On this day 25 years ago, Christopher Reeve sustained a spinal cord injury; today there is still no fix, no cure.

COVID19 abruptly cut short the SCI Roadmap project inspired by Reeve’s unrelenting cure vision.

People in chairs are still waiting for a superhero..

I spent the past year immersing myself in all aspects of the SCI community: people living with the injury, their caretakers and advocates, researchers and clinicians, foundations and other stakeholders.

I reached out to everyone in SCI who would share their feedback with me.

If I learned one thing it’s that the SCI clinical translational opportunities are in no short supply, as I’ll outline below.

The heavy lift was overcoming institutional baggage, a few blocking egos, and the false dichotomy of care vs cure missions.

The opportunity most ripe for the picking and scientifically in the making for decades by Reggie Edgerton and his disciples is neuromodulation

In retrospect, the focus on epidural stimulation and a centralized (read, unscalable) all-encompassing rehab regiment was a mistake.

The Big Idea/Louisville never reached it full potential after Arnie Snider died. For the last decade, only a few dozen patients have received epistim + locomotor training instead of a non-invasive alternative called transcutaneous spinal cord stimulation w/ flexible or no rehab.

See @daviddarrow’s E-STAND trial at Mayo Clinic and a startup called Stim Sherpa ( https://stimsherpa.com ) as the counterpoint.

Also see Chet Moritz’s work at U of Washington on transcutaneous stimulation. Both groups see positive effects on dysautonomia, eg blood pressure.

The SCI field recognizes that biomarker discovery (cc @nikos_kyritsis) and a combinatorial therapeutic framework are prerequisites for the clinic, much like what the folks at the @NEALSConsortium are doing with adaptive and platform trials: https://www.neals.org 

An open clinical trial data commons is needed to determine the personalized order and intensity of interventions.

Steven Kirshblum at @KesslerFdn told me there are 5 interventions we should be testing today in a coordinated manner across multiple clinical sites:

1) Neuromodulation, starting with transcutaneous
2) moderate acute intermittent hypoxia
3) stem cell therapies
4) BCI (see @neuralink)
5) activity-based training aka rehab

Design trials to prove efficacy of single intervention, and then stack other interventions on top.

If the rationale for neuromodulation is to maximize spared function in a spinal cord injury (even in “complete” injuries), what to do about the injury site (glial and fibrotic scars, cavitation, failure of wound repair) and regenerating or replacing lost cells and connectivity?

Much ink has been spilled and many workshops convened to debate what constitutes (neuro)plasticity versus regeneration.

Are axonal sprouting and relay circuits (which don’t evolve naturally) sufficient or is long-distance axonal growth required for lasting functional recovery?

Several different pharmacological approaches to promoting plasticity that were discovered two decades ago are being put to the test in people: 1) Nervgen/$NGEN’s ISP-1 in Ph 1 based on Jerry Silver’s work; 2) ReNetX’s no-go trap entering Ph 2 based on Steven Strittmatter’s work.

Folks in academia are pushing hard on chondroitinase. Hassan Al-Ali and Vance Lemmon from @BuonicontiFund have a polypharmacological kinase inhibitor that simultaneously promotes growth-intrinsic pathways and removes inhibitory signals. @NovoronBio has a LRP1/Rho inhibitor.

Will any of those plasticity promoters move the needle enough as monoagents or will they have to be combined to see robust efficacy? That’s why we do clinical trials.

There’ll likely be a need to safely turn on and later turn back off again long-distance axonal growth programs.

The work of @Blackmorelab is pioneering, IMO. I’m also excited by a company called @Axonis_US, which has identified PTEN as a regeneration target. Microtubles could be another regeneration target. Who knows what other targets are out there? Lots more work to be done here.

Passive regeneration is not going to happen. Rehab will be key. Lost functions must be relearned, retrained, and reinforced. Rehab hospitals like @SpauldingRehab @CraigHospital and CFWs like @PushToWalk @NextStepLA are precursors to financially sustainable SCI wellness centers.

I had envisioned that a series of venture philanthropy funds would invest in a diverse portfolio of companies spanning discovery to clinical stages, balancing bets on priming therapies that improve quality of life and independent living with blue sky bets on curative therapies.

SCI funders (and corporate sponsors, other donors) will need to create two additional complementary funding mechanisms: 1) a preclinical replication fund to that could be feeder for Wings For Life’s first-in-human ATP program; 2) a SBIR-like seed fund focused exclusively on SCI.

I also imagined interactive fundraising salons and live neuromodulation demos where specific technologies could be publicized and requests for funding n-of-1 pilots issued.

In order for there to be a self-sustaining pipeline of entrepreneurial talent and deal flow, the SCI community needs a startup accelerator like Y Combinator.
@praxis_sci has boldly set out to do just that.

In spite of everything, I’m hopeful. The 2020s will be a decade of cures and curative/transformative therapies. Once the first SCI device or drug is approved, the floodgates will open.

I can still imagine a world without chronic SCI in 15-20 years.

Thanks to everyone I had the pleasure of working with and meeting while I was @ReeveFoundation, in particular @adnamaleah @Blackmorelab @Harvey_Sihota @paolocipolla @endparalysis @U2FP_W2W @AlexReeveGivens and many more.

This week, I embarked on my next patient-inspired n-of-1 adventure.

Will have more to say soon!