K.M. Flanigan

The 2-min walk test is sufficient for evaluating walking abilities in sporadic inclusion body myositis.

Sporadic inclusion body myositis causes progressive functional loss due to declining muscle strength. Although the underlying cause is unknown, clinical trials are underway to improve strength and function. Selection of appropriate outcome measures is critical for the success of these trials. The 6-min walk test has been the de facto standard for assessing function in neuromuscular disease; however, the optimal walking test has not been determined in this disease. In this study, 67 individuals with sporadic inclusion body myositis completed a battery of quantitative strength and functional tests including timed walking tests, patient-reported outcomes, and other tasks. The 2-min and 6-min walk tests are highly correlated to each other (r=0.97, p<0.001) and to all lower extremity strength, patient-reported, and functional measures in this population. All subjects completed the 2-min walk test, but 7% of subjects were unable to walk the full 6-min of the 6-min walk test due to fatigue. The 2-min walk test demonstrates similar correlation to all outcomes compared to the 6-min walk test, is less fatiguing and better tolerated. Results suggest that the 2-min walk test is a better alternative to tests of longer duration. Further research is needed to determine longitudinal changes on this outcome.

Correlation of knee strength to functional outcomes in becker muscular dystrophy

Introduction: The correlation of strength with performance on functional outcomes has not been evaluated in Becker muscular dystrophy (BMD), yet the determination of proper outcome measures is critical to the success of upcoming trials designed to improve strength. Methods: Lower extremity strength and performance on functional outcome measures were tested in 25 ambulatory subjects with BMD. Results: All subjects demonstrated marked knee extensor and flexor muscle weakness. Knee extensor strength was correlated with performance on the Berg Balance Scale and stair climbing. Knee flexor strength was highly correlated with performance on all functional outcomes, including timed walking distances. Conclusions: This profile differs from that previously reported in other neuromuscular diseases and demonstrates the importance of designing outcome measures for clinical trials in muscle disorders with considerations for the disease process, the mode, and the target of intervention. The findings emphasize that 1 set of outcomes is not appropriate for all neuromuscular diseases. Muscle Nerve, 2013

Dp412e: a novel human embryonic dystrophin isoform induced by BMP4 in early differentiated cells

BackgroundDuchenne muscular dystrophy (DMD) is a devastating X-linked recessive genetic myopathy. DMD physiopathology is still not fully understood and a prenatal onset is suspected but difficult to address.MethodsThe bone morphogenetic protein 4 (BMP4) is a critical signaling molecule involved in mesoderm commitment. Human induced pluripotent stem cells (hiPSCs) from DMD and healthy individuals and human embryonic stem cells (hESCs) treated with BMP4 allowed us to model the early steps of myogenesis in normal and DMD contexts.ResultsUnexpectedly, 72h following BMP4 treatment, a new long DMD transcript was detected in all tested hiPSCs and hESCs, at levels similar to that found in adult skeletal muscle. This novel transcript named “Dp412e” has a specific untranslated first exon which is conserved only in a sub-group of anthropoids including human. The corresponding novel dystrophin protein of 412-kiloDalton (kDa), characterized by an N-terminal-truncated actin-binding domain, was detected in normal BMP4-treated hiPSCs/hESCs and in embryoid bodies. Finally, using a phosphorodiamidate morpholino oligomer (PMO) targeting the DMD exon 53, we demonstrated the feasibility of exon skipping validation with this BMP4-inducible hiPSCs model.ConclusionsIn this study, the use of hiPSCs to analyze early phases of human development in normal and DMD contexts has led to the discovery of an embryonic 412 kDa dystrophin isoform. Deciphering the regulation process(es) and the function(s) associated to this new isoform can contribute to a better understanding of the DMD physiopathology and potential developmental defects. Moreover, the simple and robust BMP4-inducible model highlighted here, providing large amount of a long DMD transcript and the corresponding protein in only 3 days, is already well-adapted to high-throughput and high-content screening approaches. Therefore, availability of this powerful cell platform can accelerate the development, validation and improvement of DMD genetic therapies.

Modeling functional decline over time in sporadic inclusion body myositis.

