Novel Treatment for Childhood Paralysis Shows Upside in Early Trials

If an infant is born with cerebral palsy or experiences an injury to the brachial plexus at birth, muscle contractures, or tightness of muscles, that severely restrict limb function can occur. These muscular defects lead to impeded skeletal growth, pain, loss of mobility, and dependence on expensive medical and supportive care. Many pediatric patients with this condition undergo surgery or other therapies for temporary relief but this does not treat the underlying contractures.

Aiming to address the lack of treatment options for patients with this childhood paralysis, researchers from the Cincinnati Children’s Hospital Medical Center have recently found that bortezomib helped restore disrupted muscle growth and prevent contractures in mice. This preclinical study was published on October 29 in the journal JCI Insight.

“After four weeks of treatment shortly after birth, our study found that bortezomib significantly reduced shoulder and elbow contractures in a mouse model that mimics these common childhood conditions,” explained Roger Cornwall, MD, Division of Pediatric Orthopaedics. “Future studies confirming the efficacy of this approach could ultimately render obsolete the destructive surgeries currently required to alleviate contractures in a variety of conditions.”

Damage to the brachial plexus at birth and cerebral palsy are the most common causes of childhood paralysis when combined, occurring once in every 200 births. Though these conditions differ in their causes, they both result in the same contractures of the muscles that limit mobility and skeletal growth, leading to bone deformities and dislocations of the joints. to bone deformities and joint dislocations.

Discovery focused on muscle growth disruption

Alongside co-author Douglas Millay, PhD, Division of Molecular Cardiovascular Biology, and colleagues, Cornwall created and studied a mouse model of a brachial plexus injury. The team found that the contractures occurred due to paralyzed muscles lacking the ability to grow to a normal length when deprived of the proper signaling input from the nervous system early in the muscle development process.

Through their research, Cornwall and colleagues learned that healthy longitudinal muscle growth depends on a balance between the formation and breakdown of muscle proteins. In the past, scientists have assumed that muscle growth primarily relies on the activity of stem cells, however, the researchers found that this is not required specifically for the growth of longitudinal muscle.

The team then tested a chemotherapy drug known as bortezomib that inhibits protein breakdown, as a potential drug to re-balance this aspect of muscle growth. Bortezomib was found to make a significant impact in the mouse study but required a second medication to reduce fatal toxicity.

The drug was most effective when administered soon after birth, and the researchers are not certain as to how much older patients would benefit from this treatment. They note that mature adults would be unlikely to see any therapeutic effects from this approach.

Furthermore, the toxicity of bortezomib in this study makes its use in human children a question of concern for clinical trials. Nonetheless, bortezomib, currently an FDA-approved cancer treatment for adults, showed early success in this trial that gives the researchers optimism in treating childhood paralysis.

“This discovery provides, for the first time, a proof of concept that something we have always considered to be a purely mechanical consequence of limb immobility is actually a biological problem with a medical, rather than physical, solution,” Cornwall concluded.