BARRIER BRAKING DRUG AMY LEAD TO SPINAL CORD INJURY TREATMENTS
Injections of a new
drug may partially relieve paralyzing spinal cord injuries, based on
indications from a study in rats, which was partly funded by the National
Institutes of Health
The results
demonstrate how fundamental laboratory research may lead to new therapies.
"We're very
excited at the possibility that millions of people could, one day, regain
movements lost during spinal cord injuries," said Jerry Silver, Ph.D.,
professor of neurosciences, Case Western Reserve University School of Medicine,
Cleveland, and a senior investigator of the study published in Nature.
Every year, tens of
thousands of people are paralyzed by spinal cord injuries. The injuries crush
and sever the long axons of spinal cord nerve cells, blocking communication
between the brain and the body and resulting in paralysis below the injury.
On a hunch, Bradley
Lang, Ph.D., the lead author of the study and a graduate student in Dr.
Silver's lab, came up with the idea of designing a drug that would help axons
regenerate without having to touch the healing spinal cord, as current
treatments may require.
"Originally this
was just a side project we brainstormed in the lab," said Dr. Lang.
After spinal cord
injury, axons try to cross the injury site and reconnect with other cells but
are stymied by scarring that forms after the injury. Previous studies suggested
their movements are blocked when the protein tyrosine phosphatase sigma (PTP
sigma), an enzyme found in axons, interacts with chondroitin sulfate
proteoglycans, a class of sugary proteins that fill the scars.
Dr. Lang and his
colleagues designed a drug called ISP to block the enzyme and facilitate the
drug's entry into the brain and spinal cord. Injections of the drug under the
skin of paralyzed rats near the injury site partially restored axon growth and
improved movements and bladder functions.
"There are
currently no drug therapies available that improve the very limited natural
recovery from spinal cord injuries that patients experience," said Lyn
Jakeman, Ph.D., a program director at the NIH's National Institute of
Neurological Disorders and Stroke, Bethesda, MD. "This is a great step
towards identifying a novel agent for helping people recover."
Initially, the goal of
the study was to understand how interactions between PTP sigma and chondroitin
sulfate proteoglycans prevent axon growth. Drugs were designed to mimic the
shape of a critical part of PTP sigma, called the wedge. Different designs were
tested on neurons grown in petri dishes alongside impenetrable barriers of
proteoglycans. Treatment with ISP freed axon growth.
"It was amazing.
The axons kept growing and growing," said Dr. Silver.
Next the researchers
tested the potential of the drug on a rat model of spinal cord injury. For
seven weeks they injected rats with the drug or a placebo near the site of
injury. A few weeks later the rats that received the drug showed improvements
in walking and urinating while the placebo treatments had no effect. The
results suggested the drug passed into the brain and spinal cord.
When the researchers
looked at the spinal cords under a microscope they found that the drug induced
sprouting of axons that use the neurochemical serotonin to communicate. The
sprouting axons were seen below the injury site. Treating some rats with a
blocker of serotonin communication partially reversed the beneficial effects of
ISP injections, suggesting the newly sprouting axons helped the rats recover.
The ISP drug did not
cause spinal cord axons known to control movements to cross the scar and
reconnect with brain neurons above the injury site. Dr. Silver and his
colleagues think this means the ISP-induced sprouting helped the rats recover
by increasing the signal sent by the few remaining intact axons.
"This is very
promising. We now have an agent that may work alone or in combination with
other treatments to improve the lives of many," said Dr. Silver. He and
his colleagues are seeking to test the ISP drug in preclinical trials.
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