Dataset Information

Outcome Measures in Facioscapulohumeral Muscular Dystrophy Clinical Trials.

ABSTRACT: Facioscapulohumeral muscular dystrophy (FSHD) is a debilitating muscular dystrophy with a variable age of onset, severity, and progression. While there is still no cure for this disease, progress towards FSHD therapies has accelerated since the underlying mechanism of epigenetic derepression of the double homeobox 4 (DUX4) gene leading to skeletal muscle toxicity was identified. This has facilitated the rapid development of novel therapies to target DUX4 expression and downstream dysregulation that cause muscle degeneration. These discoveries and pre-clinical translational studies have opened new avenues for therapies that await evaluation in clinical trials. As the field anticipates more FSHD trials, the need has grown for more reliable and quantifiable outcome measures of muscle function, both for early phase and phase II and III trials. Advanced tools that facilitate longitudinal clinical assessment will greatly improve the potential of trials to identify therapeutics that successfully ameliorate disease progression or permit muscle functional recovery. Here, we discuss current and emerging FSHD outcome measures and the challenges that investigators may experience in applying such measures to FSHD clinical trial design and implementation.

SUBMITTER: Ghasemi M

PROVIDER: S-EPMC8870318 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Outcome Measures in Facioscapulohumeral Muscular Dystrophy Clinical Trials.

Ghasemi Mehdi M Emerson Charles P CP Hayward Lawrence J LJ

Cells 20220216 4

Facioscapulohumeral muscular dystrophy (FSHD) is a debilitating muscular dystrophy with a variable age of onset, severity, and progression. While there is still no cure for this disease, progress towards FSHD therapies has accelerated since the underlying mechanism of epigenetic derepression of the double homeobox 4 (<i>DUX4</i>) gene leading to skeletal muscle toxicity was identified. This has facilitated the rapid development of novel therapies to target <i>DUX4</i> expression and downstream d ...[more]

PMID: 35203336

Similar Datasets

Project description:BackgroundFacioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle. For MRI to be a useful biomarker in an FSHD clinical trial, it should reliably detect changes over relatively short time-intervals (~ 1 year). We hypothesized that fatty change over the study course would be most likely in muscles already demonstrating disease progression, and that the degree of MRI burden would be correlated with function.MethodsWe studied 36 patients with FSHD and lower-extremity weakness at baseline. Thirty-two patients returned in our 12-month longitudinal observational study. We analyzed DIXON MRI images of 16 lower-extremity muscles in each patient and compared them to quantitative strength measurement and ambulatory functional outcome measures.ResultsThere was a small shift to higher fat fractions in the summed muscle data for each patient, however individual muscles demonstrated much larger magnitudes of change. The greatest increase in fat fraction was observed in muscles having an intermediate fat replacement at baseline, with minimally (baseline fat fraction < 0.10) or severely (> 0.70) affected muscles less likely to progress. Functional outcome measures did not demonstrate marked change over the interval; however, overall MRI disease burden was correlated with functional outcome measures. Direct comparison of the tibialis anterior (TA) fat fraction and quantitative strength measurement showed a sigmoidal relationship, with steepest drop being when the muscle gets more than ~ 20% fatty replaced.ConclusionsAssessing MRI changes in 16 lower-extremity muscles across 1 year demonstrated that those muscles having an intermediate baseline fat fraction were more likely to progress. Ambulatory functional outcome measures are generally related to overall muscle MRI burden but remain unchanged in the short term. Quantitative strength measurement of the TA showed a steep loss of strength when more fatty infiltration is present suggesting that MRI may be preferable for following incremental change or modulation with drug therapy.

Dataset Information

Outcome Measures in Facioscapulohumeral Muscular Dystrophy Clinical Trials.

Publications

Outcome Measures in Facioscapulohumeral Muscular Dystrophy Clinical Trials.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets