progressive loss of muscle function; patients with DMD eventually die from cardiac or respiratory failure. Nonsense mutation DMD (nmDMD) is caused by a premature stop codon that stops dystrophin synthesis, functional dystrophin is absent in these patients. Ataluren is a drug that promotes readthrough and expression of the dystrophin protein in patients with nmDMD.
Study 019 was a phase 3, long-term safety study that enrolled 94 patients with nmDMD for 4.5 years. Patients who received ataluren in addition to the standard care (corticosteroids/palliative therapies) lost ambulation 2.5 years later and experienced slower decline in lung function compared with a matched cohort of patients derived from CINRG DNHS database, who received only standard of care. These findings suggest that the addition of ataluren to the standard of care slows the progression of DMD and delays loss of respiratory function in these patients
The standard of care for patients with Duchenne muscular dystrophy (DMD) includes corticosteroid treatment with deflazacort, prednisone or prednisolone. We evaluated the longitudinal effect of treatment of patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) with either deflazacort or prednisone/prednisolone over 48 weeks. To conduct such an analysis, we considered the “failure” of each patient to perform the 17 items of the North Star Ambulatory Assessment (NSAA) at six consecutive visits over the 48-week period. We then constructed curves showing the mean cumulative number of failures for each treatment group. The difference between treatment groups was estimated, assuming the ratio of the two curves was constant over time. The ratio of the two curves was 72%, significantly favouring deflazacort (p=0.028). These data demonstrate a longitudinal, sustainable, cumulative treatment benefit of deflazacort in terms of preservation of motor function in patients, as compared to prednisone/prednisolone.
This poster presents the long-term follow up outcome of 16 study participants who each have a dystrophin gene deletion mutation that can be returned to ‘in-frame’ with skipping of exon 53. All participants were treated for 2 years with viltolarsen, a drug that results in skipping of dystrophin exon 53. The poster reports on efficacy and safety outcomes from week 37 to week 109 of treatment.
Clinical trials are essential to advance therapies for DMD. Participation in clinical trials is a significant time commitment and burden to patients and families. Parents should have access to data from the clinical trial on their child, but this is often not provided, leaving families in the dark. This NIH-funded ethics research project has developed a centralized mechanism for return of clinical trial data directly from the Sponsor (ReveraGen) to patient families on a global scale. This poster describes our experience to date with this return-of-results program. We describe the effectiveness of outreach using advertisements via non-profit stake holder foundations and social media. We describe pre-return survey results regarding the expressed wishes of DMD families regarding clinical trial data return. We summarize the educational materials provided, that aim to aid families in the interpretation of research-focused clinical outcome (timed function tests), and exploratory laboratory data and biomarkers (blood tests).
FibroGen is studying an investigational treatment option to determine if it can help improve the condition of patients with Duchenne. Pamrevlumab, our proprietary fully human antibody, targets connective tissue growth factor (CTGF), the central mediator of tissue remodeling and fibrosis. Pamrevlumab represents a potential treatment for a broad array of fibrotic and proliferative disorders that affect organ systems throughout the body. Pamrevlumab is currently in Phase 3 clinical studies for the treatment of Duchenne muscular dystrophy.
Time to rise from supine to standing position is often used as an endpoint in clinical studies. This analysis, based on data from the Cooperative International Neuromuscular Research Group (CINRG) natural history study provides a rationale for why the rise times are typically presented as velocities and how to interpret the velocity changes. The analysis characterized the evolution of TTSTAND velocity by age both glucocorticoid using and non-using patients and estimates the difference between the GC-users and non-users.
We describe the dispersion of DMD individuals around their healthcare facilities using the largest population-based surveillance data on DMD in the US. This study contributes to the characterization of the burden of care in terms of time/distance traveled to healthcare services. This burden can impact individuals with DMD, their relatives, and caregivers.
The DMD Care Considerations are based on expert opinions and are designed to help clinicians provide optimal respiratory care to individuals with DMD. Data such as the PFTs collected in this study can help refine and optimize the care guidelines. Currently, the care considerations propose using a tiered approach to pulmonary care with initiation of lung volume recruitment first, followed by cough assist, and then noninvasive ventilation. These data suggest that there may be very few, if any, instances in which lung volume recruitment criteria are met prior to cough assist criteria, and that MEP, which is not performed as often in clinic, may be just as important to evaluate as FVC. There may be a need to reexamine the pulmonary intervention care guidelines to best match the needs of the DMD community.
Corticosteroids, including deflazacort and prednisone/prednisolone, are standards of care in patients with Duchenne muscular dystrophy. In this study, we describe reasons for switching from prednisone/prednisolone to deflazacort in these patients, using chart review data from patients with dystrophinopathies.
