Clinical trial readiness to solve barriers to drug development in FSHD (ReSolve): protocol of a large, international, multi-center prospective study
Facioscapulohumeral muscular dystrophy (FSHD) is a dominantly-inherited progressive muscular dystrophy caused by de-repression of the DUX4 gene, which causes disease by a toxic-gain-of-function. As molecularly ta...
Facioscapulohumeral muscular dystrophy (FSHD) is caused by loss of repression at the D4Z4 locus resulting in aberrant expression of the homeobox transcription factor DUX4. DUX4 expression activates its downstream transcriptional program resulting in cell death, skeletal muscle loss and progressive motor disability. Fulcrum Therapeutics is developing losmapimod to treat FSHD at its root cause by inhibiting DUX4 expression. Pre-clinical studies demonstrate that losmapimod is a potent and highly selective small molecule inhibitor of p38 α/β resulting in reduction of DUX4 activity and its downstream transcriptional ...
Facioscapulohumeral muscular dystrophy (FSHD) type 1 is a common muscular dystrophy with an estimated prevalence of 1 in 15,000 caused by a heterozygous contraction of D4Z4 repeats on a chromosome with a 4qA haplotype . The classical phenotype includes facial weakness followed sequentially by scapular fixator, humeral, truncal, and lower-extremity weakness. However, the clinical picture is diverse and often atypical including scapular or scapuloperoneal muscular dystrophy, infantile facial diplegia, limb girdle muscular dystrophy, distal or monomelic myopathy and bent spine syndrome.
This study aims to investigate the reliability, validity and clinical utility of a modified FSH-COM in children with FSHD aged 5-18 years.
DUX4 de-repression causes Facioscapulohumeral muscular dystrophy (FSHD), which is associated with progressive muscle wasting and weakness that may lead to wheelchair dependence. There are currently no treatments that alter the course of FSHD and therapy development is an unmet need in the field. DUX4 genome editing using the CRISPR-Cas9 approach is promising but also has challenges, partly because the DUX4 gene is present in potentially hundreds of copies, embedded within identical or nearly identical D4Z4 repeats.
To find the involvement pattern of skeletal muscle in FSHD patients and its correlation with clinical evaluations. PATCHS MRI scans of multi-section muscles consist of bilateral 6 muscle groups including scapular girdle, humeral, pelvic girdle, thigh, calf and axial muscles, with a total of 78 muscles. PATCHS MRI scans in 30 Chinese FSHD1 patients were semi-quantitively assessed for fat infiltration and were correlated to multiple clinical outcome measures. Cluster analysis was conducted to identify the different involvement pattern of muscles.
Aim of this multicenter study was to define the radiological features of facioscapulohumeral muscular dystrophy type 2 (FSHD2), the similarities or differences with FSHD1, and to explore correlations with molecular data in order to improve knowledge about this rare disorder. Muscle MRI scans of 34 molecularly confirmed FSHD2 patients from 9 European neuromuscular centers were analyzed, to assess the pattern of involvement and the extent of fatty replacement and muscle oedema. The most frequently affected muscles were the abdominals, semimembranosus, soleus and gluteus minimus in the lower limbs; trapezius, serratus anterio...
In this study, we developed a quantitative STIR method, and tested its ability to identify STIR+ lesions in 9 healthy controls and 7 patients with Facioscapulohumeral muscular dystrophy and compared the results with visual STIR evaluation and quantitative T2 relaxation time mapping.
The precise classification of FSHD is crucial for deepening the understanding of disease as well as the efficient diagnosis and follow-up. We aimed to explore the difference of clinical severity in FSHD patients classified by the Comprehensive Clinical Evaluation Form (CCEF). Totally 54 Chinese FSHD1 patients, diagnosed by molecular combing or southern blot, were classified by CCEF, proposed by the Italian Clinical Network for FSHD. All patients were evaluated by structured questionnaire, as well as the manual muscle test (MMT), FSHD clinical score (CS), Ricci score (CSS), 6-minute walking test (6MWT) and motor function measure (MFM).
Facioscapulohumeral muscular dystrophy (FSHD) presentation often varies in severity, rate of progression and age-of-onset, even in families with several affected relatives. Modifier genes could contribute to FSHD variability by influencing DUX4 expression and toxicity. We hypothesized that DUX4 mRNA could be a potential target of miRNAs expressed in skeletal muscles, and therefore, miRNAs could function as modifiers of FSHD severity. Using a candidate approach, we found that a natural human miRNA (mir-675) can directly inhibit DUX4 expression and counteract DUX4 pathogenicity in skeletal muscle and non-muscle cells (manuscript submitted).
Facioscapulohumeral muscular dystrophy (FSHD) is among the most common forms of muscular dystrophy. FSHD is caused by aberrant expression of the toxic DUX4 gene in muscle. Detecting endogenous DUX4 in patient tissue using conventional methods can be challenging, due to the low level of DUX4 expression. In addition to impacting basic research, the difficulty to reliably detect DUX4 expression could pose challenging for future prospective clinical trials involving DUX4 inhibition therapies, where DUX4 levels would be useful as a therapeutic outcome measure.