Duchenne muscular dystrophy (DMD) is a lethal, progressive muscle wasting
disease caused by a loss of sarcolemmal bound dystrophin, which results in
the death of the muscle fibers leading to the gradual depletion of skeletal
muscle. There is significant evidence demonstrating that increasing levels
of the dystrophin-related protein, utrophin, in mouse models results in
sarcolemmal bound utrophin and prevents the muscular dystrophy pathology.
The aim of this work was to develop a small molecule which increases the
levels of utrophin in muscle and thus has therapeutic potential.
Methodology and Principal Findings
We describe the in vivo activity of SMT C1100; the first
orally bioavailable small molecule utrophin upregulator. Once-a-day
daily-dosing with SMT C1100 reduces a number of the pathological effects of
dystrophin deficiency. Treatment results in reduced pathology, better muscle
physiology leading to an increase in overall strength, and an ability to
resist fatigue after forced exercise; a surrogate for the six minute walk
test currently recommended as the pivotal outcome measure in human trials
Conclusions and Significance
This study demonstrates proof-of-principle for the use of in
vitro screening methods in allowing identification of
pharmacological agents for utrophin transcriptional upregulation. The best
compound identified, SMT C1100, demonstrated significant disease modifying
effects in DMD models. Our data warrant the full evaluation of this compound
in clinical trials in DMD patients.