Possible Treatment Found for Contractures in Childhood Paralysis, Early Study Shows

Possible Treatment Found for Contractures in Childhood Paralysis, Early Study Shows

Scientists at Cincinnati Children’s Hospital Medical Center have found that using the cancer medicine Velcade (bortezomib) in mice prevents the formation of muscle contractures, or tightness of muscles — one of the most disabling problems faced by children with cerebral palsy (CP) or brachial plexus injury (NBPI).

This research paves the way for a new and more effective treatment approach for preventing contractures in children born with these conditions, the investigators said.

Their study, “Proteasome inhibition preserves longitudinal growth of denervated muscle and prevents neonatal neuromuscular contractures,” was published in the journal JCI Insight.

Over time, muscle contractures — which develop when normally elastic tissues are replaced by non-stretchy, fiber-like ones — disrupt children’s growth in cerebral palsy and NBPI, leading to pain and loss of mobility. Patients may undergo surgery or other treatments to ease the symptoms.

No therapies currently exist that directly tackle the root cause of contractures in childhood paralysis — because scientists did not know their biological cause.

But now, a team of researchers at Cincinnati Children’s discovered the culprit to be too much protein destruction in muscles. These scientists found that an approved therapy to treat multiple myeloma and mantle cell lymphoma, called Velcade (marketed by Takeda), can counteract the process and prevent contractures in mice.

In a previous study of a mouse model of NBPI, the team — led by Roger Cornwall, MD, a pediatric surgeon at Cincinnati Children’s — had found that contractures occurred because paralyzed muscles cannot grow normally in length during early muscle development.

In their new study, the researchers observed that longitudinal muscle growth was actually halted due to a higher than normal breakdown of muscle proteins.

This discovery challenged the long-held view that muscle growth depends mostly on the activity of muscle progenitors, or stem cells.

“For decades, neuromuscular contractures have been considered a mechanical problem absent any biological explanation, and only palliative mechanical solutions for them have been available,” the researchers said.

Based on the findings, the team tested a new approach to this debilitating and previously unsolved clinical problem. They tested the use of Velcade — a chemotherapy known to inhibit protein breakdown — in mice models of NBPI shortly after birth.

The treatment proved effective, but required a second medication, [Gly14]-Humanin G, to reduce Velcade’s known toxic effects.

“After four weeks of treatment shortly after birth, our study found that bortezomib [Velcade] significantly reduced shoulder and elbow contractures in a mouse model that mimics these common childhood conditions,” Cornwall said in a press release.

Although animal models of CP contractures do not exist, researchers believe the NBPI model can offer valuable insights into the mechanism behind, and therapeutic strategies to prevent contractures in both conditions.

Contractures in CP also are marked by impaired longitudinal muscle growth and appear early after birth, identical to what is seen in the mouse model of NBPI.

“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,” Cornwell said.

Given Velcade’s toxicity, it remains unclear whether it would be deemed safe to test the new therapy in clinical trials.

It also is not known how much older children might benefit from this approach, since the treatment’s benefits appear to be strongest when given soon after birth.

But the positive results of these early experiments give scientists a starting point from which to work, and could eventually lead to a treatment that could transform childhood paralysis care.

“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 said.

These findings “provide the first strategy to prevent neuromuscular contractures by correcting the underlying deficit in longitudinal muscle growth.” Moreover, such an approach may well be harnessed to prevent this same problem resulting from other neuromuscular disorders, the researchers said.