A shared priority across the Duchenne community is reducing the burden associated with accessing a diagnosis and optimizing the care pathway for all individuals and families. Newborn screening (NBS) is one approach being explored. We looked at the NBS landscape across 10 countries in an effort to increase the understanding of previous NBS efforts, share learnings from those efforts, and identify opportunities to advance NBS for the early diagnosis and care management of patients and families with DMD.
As the development of therapies for DMD continues to accelerate and our understanding of the highest standards of care increases further. Whilst the masterclasses are aimed at clinicians, it would be good for parents to know that this work is being carried out and to hear about the impact of the masterclasses.
Duchenne or Becker muscular dystrophy patients and families will be interested in learning about the most important information needs of young people with these conditions. In listening to my poster presentation, patients and their families will learn what the most important topics are to those who were interviewed. They will also learn that patients with Duchenne muscular dystrophy have different information needs than patients with Becker muscular dystrophy. In addition, they will learn that the topics of interest change between younger and older patients.
Parents, physicians, and other who care for young people with either Duchenne or Becker muscular dystrophy will learn more about what resources are important for young people at various stages in their disease process. Learning about the information needs of young people with Duchenne or Becker muscular dystrophy should enhance the available resources for these individuals and their families.
The TREAT-NMD Global Registries Platform poster offers insight to the DMD community of the development process for the application and the importance attached to harmonising and standardising of patient data collection. It notes the contribution to the project of key opinion leaders in the field of DMD research from clinical, academic and patient led organisations as well as the participation of technical IT industry partners in developing the application to meet global patient privacy and data security standards. The poster also describes the collaboration underpinning the development process; a close partnership with a range, clinical, patient and dual-reported DMD registries from around the world to ensure that patient needs drive the project and its outcomes.
AAV is the vector of choice for delivering a therapeutic gene to the muscle in DMD patients. Muscle is composed of different types of fibers. Dystrophic pathology affects the composition of the muscle fiber type. An important question in AAV-mediated DMD gene therapy is to understand which types of myofibers are transduced by different AAVs and how AAV gene therapy affects myofiber type composition. In this study, we examined myofiber type transduction profiles of AAV8 and AAV9 in the canine DMD model. AAV8 and AAV9 are currently being used to treat neuromuscular diseases in human patients. Our results will inform future DMD gene therapy development.
This poster is relevant for members of the Duchenne community interested in learning about ongoing preclinical research to enhance the effect of oligonucleotide-based exon skipping therapies in the skeletal and cardiac muscle.
Heart failure is increasingly becoming the main contributor to mortality in DMD patients. It is therefore imperative to have a small, preclinical animal model that shows a similar cardiac disease progression to DMD patients in order to facilitate therapeutic development. In this study, we carefully characterized the heart function of the D2.mdx mouse model of DMD. We believe this mouse model will be useful in better understanding the defects observed in dystrophin deficient hearts and will be critical in better evaluating the efficacy of potential therapies on correcting the cardiac dysfunction that is representative of DMD patients.
Heart failure in a significant problem in patients with Duchenne muscular dystrophy (DMD). This study shows that a mouse model of DMD that increasing how hard the heart beats results in lots of heart damage. Interestingly, this injury is reduced in mice taking losartan, an AT1R blocker that is sometimes used to treat heart disease in DMD patients. ACE inhibitors are the most commonly prescribed heart drug in DMD. Mice taking lisinopril, a common ACE inhibitor, are NOT protected from injury. To determine if this difference is seen in DMD patients, we examined the medical records of over 500 DMD patients to determine what cardiac drugs they were taking and what their heart function was. This analysis shows that 34% of patients on ACE inhibitors were in heart failure compared to only 13% of patients on an AT1R blocker. These data suggest that AT1R blockers may limit heart failure in DMD.
REGENXBIO is developing a novel, microdystrophin gene therapy (RGX-202) for DMD. RGX-202 features key design elements including: 1) AAV8 capsid selected for efficient delivery of the microdystrophin transgene to skeletal and heart muscle; 2) a muscle-specific promoter (Spc5-12) selected to express the microdystrophin protein primarily in the muscle cells; 3) a novel microdystrophin transgene which contains coding regions, including a portion of the C-Terminal (CT) domain, designed to provide essential functional elements of naturally occurring, full-length dystrophin. In this poster presentation, we will provide background on gene therapy, introduce RGX-202, and share preclinical data that provide rationale for the further development of RGX-202 as a potential microdystrophin gene therapy for DMD.