Kate WilletteThis month’s column is about three molecules, a mom, a tenacious father-in-law and a biotech breakthrough with huge possible implications for people with spinal cord injuries. The story starts with the mom. Her name is Codi Darnell, and she lives with her husband and three kids in Vancouver, British Columbia. In March 2016, Darnell and her husband were renovating their house when she stepped into a 10-foot hole where a staircase would one day be. That fall was enough to cause a break at T11 and make her a paraplegic.

Darnell happens to be married to a man whose father is the sort who doesn’t take no for an answer. Here’s how she tells what happened next on her blog, HelpCodiHeal:

“We all know people who are fixers — people that see a problem and need to find a solution. My father-in-law, Dr. Harold Punnett, DMD (more affectionately known to me as Grandpa or HP), is one of those people. When he started sifting through the internet in search of a cure, we believed he was fighting an impossible battle, but we let him be. He would occasionally bring up things he found, but my focus wasn’t on a cure — it was on getting strong, getting home and learning to make the most out of my life. However, he was not deterred and one day found something really interesting.”

Sticky Walls and How to Get Around Them

The one thing most people “know” about the spinal cord is that once it’s been damaged or broken, it does not grow back. It’s not like skin. It doesn’t repair itself and function again. It doesn’t regenerate. The cord is, in part, made of impossibly tender bundles of fibers — called axons — that are supposed to be protected by the flexible bone structure of the spine.

Fortunately for us all, Codi Darnell is married to a man whose father doesn’t take “no” for an answer.

Fortunately for us all, Codi Darnell is married to a man whose father doesn’t take “no” for an answer.

When that bone structure takes a hard enough hit, the bones shatter and the bands of fragile axons are ripped apart. Each individual axon in the bundles is a gossamer thread projecting from a single neuron; each one is the carrier of information from brain to body, or body to brain.  Each axon’s job is to form the permanent connections with other cells that allow us to feel, breathe and move. The tip of a healthy axon is always the point of a permanent connection.

The massive, intricate networks of firing connections in healthy brains and spinal cords allow us to wake up every morning knowing who we are. They’re why we know how to get out of bed and what our favorite cereal is. We want those connections to be permanent, which is why we’re grateful for molecule number one: chondroitin sulfate proteoglycan. In healthy spinal cords, CSPGs form tiny traps that protect all those connections. They’re great, but after an injury they really get in the way of recovery.

In Don’t Call It a Miracle, I described what happens at the site of an injury as being sort of like what happened at Chicago O’Hare Airport on the morning of 9/11. The authorities didn’t know what was happening yet. Planes were being taken and flown into buildings. They had to try to protect the airport but no idea what to protect against, and their best idea was to put up some kind of barricade. They got their giant snowplows out of storage and arranged them, blades out, around the control tower.

That’s a bit like what happens after an injury — CSPG molecules that usually protect established connections are recruited instead to form a protective structure around the lesion. The very same mechanism that makes the connections reliable is what prevents post-injury broken axons from growing back.

Those CSPGs fill up the injury site and sit there, ready to fend off invaders while simultaneously helping to limit the spread of damage inside the cord. Unlike the airport authorities, though, we can’t just put the metaphorical snowplows away; we can’t get rid of the protective wall. When axons get over the shock of being abruptly severed, they start trying to re-grow and get back to sending information up and down the cord, but instead something terrible happens. They encounter that wall of CSPGs. Even worse, they get stuck in it, struggling helplessly like flies on flypaper.

Why? Because of molecule number two: protein tyrosine phosphatase sigma. Without going too crazy on the chemistry, we can think about PTPσ as a sort of Lego that appears on the seeking end of an axon. The Lego molecule causes those axons to find CSPGs and get stuck on them.

If you’re still following along, you see the problem. We have axons that want to grow, but the interaction between molecule number one and molecule number two makes that impossible. The goal would then be to interrupt that interaction — to either get rid of the CSPGs, or to fool the PTPσ molecules into not seeing them.

As it turns out, it’s hard to get rid of that wall of CSPGs, which makes sense. It should be hard. These are molecules we need and want in our brains and spinal cords; we just don’t want them filling up the injury site.

Dr. Harold Punnett, DMD

Dr. Harold Punnett, DMD

Enter molecule number three: intracellular sigma peptide. This one was custom-designed a few years back in the lab of Dr. Jerry Silver, a neuroscientist and professor at Case Western University. ISP is a cool molecule. Here’s what Silver said about it in an article published last spring:

“We developed a molecule that negates the [PTPσ] signal, allowing the regenerating axons to ignore and bypass CSPGs. When the molecule was administered noninvasively via injections under the skin, it interfered with … the signaling … allowing for robust axon regrowth resulting in greatly improved bladder function and improved locomotion in animal models of spinal cord injury.”

In plain English, he’s saying that they used a regular small needle — the kind they use for flu shots — to give paralyzed rats a dose of ISP, and then watched while the rats recovered the ability to pee and walk and climb tiny ladders. Molecule number three works, at least in rats.
By now you may have guessed that the “really interesting thing” that Darnell’s father-in-law found was a report about Silver’s work with molecule number three. Once he saw that commercialization of the molecule might lead to healing for Darnell, Punnett went to work.

What’s Next

By March 2019, almost exactly three years after Darnell’s injury, a whole lot of things were in place. Punnett helped found a biotech company called NervGen. That company acquired a license to Dr. Silver’s molecule, ISP, and renamed it NVG-291. The company had a $10 million IPO, and its officers rang the opening bell on the Toronto Exchange last May.

At Working 2 Walk in Cleveland last October, Silver and NervGen’s director of research, Dr. Marc DePaul, said they are currently on track to conduct a safety study using healthy volunteers during the first quarter. The study is intended to show that injecting the molecule does no damage to healthy nervous systems. Immediately following that, during the second half of 2020, they are planning a safety trial for people with spinal cord injuries. At some point, if all goes well, the mom who lives today with axons that won’t grow will be able to get that injection.

Resources
• Codi’s website, helpcodiheal.com
• Codi’s post about Dr. Punnett, helpcodiheal.com/ng/#more-1688
• Dr. Silver and Dr. DePaul’s presentations at Working 2 Walk, wirestream.tv/customer/unite2fightparalysis/2019/10-04/#
• “Emerging Treatments for Spinal Cord Injury” by Dr. Jerry Silver, static.wixstatic.com/ugd/ae5838_3c8ed15bec794c1db82839a4d583531f.pdf
• Interview with Dr. Punnett, usabusinessradio.com/t-11-paraplegic-inspires-canadian-father-in-law-to-find-fund-cure
• NervGen, nervgen.com