Jan-Eric Ahlfors: Part 2 (Human Studies)

NOTE: This talk was delivered earlier today, but every slide carried a bright yellow line at the bottom declaring that the information on it was confidential and not to be shared without written permission. So I made a live draft, thinking I could catch up with Dr Ahlfors later and see what would be okay to post. “Later” turned out to be right before dinnertime . . . plus I had to do some thinking about how to discuss this material — which is why I’m just now getting back to it now, close to midnight.

Before I go further, I need to make sure we all understand the situation here. As Dr. Ahlfors told us yesterday, his path with respect to working on SCI is pretty unusual. You can refresh yourself with what I wrote during the first half of his talk here.  The readers digest version of that (plus some more info I’ve been finding on the web) is that after interning at a hospital, he went to work as an undergraduate in a lab & was encouraged to get creative by the PhDs and post-docs there. The lab is called New World Laboratories. According to its website, New World Labs …

… has not only invented a series of revolutionary platform technologies, but has also “re-invented” the classical (and lately not that successful) Biotech model: Instead of developing product ideas based on existing academic results and building companies around them, new technologies are being designed from scratch …

Jan-Eric is also the CEO of a non-profit known as the Novagenesis Foundation, which describes itself this way:

We are an example of how you must put aside dogma and courageously walk a new way to achieve. Innovate, design and build to succeed. Apply new thinking to areas of medical research and development that have failed to progress for too many years.

I have to say, this language sounds so much like what we in the SCI community sometimes mutter amongst ourselves when we’re feeling frustrated that it kind of scares me.

What Jan-Eric described yesterday was pre-clinical (meaning dish and animal) work that relied on NWL’s trademarked and patented technologies, namely a Regeneration Matrix and some Directly Reprogrammed Neural Stem Cells. Direct reprogramming is a process by which one kind of cell is manipulated with molecules to straight up turn into a completely different kind of cell. Again, sounds like magic.

But he described some very promising animal model results yesterday, and promised to talk about work in humans today. So that’s what this post is about.

Jan-Eric: Yesterday I was telling you about our work in the lab. Our company is called Ophiuchus, named after a constellation where new stars are born; it’s also associated with an ancient pre-Egyptian god. (You can’t say the guy isn’t ambitious.)

He goes on: So, yesterday we talked about how direct reprogramming works in neural stem cells, and how they’re more effective than other cellular approaches.

We’ve already taken these reprogrammed cells into four human patients with sci. They were all men, and all of them had been living with motor/sensory complete injuries for some time. (9 months, 18 months, 18 months, 26 months) The treatments happened between October 2014 and February 2015 — which means within the last 8-12 months.

This is the process:

  • At the hospital, a doctor takes a bone marrow sample, and it gets shipped to the lab (60 hours at most)
  • Direct reprogramming takes place at the lab (10 weeks)
  • Sample is shipped back to the hospital (max 10 days)
  • Doctor does 1 to 10 injections of the reprogrammed cells
  • Patient does rehab for 6 months to 2.5 years

The sponsor for this work is the Federal Research Clinical Center of the Russian Federal Medical-Biological Agency, which is receiving no money for their participation. They’re paying, not being paid. And all four of the patients he’s about to discuss are Russian.

Next we see a series of videos with English subtitles … a couple of the men who got their cells extracted, reprogrammed and returned to their bodies demonstrate that they can move their legs and feet while sitting up and lying down. One of them pulls his blue-jeaned knee to his chest, lets it fall to one side and the other, bringing it back to center without using his hands. There’s no question that he has muscles firing.

Later he describes being able to feel when he needs to empty his bladder, and the old familiar relief of emptying his bowels, and the return of a spontaneous erection.

There are charts and graphs that capture the exact places on each of the four bodies where sensation and movement returned; the last patient, who began with the most function, also got the most return of function. There’s a moving measure of electrical activity in formerly lifeless legs.

But there’s no formal documentation publicly available to show what exactly was done, or how.

Q: Are clinical trials still open?

A: Since the gov’t of Russia is paying for this, it’s only open to Russian citizens.

Q: Have you considered doing this procedure on best case scenarios? (Asia C/D?)

