John Elfar, MD, Shares Research on 4-AP & Nerve Injury
Department Chair and surgeon-scientist John Elfar, MD, recently gave a short presentation on some of his translational research with the chemical 4-aminopyridine (4-AP) as a way of addressing nerve injury.
“Translational science is about bringing things that we discover [in research] to the bedside,” Elfar explained, “and just so that everybody's clear: that rarely happens. Of the myriad discoveries that we have in biomedical science that could be translated into clinical trials, only very few of them make it. So my career has been spent in that fight: to actually try to get trials done.”
Treating Severe Nerve Injury
One of Elfar’s primary interests, as a researcher and as a surgeon, is in limb salvage and nerve injuries outside the typical focus on severed nerves or gaps in nerves.
I'm interested in the limbs that are most severely mangled – when the bomb goes off, when the arm is outside of the car as the car starts to roll over.
“I'm interested in the limbs that are most severely mangled – when the bomb goes off, when the arm is outside of the car as the car starts to roll over,” he explained. Because almost all complex tissue recovery is dependent on nerves, medical breakthroughs for treating severe nerve damage will most likely help patients with a wide range of problems beyond the very specific application of limb salvage.
Elfar shared two examples of his work with 4-AP, which has been used as a pesticide in the United States but was also discovered to have medical effects.
4-aminopyridine prevents potassium from leaking out when nerves lose their myelin sleeve, a protective coating of fat and protein around the axon or main body of the nerve. In doing so, it allows the nerves to continue to conduct while injured, which Elfar believes is likely responsible for results found in studies with mice.
Approvals for Two Clinical Trials with 4-AP for Nerve Injury
Today, Elfar has two clinical trials approved by the FDA, both based on such studies.
One study showed that while nothing can bring back function in severed nerves, 4-AP does bring back function in crushed nerves – a diagnostic function that could dramatically help physicians decide on treatment.
We can't diagnose severed nerves from crushed nerves in humans. They all look the same. There's no imaging for it.
“We can't diagnose severed nerves from crushed nerves in humans,” Elfar said. “They all look the same. There's no imaging for it. There's nothing we can do in the emergency room to say we should operate and fix this severed nerve or we should leave a [crushed] nerve alone.”
This clinical trial marks the first pursuit of a diagnostic to be funded by the NIH.
In a second study, Elfar and his team found that while burn wounds typically expand following initial injury, that expansion didn’t happen in mice treated with 4-AP. The treatment also increased the rate of wound healing.
Meeting High Regulatory Bars
Asked about how to meet the sometimes very high bar for “good laboratory practice” (“GLP”) in research submitted as evidence when seeking regulatory approval for clinical trials, Elfar offered this advice.
“GLP is actually something that is very routine for us to go back and fix later,” Elfar said. “We never get an A the first time we hand it in. But the reality is that they want to help you, and so they'll give you a GLP partner and they'll even give you some funding to go and hammer that out. And that's good, because that's very expensive work.”