Certain proteins may be biomarkers of BMD progression, study suggests
DMD patients given gene therapy could also see benefits
Levels of certain proteins implicated in immune response and the body’s process to stop bleeding differ between Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD), according to a study
Also, blood levels of these proteins correlated with the degree of motor function in BMD participants, but not in those with Duchenne.
“If further evaluated and validated, these biomarker candidates may offer means to monitor disease progression in BMD patients,” the scientists wrote.
These biomarkers can be evaluated from blood (serum) samples rather than biopsy, which, according to the investigators, has limitations related to being invasive and providing information from only a small amount of tissue.
Because gene therapy for Duchenne may likely lead to a milder disease presentation similar to Becker, looking at biomarkers may benefit both the clinical management of BMD and people with DMD given gene therapy, the scientists said.
The study, “Contrasting Becker and Duchenne muscular dystrophy serum biomarker candidates by using data independent acquisition LC-MS/MS,” was published in the journal Skeletal Muscle.
Scientists: Biomarkers needed for monitoring BMD progression
Duchenne is the most common type of MD, followed by Becker. Usually, DMD symptoms begin in childhood, whereas those of BMD tend to start later in life and are often less severe.
Mutations in the DMD gene, which provides instructions to produce the protein dystrophin, cause both DMD and BMD. People with Duchenne have virtually no working dystrophin, whereas those with Becker have higher amounts that are still lower than in healthy individuals.
While studies have focused on establishing biomarkers for Duchenne, less attention has been given to Becker. Researchers have tried to translate findings from DMD to BMD, assuming that they share both underlying cause and clinical features.
“While the diagnosis of BMD is well established, biomarkers for monitoring disease progression and response to treatment are needed,” the scientists wrote. “The use of biomarkers as a surrogate endpoint in therapeutic trials in BMD would be a welcoming alternative for the currently used functional tests, which have a relatively low sensitivity to changes in disease progression.” A surrogate clinical trial endpoint predicts a treatment’s clinical benefit, but isn’t directly measuring it.
“However, our understanding of longitudinal protein profiles in BMD patients is limited and few, if any, longitudinal BMD proteomic studies [large-scale studies of proteins] have been published to date,” they added.
21 proteins exhibited different relationships with age in DMD, BMD: Study
The researchers investigated blood-based biomarkers in 19 DMD patients and 34 BMD patients, who contributed one to five blood samples during a mean follow-up of 3.4 years. Half of the BMD participants also had samples collected a mean of 4.7 years prior to the first study visit.
DMD participants had a mean age of 7.4. While four could walk at the beginning of the study, all had lost this ability by the end of the study. BMD participants had a mean age of 39.9 at the time of the first sample, when most (79.4%) could walk. Four of these were non-ambulatory by the final sample.
Levels of 29 proteins significantly correlated with age in DMD participants. Two proteins showed such correlation in BMD.
“While age is a good predictor of disease progression in DMD patients, it is less so for BMD, where progression is more heterogenous and less age dependent according to functional scales,” the researchers noted.
The team also identified 21 proteins that exhibited significantly different relationships with age in DMD and BMD. One protein, pyruvate kinase, which is involved in a key metabolism pathway, correlated with age in both Duchenne and Becker, but showed a steeper age trajectory (a significant change in the rate of decline or increase of protein abundance) in DMD.
While age is a good predictor of disease progression in DMD patients, it is less so for BMD, where progression is more heterogenous and less age dependent according to functional scales.
In the BMD group, the researchers looked for significant correlations between protein levels and measures of motor function. Levels of 10 proteins correlated with a motor function tool called North Star Ambulatory Assessment, seven of which were involved in the immune response.
This suggests “an increase in inflammation in BMD patients as the disease progresses,” the team wrote.
Twelve BMD participants also underwent a muscle biopsy to measure dystrophin. One protein, called alpha-2-macroglobulin (A2M), had a statistically significant correlation with dystrophin.
“A2M decreased faster over both time and age in patients with low dystrophin expression compared to patients with high expression of dystrophin,” the team noted. “This observation was in agreement with the age-related decline of A2M in DMD patients. Interestingly, A2M did not decrease with age or time alone in the BMD patients.”
Overall, “these results revealed 10 potential biomarkers reflecting disease progression in BMD and suggest that BMD progression monitoring biomarkers are more likely found to be proteins involved in the innate immune response (C4BPB, PGLYRP2, GSN, CFI, C3, HPX and APCS), extracellular matrix organization (PLGLB1/ PLGLB2 and TNXB) and hemostasis (CLEC3B),” the scientists concluded.
The extracellular matrix, made of proteins and other molecules, provides structural support to cells; hemostatis refers to the body’s way of stopping bleeding and repairing after injury.
Limitations of the study were the wide age variation at the time of sampling in BMD participants and the lack of samples from age-matched healthy controls, according to the investigators.
“To evaluate the effect of aging and validate the biomarkers presented in this paper, future studies have to include age-matched controls,” they wrote.
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