Morning Sumatra With Nervgen Co-founder Dr. Harold Punnett

By now most readers know at least the base-case scenario about NervGen, why BioPub is bird-dogging its origins and covering it as among the most auspicious investments in the biotech firmament when it debuts later this month on a Canadian stock exchange. Even with sweeping material success in the business, clinical and investing worlds, Punnett has never shed either the common touch or sweeping, impelling humanitarian interests.

Some years back, Punnett and family suffered an event that would cause Punnett ever after to see a burning bush. Daughter-in-law Codi, mother to Punnett’s grandchildren, fell into a hole, the integrity of her spinal cord not surviving the trauma. Codi hadn’t invited this by anything untoward or risky she was doing; the event had a creepy casualness about, one that reminds you “There but for the grace of…” She remains a complete T-11 paraplegic. Readers are encouraged to visit Codi’s website: https://helpcodiheal.com/?fbclid=IwAR3IEwSNMzeGnvfmlRlYannVBdcUW7TPs8HmfS4kTgu-Z6UjZT2BlwOyo-k

Punnett refused to accept the spinal-cord no-win-situation, the nihilistic pronouncements of Codi’s physicians. As a dental surgeon in British Columbia, Punnett of course is well-versed in medicine and physiology, including much of the whole set-piece of a medical education, with heavy coursework in embryology and cell biology. The training of either a physician or a dentist makes the medical scientific literature accessible. We don’t know for sure, but we can imagine Punnett’s thought processes as a trained clinician flowing along these lines: that there is a point during embryogenesis when things seem privileged and a certain suspension of disbelief is in play, when nerves grow and connect and link up and behave in a highly plastic manner; yet we know with each passing year in neuroscience that the central nervous system retains plasticity even into advancing age and in fact remains more malleable that we were ready to accept a few years ago; that the body has vast powers of self-healing, that chief among its constituents are vibrant pluripotent stem cells flowing in every vessel, ever ready to regenerate tissues and take up slack. Punnett could nearly deduce, it seems, that the elements are in place for the injured spinal cord to heal….but that something derails its drive to do so. Mind you, Punnett hasn’t uttered this to me verbatim, and yet over the months I’ve had many fine conversations with him and have gleaned a sense of how subtle his mind is. But Punnett embarked into the neuroscience literature and began a networking juggernaut themed around the issue of somehow reijggering the cell biology of the  spinal cord to allow it to heal, faithful at some level that, speaking in anthropomorphic terms, it had a certain muffled urge to do so.

The rest is a kind of history: Punnett reached out to Case Western neuroscientist Dr. Jerry Silver, whom readers have met and will continue getting to know, eager to discuss Silver’s work. Silver was happy to oblige because Silver has grown weary of not having his work, his data, believed by the broader science community. Don’t get me wrong: no one regards Silver the man as lacking credibility. But many have been reluctant to accept his lab’s recurring data, which is that with injections of a peptide Silver’s lab invented, ISP (intracellular sigma peptide), Silver can cause severely spinal-cord-injured mice to walk again, to walk ostensibly normally.

How does ISP work? To cut to the chase, it subdues activity of a neuronal receptor called protein tyrosine phosphatase sigma (in a prior article we ineffectively abbreviated this PTPs, as if were speaking of a plural of PTP….in future we’ll dub it PTPsigma). Scientifically, PTPsigma has proven to be one tough nut to crack. Silver’s lab, as we’ll soon cover, discovered that knockout mice, mice lacking the genes for PTPsigma and thus not expressing any PTPsigma, exhibit spinal cord healing after severing injury, the axons finding their opposite members and mostly knitting up. So, why would nature plonk something like PTPsigma as an obstacle to healing? First, evolution is a work in progress and is famed for certain other ill-considered outcomes. But the truth is, as model Denise Richards loves to say, rolling the world up into a ball, “It’s complicated.” In fact you need to know the totality of all that’s going on with PTPsigma, and we’ll cover that in a future article.

Meanwhile, let’s de-complicate things and put them this way: giving an animal or human ISP injections is roughly the biological equivalent of being a PTPsigma knockout organism. With me? Great!

