Davis: Researchers have identified 44 proteins in the blood of patients with
Duchenne muscular dystrophy that occur at significantly different
concentrations in comparison to healthy individuals of the same age.
Some protein biomarkers increase with disease progression, while others
decrease. These biomarkers are expected to be useful to researchers and
clinicians to study physiological processes of this rare muscle disease,
as well as to monitor treatment progress and develop more effective
therapies and diagnostic tools.
The findings have been published in the Proceedings of the National Academy of Sciences of the United States of America in an article titled, “Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy,” which is now available online.
“Having
biomarkers for a disease is extremely important to evaluate the
efficacy of experimental treatments,” said Craig McDonald, professor and
chair of Physical Medicine and Rehabilitation at UC Davis School of
Medicine and a principal investigator of the study. “This is especially
important in Duchenne muscular dystrophy, in which only a few
quantifiable measures currently exist.”
Duchenne muscular
dystrophy is a recessive X-linked genetic disorder that affects about 1
in 3,600 boys worldwide (girls who carry a single mutation are usually
not affected). A mutation in the dystrophin gene either reduces or
eliminates activity of a structural protein that protects muscle from
breakdown during normal activity. Without normal dystrophin, muscle
cells are easily damaged, and muscle is progressively replaced by fat
and fibrotic tissue. Symptoms of muscle weakness become apparent in
early childhood; as the disease progresses, patients usually become
wheelchair-dependent in their early teens, and typically die in their
20s of cardiac hypertrophy resulting from severe fibrosis of heart
muscle.
The study compared the blood of 93 patients with Duchenne
muscular dystrophy ages 2 to 29 years to blood from 45 age-matched
healthy volunteers used as controls. Serum samples were analyzed using a
sophisticated assay system that uses single strands of DNA or RNA
molecules to selectively bind to proteins. More than 1,000 proteins were
identified, and 44 were found that differed significantly in
concentration between patient and normal samples: 24 were increased in
patients and 20 were decreased.
The researchers found interesting
patterns of the concentrations of biomarkers as a factor of patient age –
an indicator of disease progression. For example, 18 proteins were
present at much higher levels in the youngest patients than in healthy
children of the same age, and then decreased with age in the patients
while remaining the same or increasing slightly in the controls. The
authors speculate that these proteins probably result from muscle damage
and cell death: One would expect high levels in patients early in the
course of the disease, then a decline over time because of diminishing
muscle mass.
Other markers that were identified are associated
with inflammation and could be used to monitor efficacy of
anti-inflammatory medications used to treat the disease.
Clinical
trials require objective measures to monitor the effects of a new
therapy. For Duchenne muscular dystrophy, monitoring is currently
commonly done with measures of muscle strength and clinical measures of
function such as the six-minute walk test, which measures how far a
child can walk in six minutes without stopping. Because the latter test
depends on a child’s ability to walk, patients who are wheelchair
dependent have been limited in their participation in clinical trials,
so do not have access to promising new therapies. Very young children
who are too unreliable to perform walking and muscle strength tests are
also excluded, which according to McDonald, is especially problematic
because of the desirability of beginning treatment at the earliest age
possible.
“There have been revolutionary breakthroughs in novel
therapeutics in recent years that target underlying disease processes,
but more than half of patients are unable to participate in testing
these drugs,” said McDonald, who directs UC Davis Health System’s
Neuromuscular Disease Clinic and is an internationally recognized
Duchenne muscular dystrophy expert. “Having validated biomarkers to
assess the ability of new therapies to positively affect disease
progression will be a game-changer and open up participation to
everyone.”
McDonald expects that because biomarkers are a more
sensitive measure of treatment effects than the traditional tests of
walking and muscle strength, determining efficacy of new drugs should
take only months instead of years. His UC Davis team, which has
established one of the largest clinical-trials sites in the nation for
Duchenne, will next focus on evaluating specific biomarkers in clinical
trials to determine which can be used to reliably monitor treatment
efficacy.
Results from this work are available to researchers and
clinicians in the field of Duchenne muscular dystrophy to help
incorporate biomarkers in to future clinical trials.
“We hope that
experts in Duchenne muscular dystrophy can use biomarkers identified to
accelerate the search for new diagnostic, prognostic and therapeutic
approaches for this devastating disease,” said McDonald. “The same
technology could also be fruitfully applied to many different rare
muscle diseases.”
Research for this study was supported by the
Department of Education/National Institute on Disability and
Rehabilitation Research; the Department of Defense; the National
Institutes of Health; the Parent Project Muscular Dystrophy; National
Institutes of Health grants; The Clark Charitable Foundation; and
partially by National Institutes of Health core grants.