Biomarkers of Duchenne muscular dystrophy: current findings

Abstract

Numerous biomarkers have been unveiled in the rapidly evolving biomarker discovery field, with an aim to improve the clinical management of disorders. In rare diseases, such as Duchenne muscular dystrophy, this endeavor has created a wealth of knowledge that, if effectively exploited, will benefit affected individuals, with respect to health care, therapy, improved quality of life and increased life expectancy. The most promising findings and molecular biomarkers are inspected in this review, with an aim to provide an overview of currently known biomarkers and the technological developments used. Biomarkers as cells, genetic variations, miRNAs, proteins, lipids and/or metabolites indicative of disease severity, progression and treatment response have the potential to improve development and approval of therapies, clinical management of DMD and patients’ life quality. We highlight the complexity of translating research results to clinical use, emphasizing the need for biomarkers, fit for purpose and describe the challenges associated with qualifying biomarkers for clinical applications.

Biomarkers for Duchenne muscular dystrophy: myonecrosis, inflammation and oxidative stress

“…Some candidate DMD biomarkers have been identified in several studies and species, and their responsiveness to therapies demonstrated, whereas others may have been identified in a single study or show wide variation between individuals and between studies (Table 1 and discussed below). For example, one classic widely used clinical blood ( plasma) biomarker for DMD is the enzyme creatine kinase (CK; Box 1), which is elevated in patients and in rodent and dog DMD models, but can be highly variable (reviewed by Dowling et al, 2019;Hathout et al, 2014;Szigyarto and Spitali, 2018). Nevertheless, increased CK levels, specifically the MM muscle form measured by immunoassay in dried bloodspots, are now being used for newborn DMD screening (Moat et al, 2017).…”

“…More recently, extensive proteomic, RNA and metabolite analyses have been carried out in animal models and patients, as discussed in a number of excellent reviews on potential biomarkers for muscle, blood and urine (Aartsma-Rus et al, 2018; Aartsma-Rus and Spitali, 2015;Dowling et al, 2019;Hathout et al, 2014Hathout et al, , 2016Lourbakos et al, 2017;Parolo et al, 2018;Szigyarto and Spitali, 2018;Thangarajh et al, 2019). A large-scale proteomic approach to identify serum biomarkers associated with pathophysiological change over time (Spitali et al, 2018) concluded that ∼33 proteins were bona fide biomarkers as they were able to discriminate between DMD patients and healthy controls in all cohorts, with a concordant directional change towards either a consistent increase or decrease in patients.…”

“…The disturbed integrity of the dystrophic sarcolemma and myonecrosis exacerbate leakage. Several muscle-derived proteins, metabolites, RNAs and other molecules in the blood have been widely studied using a range of technologies (reviewed by Szigyarto and Spitali, 2018) and include enzymes such as CK and aldolase in the blood, structural proteins associated with sarcomeric contraction such as myosin light chain 1/3, myomesin 3 and fragments of titin in urine, breakdown products of myoglobin (Box 1) with ferritin in urine, and intermediate filaments such as filamin C (see Table 1). For blood biomarkers, it is important to consider whether they are measured in serum or plasma, and the anti-clotting agent for plasma samples needs to be carefully selected as sample preparation can influence detection of specific biomarkers (Szigyarto and Spitali, 2018).…”

“…Biomarkers of the consequent and delayed occurrence of fibrosis and fatty replacement of muscles, along with neurodegeneration, fall outside the scope of this Review. The progressive changes in tissue composition, which measure the severity of dystropathology over time, can be monitored by magnetic resonance imaging (MRI) in humans and animal models of DMD (Szigyarto and Spitali, 2018). Although MRI is increasingly being used as a powerful tool for measuring outcome without the need for muscle biopsy, its repeated use has limitations, including expensive equipment and expertise, high cost per measurement and inconvenience for the patient due to the immobilisation and time required for repeated measurements (Szigyarto and Spitali, 2018).…”

“…The progressive changes in tissue composition, which measure the severity of dystropathology over time, can be monitored by magnetic resonance imaging (MRI) in humans and animal models of DMD (Szigyarto and Spitali, 2018). Although MRI is increasingly being used as a powerful tool for measuring outcome without the need for muscle biopsy, its repeated use has limitations, including expensive equipment and expertise, high cost per measurement and inconvenience for the patient due to the immobilisation and time required for repeated measurements (Szigyarto and Spitali, 2018). For therapies using a drug that targets a specific molecular signalling pathway, it is clearly desirable to monitor the predicted changes in proteins or RNAs within that pathway to demonstrate drug target engagement and efficacy.…”