The latest news and information about what's going on with SCI science and research. Brought to you by Sam Maddox, author of the Christopher & Dana Reeve Foundation Paralysis Resource Guide.

Novel Drug Improves Animal Recovery

A very neat experiment was reported earlier this month showing that a new kind of drug, injected under the skin early after injury, can improve functional recovery of paralyzed animals. The work, published in the leading journal Nature, comes from the Jerry Silver group at Case Western in Cleveland, and continues the lab’s long-term focus on regenerating nerve axons at the site of spinal cord injury by understanding the biological mechanisms that prevent this regrowth.

We have previously discussed Silver’s work with the scar-eating drug chrondroitinase, or Chase and with his innovative work to create nerve bridges around the injured spinal cord, leading to recovery of respiratory function and bladder function.

In this new study, led by post-doc student Bradley Lang, with fellow student Jared Cregg, the lab designed a peptide molecule that prevents the growing tips of axons from getting stuck on sugary proteins. This “flypaper,” as Silver puts it, is caused by proteoglycans – the sticky stuff that forms a scar to seal off the area of damage. The novel peptide, called intracellular sigma peptide, or ISP, disrupts the biochemistry of the proteoglycans and prevents them from sticking to nerve cells. ISP mimics a receptor molecule called protein tyrosine phosphatase, and acts as a decoy. The proteoglycans hook up to ISP and are in effect neutralized; they can no longer detect the axons. These axons, which never lost the urge to grow, are thus set free from what Silver calls “synaptic doom.”

“It was amazing. The axons kept growing and growing,” said Silver.

What’s more, the axons apparently grew across the lesion area and restored significant levels of walking, limb coordination, and urinary function. Silver told the BBC: “What we could see was really remarkable. Some [animals] recovered to a fantastic extent and so well you could hardly tell there was an injury.”

This research was widely publicized, thanks in part to the public relations people from the main funding source, NIH. This is from an NIH press release:
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.

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.
First the team tested ISP in a lab dish. Axons could sneak past the peptide-infused sugar chains. Then on to lab rats. They didn’t know if it would work. Silver said later he told them it surely would not. But Lang persisted to follow his hunch that early treatment might not only replicate dish studies but also actually help the animals. “Originally this was just a side project we brainstormed in the lab,” said Lang.

Here’s what they did: lab rats got a thoracic contusion injury that left them severely paralyzed. One day later, and daily for the next seven weeks, the animals were given a 500 ml shot of either ISP, another peptide, or vehicle (no drug, same volume). Nothing was different for the first six or seven weeks. Then the rats with ISP began to respond – 17 of 20 got improvement in walking, grid walking (shows coordination) and urination. Not all got the same improvement but some could walk almost normally; others could urinate almost as if not injured.

Here’s what they think happened: the ISP drug did not regenerate the axons directly related to lower limb movement (e.g., those in the corticospinal tract did not respond but axons related to an important neurotransmitter called serotonin did). The seratonergic system may have boosted transmission along intact nerve pathways – demonstrating that even a small amount of preserved spinal cord white matter can be taken advantage of.

ISP did not protect sensitive nerves from toxic post-injury damage. That leads Silver to speculate about a combination with a neuroprotective drug for a robust acute therapy. Before they get to that, the lab would like to get the ISP to the clinic sooner for acute SCI.

But what about chronic SCI? ISP can keep an axon from getting stuck but can it unstick them? No, it needs to be combined with other treatments. At a Working 2 Walk conference last fall, Silver said his chronic roadmap included surgical bridges, chondroitinase and surgical clearing of scar. Add to that some genetic modifications (PTEN deletion for example) to fire up axon growth. Watch Silver’s presentation here, courtesy W2W, which also gets a nod for funding part of this new study.
Posted by Community Admin on Dec 15, 2014 6:04 PM America/New_York