Biomarkers in Duchenne Muscular Dystrophy: Current Status and Future Directions

Abstract

Duchenne muscular dystrophy is a severe, X-linked disease characterized by decreased muscle mass and function in children. Genetic and biochemical research over the years has led to the characterization of the cause and the pathophysiology of the disease. Moreover, the elucidation of genetic mechanisms underlining Duchenne muscular dystrophy has allowed for the design of innovative personalized therapies. The identification of specific, accurate, and sensitive biomarkers is becoming crucial for evaluating muscle disease progression and response to therapies, disease monitoring, and the acceleration of drug development and related regulatory processes. This review illustrated the up-to-date progress in the development of candidate biomarkers in DMD at the level of proteins, metabolites, micro-RNAs (miRNAs) and genetic modifiers also highlighting the complexity of translating research results to clinical practice. We highlighted the challenges encountered in translating biomarkers into the clinical context and the existing bottlenecks hampering the adoption of biomarkers as surrogate endpoints. These challenges could be overcome by national and international collaborative efforts, multicenter data sharing, definition of public biobanks and patients’ registries, and creation of large cohorts of patients. Novel statistical tools/ models suitable to analyze small patient numbers are also required. Finally, collaborations with pharmaceutical companies would greatly benefit biomarker discovery and their translation in clinical trials.

How Can Proteomics Help to Elucidate the Pathophysiological Crosstalk in Muscular Dystrophy and Associated Multi-System Dysfunction?

“…Besides testing novel pharmacological strategies [ 257 , 381 , 382 , 383 , 384 ] and immunomodulatory interventions [ 355 , 356 , 357 , 358 , 364 ], a variety of innovative therapeutic approaches are currently evaluated in the field of muscular dystrophy [ 385 , 386 , 387 , 388 , 389 ], including exon skipping [ 148 , 390 , 391 , 392 , 393 ], genomic editing [ 394 , 395 , 396 ], codon read-through [ 397 ], gene replacement with the help of adeno-associated viral vectors [ 398 , 399 , 400 , 401 , 402 ], dystrophin substitution with its autosomal homolog utrophin [ 403 , 404 , 405 ], and muscle stem cell therapy [ 406 , 407 , 408 , 409 ]. Hence, for the optimum pre-clinical testing of new therapies, the clinical evaluation of diverse patient cohorts during the various phases of clinal studies/trials, and long-term therapeutic monitoring, robust and specific biomarkers for the routine screening of the status of dystrophic patients are required [ 144 , 264 , 265 , 410 , 411 ]. Ideal protein biomarkers would be measurable in a non-invasive, or at least minimally invasive, way and be suitable for repeated sampling procedures […”

“…Hence, for the optimum pre-clinical testing of new therapies, the clinical evaluation of diverse patient cohorts during the various phases of clinal studies/trials, and long-term therapeutic monitoring, robust and specific biomarkers for the routine screening of the status of dystrophic patients are required [ 144 , 264 , 265 , 410 , 411 ]. Ideal protein biomarkers would be measurable in a non-invasive, or at least minimally invasive, way and be suitable for repeated sampling procedures [ 325 , 345 , 410 , 411 , 412 ].…”

SPP1 promotes tumor progression in esophageal carcinoma by activating focal adhesion pathway

“…Secreted phosphoprotein 1 (SPP1; known as osteopontin) is a kind of secreted acidic protein ( 6 ), which is commonly expressed in osteocytes, macrophages, and endothelial cells, etc. ( 7 - 10 ) and regulates various biological functions, including bone remodeling, chemotaxis, cell activation, and apoptosis ( 6 , 11 - 15 ). Under pathological conditions, SPP1 is highly expressed in several types of cancers such as colorectal cancer, gastric cancer, liver cancer, pancreatic cancer and breast cancer, to name a few ( 16 , 17 ).…”