Now, among Punnett’s many roles in a nascent NervGen is that of ambassador. And with me, Punnett has been welcome raconteur, ever poised to exuberate about the full ramifications of where NervGen might go (Dr. Seuss: “Oh the places you’ll go!”), corollary healing actions ISP might have. Blessed are they, in my book, who have seen burning bushes. I’m copacetic with all kindred spirits who have fire in the belly. (Longtime readers of this forum know that years ago I interviewed Baltimore “trash” film director John Waters, ever deliriously, even maddeningly, happy. I had an original  Odorama scratch-n-sniff card from one of Waters’ films and asked him to autograph it. He did…signing his name in a kind of whacked-out filigree. “OK, John,” I said. “What is THAT about?!” “What is WHAT about?” “What’s the secret to always being happy as a pig in mud like you are?” “That’s easy! BE OBSESSED!”). The cliche sullies nothing here: Punnett is magnificently obsessed.

Punnett of course has regaled me by now (and shortly I shall regale you in turn) about how ISP may prevent death post MI by driving healing of nerve fibers within infarcted myocardium. By how strong evidence has it driving remyelination and causing recovery in animal models of multiple sclerosis. About how ISP treatment could neurologically reconstitute severed limbs. He’s even shared evidence whose upshot is that ISP might prove a useful therapy for the sometimes painful sensory neuropathy of diabetes.

But think for a minute. Draw a breath. In biotech right now, what’s the question of the ages? (No, it’s not “What’s the frequency, Kenneth?”) You know someone dying from it. And you’ve got one in seven odds of succumbing to it yourself, yet we’ve not got a duke of an idea what drives it or how to treat it? OR DO WE?

In my hot little hands, I’ve got a sheaf of data resulting from work of Silver and colleagues, data not yet published. Did you know that  certain strains of laboratory mice are genetically rigged to experience onset of a mouse model of Alzheimer disease? And that treating these mice with ISP abates the onset of Alzheimer features?

Let me hum a few bars of this familiar song you now recognize. Alzheimer’s disease is where for unknown reason, brain tissue accumulates neurotoxic strands of insoluble proteins that mainly include amyloid beta and tau. The source of these proteins appears to be a molecule called APP, amyloid precursor protein, that’s getting gnawed on by enzymes called beta- and gamma-secretases. (Inhibitors of these are in clinical trials.)

Silver and colleagues have discovered that PTPsigma knockout mice exhibit neurophysiology is which the affinity for beta-secretase for APP is lowered so drastically that amyloid functionally fails to accumulate in the brains of these mice. But as we explained in “The Silver Lining NervGen Playbook Part 1,” ISP throttles back, reels in, the activity of PTPsigma. Ergo, it was only left to Silver associates to treat Alzheimer-predisposed mice with ISP. And it worked. It was indeed quite highly effective.

What makes the work particularly interesting is that PTPsigma “deficiency” results in lowered Tau accumulation too. In our prior column we alluded to how PTPsigma is a cell surface receptor for chondroitin sulfate proteoglycan which at spinal cord injury is elaborated by glial cells in a kind of molecular expression of outrage. Come to find out, APP possesses features of, partly is, ALSO chondroitin sulfate proteoglycan…and from there things grow ever more interesting and complex. We may be able to clear it with Dr. Silver to house this work in our media center, but can also get it if he prefers we not as it remains unpublished and naturally he is seeking publication of the data.

While my soul feels as if my friend Harold Punnett was across the table from me in the bodega before dawn this morning sharing cups of sumatra with me, I did not of course see him there with my physical eye. Punnett is on the west coast and I’m on the east, and he often leaves pleasantries for me in my inbox when I awaken at 4 am each morning to feed the BioPub and take it round the block on a leash. But I enjoyed our time together, Harold, and safe home. Top up your travel mug for the road? You’ve got a lot of pubsters in awe of the larger-than-life cut of your jib. We’re all grateful, as either pre- or post-IPO participants, to be aboard with this transfixing thing called NervGen you’ve got going. These are times so interesting they make the souls of men rapt and keep them glued to the internet. We’ve always got an open slot for you on the BioPub dance card, Dr. Punnett.

[Disclosures: The author is a participant in the NervGen IPO via Haywood Partners of Vancouver but has no other potential conflicts of interest to disclose. Copyright 2019 BioPub and the author, Helixir Media, LL.C. All rights reserved. May not be reproduced without permission of the editors. This article is neither advice to purchase shares in NervGen or a solicitation for participation in the IPO. Neither BioPub, Helixir Media nor the editors have any pecuniary relationship with NervGen or its officer, affiliates or underwriters.]