Dataset Information

N-terminal titin fragment: a non-invasive, pharmacodynamic biomarker for microdystrophin efficacy.

ABSTRACT:

Background

Multiple clinical trials to assess the efficacy of AAV-directed gene transfer in participants with Duchenne muscular dystrophy (DMD) are ongoing. The success of these trials currently relies on standard functional outcome measures that may exhibit variability within and between participants, rendering their use as sole measures of drug efficacy challenging. Given this, supportive objective biomarkers may be useful in enhancing observed clinical results. Creatine kinase (CK) is traditionally used as a diagnostic biomarker of DMD, but its potential as a robust pharmacodynamic (PD) biomarker is difficult due to the wide variability seen within the same participant over time. Thus, there is a need for the discovery and validation of novel PD biomarkers to further support and bolster traditional outcome measures of efficacy in DMD.

Method

Potential PD biomarkers in DMD participant urine were examined using a proteomic approach on the Somalogic platform. Findings were confirmed in both mdx mice and Golden Retriever muscular dystrophy (GRMD) dog plasma samples.

Results

Changes in the N-terminal fragment of titin, a well-known, previously characterized biomarker of DMD, were correlated with the expression of microdystrophin protein in mice, dogs, and humans. Further, titin levels were sensitive to lower levels of expressed microdystrophin when compared to CK.

Conclusion

The measurement of objective PD biomarkers such as titin may provide additional confidence in the assessment of the mechanism of action and efficacy in gene therapy clinical trials of DMD.

Trial registration

ClinicalTrials.gov NCT03368742.

SUBMITTER: Boehler JF

PROVIDER: S-EPMC10790446 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Publications

N-terminal titin fragment: a non-invasive, pharmacodynamic biomarker for microdystrophin efficacy.

Boehler Jessica F JF Brown Kristy J KJ Ricotti Valeria V Morris Carl A CA

Skeletal muscle 20240116 1

<h4>Background</h4>Multiple clinical trials to assess the efficacy of AAV-directed gene transfer in participants with Duchenne muscular dystrophy (DMD) are ongoing. The success of these trials currently relies on standard functional outcome measures that may exhibit variability within and between participants, rendering their use as sole measures of drug efficacy challenging. Given this, supportive objective biomarkers may be useful in enhancing observed clinical results. Creatine kinase (CK) is ...[more]

PMID: 38229112

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Project description:BackgroundSarcopenia is a gradual decline in skeletal muscle mass and strength, which eventually leads to reduced physical performance. 50% of people aged 60-80 years suffer from sarcopenia. Considering the devastating outcomes and the importance of promoting healthy ageing, the diagnosis and prevention of sarcopenia is of utmost importance. Recently, C-terminal agrin fragment (CAF) has been identified as an indicator for early diagnosis of sarcopenia. So far, systematic reviews demonstrating CAF as a biomarker for sarcopenia have been conducted, but a meta-analysis is still needed. This study contains systematic review as well as detailed meta-analysis to better understand the association of CAF and sarcopenia.MethodsArticles were primarily obtained from four different databases. Studies demonstrating the association between CAF and sarcopenia were selected. Data extraction and analysis were performed using STATASE 16 software. The risk of bias and quality assessment of each study was carried out using Joanna Briggs Institute (JBI) Critical Appraisal Tool. Meta-regression, subgroup and sensitivity analysis were conducted to identify the source of heterogeneity.ResultsSeventeen studies were included in the qualitative analysis, out of which 10 were included in the quantitative analysis. The meta-analysis showed that CAF levels were significantly higher in sarcopenia patients, with an effect size of 1.93 (ROM = 1.93, 95% CI [1.49 to 2.36]; p = 0.00) and 1.38 (ROM = 1.38, 95% CI [0.94 to 1.83], p = 0.00) when compared with non-sarcopenic and non-sarcopenic (other co-morbidities) group, respectively. CAF levels were also negatively associated with hand grip strength (HGS) and skeletal muscle index (SMI) with an effect size of 1.09 (ROM = 1.09 with 95% CI [1.05 to 1.13], p = 0.00) and 1.10 (ROM = 1.10 with 95% CI [1.05 to 1.14], p = 0.00), respectively. Meta-regression and subgroup analysis revealed that although sarcopenia is associated with increasing age, the correlation between CAF and age was statistically insignificant (p = 0.44), suggesting that the variation of age among sarcopenia patients could be source of heterogeneity among studies. All the studies included in the meta-analysis reported low risk of bias.ConclusionsOur meta-analysis concluded that elevated CAF levels were associated with sarcopenia and decreased HGS and SMI. CAF could serve as a valuable marker for the early detection and monitoring of sarcopenia, ultimately facilitating the management and treatment of this debilitating condition.

Dataset Information

N-terminal titin fragment: a non-invasive, pharmacodynamic biomarker for microdystrophin efficacy.

Background

Method

Results

Conclusion

Trial registration

Publications

N-terminal titin fragment: a non-invasive, pharmacodynamic biomarker for microdystrophin efficacy.

Similar Datasets

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