Introduction: The ability to individualize recommendations or expectations of disease progression based on a patients unique characteristics has merit for use in sporadic inclusion body myositis (sIBM). Methods: Fifty‐five subjects with sIBM completed a battery of strength and functional outcomes at 2 study visits. These were used to develop mathematical models of disease progression in patients with sIBM for use in clinical and research settings. Results: The 6‐minute walk test (6MWT) distance declined by an average of 27.5 meters (12%) per year. Significant factors that predict 6MWT were knee extension and plantarflexion strength and body weight, whereas the ability to stand from a chair was impacted by elbow extension strength. Stepping up on a curb was influenced by the patients age at diagnosis and by knee extension. Statistical models to predict functional decline in sIBM were developed. Conclusion: Statistical models help explain the complex factors that influence decreased walking ability and other functional activities in sIBM. Muscle Nerve 55: 526–531, 2017

497. Follistatin Gene Therapy Improves Six Minute Walk Distance in Sporadic Inclusion Body Myositis (sIBM)

Treatment of sIBM poses many challenges. The cause of this disease is enigmatic, and although considered to be an inflammatory myopathy, there is resistance to anti-inflammatory and immunosuppressive agents. sIBM muscle biopsies show vacuolated muscle fibers, widespread inflammation, and intracellular amyloid deposits. Follistatin is a potent inhibitor of the myostatin pathway and its potential as a therapeutic vehicle is enhanced by a pathway independent of the activin IIB receptor. We have demonstrated both safety and efficacy following direct intramuscular injection of follistatin in the quadriceps muscle in a previously reported gene therapy trial in Becker muscular dystrophy (Mendell JR, et al Mol Ther 2015). No off target effects were encountered attributed to the use of an alternatively spliced follistatin isoform, FS344, also used in the current sIBM gene therapy trial. Enrollment in the current gene therapy trial included 6 subjects with either definite or possible sIBM (Griggs RC, et al. Ann Neurol 1995). Pretreatment MRIs were obtained to determine areas of relative muscle sparing/lack of fibrosis. The intramuscular injections of AAV1.CMV.FS344 to 12 to 14 sites in the quadriceps muscle delivered 1.2X1012 vg/kg. Injections were performed with direct ultrasound guidance to target the most normal appearing muscle bundles, and intramuscular position was confirmed with simultaneous EMG. A three-patient, single limb, safety trial preceded the Phase I/IIA trial reported here. During the ongoing gene therapy trial, a control sIBM group (n=20) was prospectively studied by performance of the 6MWT with follow up from 9-28 months.The 6MWT was the primary functional outcome (See table below). sIBM patients treated with AAV1.CMV.FS344 increased the 6MWT distance by 46.5m (457 to 503.5, p =0.001). Untreated sIBM controls lost 38.5m over a similar time period resulting in net difference of 85.0m between groups (p=0.0007). To validate findings and confirm the lack of selection bias we compared a subgroup of untreated sIBM controls (n=8), matched for age, gender, and 6MWD at baseline. Matched controls lost 39m (p=0.0036) in the 6MWD, a virtually identical loss to the larger control group.The results of this study demonstrate that sIBM can benefit from follistatin gene therapy based on improvement in distance walked in the 6MWT. We did find a hierarchy of response based on muscle preservation and avoiding gene delivery to areas of fibrosis. In this study, gene delivery was limited to the quadriceps muscle, but in future trials more widespread delivery could potentially be more effective.Six Minute Walk Distance Pre- and Post-Treatment* [median values (interquartile ranges provided)]GroupBaseline (m)Final Compared to Baseline (m)Change from Baseline (m)Change per Month (m)sIBM Gene Therapy Pts (n =6)457 (431,475)Improved to 503.5 (443, 573)+46.5 (2,117)+3.09 (0.39, 8.9)Untreated sIBM Controls (n =20)393 (356.5,.451.5)Declined to 354.5 (303.5,410.5)−38.5 (−73,−22) p =0.0007−2.3 (−4,−1. 1) P =0.0032Matched sIBM Controls for age, gender, and 6MWD (n = 8)459 (439.5,469)Declined to 420 (388.5,447.5)−39.0 (−77,−8) p = 0.0036−2.2 (−4.8. −0.7) P=0.0118 View Table in HTML Data analysis used SAS 9.3 (SAS Institute, Cary NC) with two-sided p-values.

Response to Letter by Yilmaz et al Regarding Article, “Analysis of Dystrophin Deletion Mutations Predicts Age of Cardiomyopathy Onset in Becker Muscular Dystrophy”

We thank Drs Yilmaz, Suttie, and Petersen for recognizing the novelty and value of our approach that incorporates protein structure information into genotype-phenotype studies. In their letter, they pointed out the limitations in sensitivity of conventional echocardiography to detect the earliest signs of cardiac involvement in patients with dystrophinopathy. We acknowledge that cardiovascular magnetic resonance (CMR) imaging is more sensitive at localizing the earliest focal posterior left ventricular wall lesions. However, the letter by Yilmaz et al did not explain …