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

IF 5.3 2区 医学 Q2 CELL BIOLOGY
Jessica F. Boehler, Kristy J. Brown, Valeria Ricotti, Carl A. Morris
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Abstract

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. 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. 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. 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. ClinicalTrials.gov NCT03368742.
N 端 titin 片段:微囊营养素疗效的非侵入性药效生物标志物
目前正在进行多项临床试验,以评估 AAV 引导基因转移对杜氏肌营养不良症(DMD)患者的疗效。这些试验的成功目前依赖于标准的功能性结果测量,而这些结果测量在参与者内部和参与者之间可能会表现出差异性,因此将其用作药物疗效的唯一测量方法具有挑战性。有鉴于此,支持性客观生物标志物可能有助于提高观察到的临床结果。肌酸激酶 (CK) 传统上被用作 DMD 的诊断生物标志物,但由于同一受试者体内随着时间的推移会出现很大的变异,因此很难将其作为可靠的药效学 (PD) 生物标志物。因此,有必要发现和验证新型 PD 生物标记物,以进一步支持和加强 DMD 的传统疗效指标。我们在 Somalogic 平台上采用蛋白质组学方法对 DMD 患者尿液中潜在的 PD 生物标志物进行了检测。研究结果在 mdx 小鼠和金毛寻回犬肌营养不良症 (GRMD) 犬血浆样本中均得到了证实。在小鼠、狗和人体内,钛蛋白 N 端片段的变化与微小肌营养不良蛋白的表达相关。此外,与 CK 相比,titin 水平对表达的较低水平的微管营养素敏感。对客观的腹膜透析生物标志物(如 titin)进行测量,可为评估 DMD 基因疗法临床试验的作用机制和疗效提供更多信心。ClinicalTrials.gov NCT03368742。
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来源期刊
Skeletal Muscle
Skeletal Muscle CELL BIOLOGY-
CiteScore
9.10
自引率
0.00%
发文量
25
审稿时长
12 weeks
期刊介绍: The only open access journal in its field, Skeletal Muscle publishes novel, cutting-edge research and technological advancements that investigate the molecular mechanisms underlying the biology of skeletal muscle. Reflecting the breadth of research in this area, the journal welcomes manuscripts about the development, metabolism, the regulation of mass and function, aging, degeneration, dystrophy and regeneration of skeletal muscle, with an emphasis on understanding adult skeletal muscle, its maintenance, and its interactions with non-muscle cell types and regulatory modulators. Main areas of interest include: -differentiation of skeletal muscle- atrophy and hypertrophy of skeletal muscle- aging of skeletal muscle- regeneration and degeneration of skeletal muscle- biology of satellite and satellite-like cells- dystrophic degeneration of skeletal muscle- energy and glucose homeostasis in skeletal muscle- non-dystrophic genetic diseases of skeletal muscle, such as Spinal Muscular Atrophy and myopathies- maintenance of neuromuscular junctions- roles of ryanodine receptors and calcium signaling in skeletal muscle- roles of nuclear receptors in skeletal muscle- roles of GPCRs and GPCR signaling in skeletal muscle- other relevant aspects of skeletal muscle biology. In addition, articles on translational clinical studies that address molecular and cellular mechanisms of skeletal muscle will be published. Case reports are also encouraged for submission. Skeletal Muscle reflects the breadth of research on skeletal muscle and bridges gaps between diverse areas of science for example cardiac cell biology and neurobiology, which share common features with respect to cell differentiation, excitatory membranes, cell-cell communication, and maintenance. Suitable articles are model and mechanism-driven, and apply statistical principles where appropriate; purely descriptive studies are of lesser interest.
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