A: It would be pretty strange if it only worked on the worst cases . . . obviously it would be heaven to work on the best-case patients . . . we expect that it would work even better. We need partners . . . it all costs money & requires people; there’s much to be done.

Q: How will this become available in the USA?

A: The FDA would certainly require trials here . . . the goal is to get their permission. We really weren’t prepared for any of this return of function, but these patients have changed the timeline on which we were operating. We thought we’d have time after some safety studies. These were supposed to be safety studies.

Q: (It’s Naomi Kleitman, formerly of the NIH and currently Senior VP for Grants and Research at the Neilsen Foundation). When we speak to an audience like this, we have to be so careful. Going back to your stuff yesterday, you implied that regeneration had happened and that you were making new connections . . . you have to be careful about that and you have to show data. You showed some interesting functional restoration in people today. But patients do get the kind of recovery you saw over time . . . though yes, the movement in the leg is very cool. I really hope that you put your conversation in front of an audience like this into a little bit better context. We welcome that discussion. But if you’re talking about going to the FDA, you’ll have to clearly define your cell product, your manufacturing process . . . I just want this audience to keep asking questions.

And before Jan-Eric can really engage with the issues she raises, Barry says the 2 of them should talk offline … meaning that he thinks the whole group may not benefit from this kind of conversation.

So, what to make of this, friends? Is what we heard a convincing sales pitch or a genuine outside-the-box moment? How could we possibly be sure? The standard we usually hold scientists to is peer review. When the paper that outlines methods, materials, results and data is out there for everyone to read and discuss, that creates a certain confidence: this was done in a way that makes sense and can be replicated by anyone who has the protocol. When there’s no data to examine, what prevents an enthusiastic & well-meaning scientist from reading too much into his or her own work?

My skeptical self rejects anecdotal evidence; it’s too much like hearing patients who’ve gone off to get some poorly understood “stem cells” in India or China or Lima, only to find out that the stories of recovery weren’t reliable and the doctors doing the treatments can’t (or won’t) explain what’s going on.

My impatient self knows, though, that there’s a lot of wasted time in the standard way of doing things. What if this is the one time when doing an end run around the process worked? That would be amazing.

I don’t know which it is, though, and that’s my problem. I don’t have a way to know one way or the other. All I can say at this point is that it was a very interesting experience to be in the room where this material was being shown. With me were lots and lots of people sitting in power chairs, along with many scientists who have been doing the peer-reviewed paper thing for years, along with dozens of physical therapists and people from the NIH and the FDA itself. I could have listened to a discussion of this presentation for the rest of the day in that setting. I hope we hear more, and soon.

By the way, here’s a link to an article from a few years ago about Direct Reprogramming, for those of you who want more. It’s a very new technology.

Also, for any Russian readers who might be interested, the trial will be ongoing for another couple of years. Information is here.

Activity and Chronic SCI: Rebecca Martin & Beth Myers, Kennedy Krieger

The cord after injury . . ugh, yeah. Five major issues, all of which need attention. You have to block the molecules that are inhibiting axons from growing. You need some cells for remyelinating or regeneration. You need either a bridge or a scaffold — something to go around or through the injury site. That’s the big picture.

BUT you also need therapy. Activity promotes remyelination of surviving axons; if you have some axons without myelin, activity can help get them insulated again. The cord also has the capacity to learn (because it’s part of the brain), and activity is the way that happens. (Showing a video of a woman on a stim-bike; her arms are visibly firing in sync with the movement of her legs . . . as if she’s swinging them).

She has data about a group of their patients, all chronic. The transition probability is what they call the likelihood that a particular patient will go from one ASIA class to another; theirs isn’t huge, but it’s much better than that of traditional post-injury activity. And their patients are less likely to develop osteoparosis.

“We’re weird.” Okay, ten years ago we used to be weird, because ten years ago nobody thought it made sense to stand a person up, or to exercise the muscles below the level of the injury. Now they’re asking us what we’re doing.

We’re doing Activity-based restorative therapy. ABRT.

That means:

  • We want to activate the nervous system above and below the injury
  • High intensity practice for 2 – 5 hours per day
  • Non patterned and patterned movements
  • Restores lost function
  • Minimizes or eliminates compensatory devices

There are 5 key components to ABRT, learned painfully and slowly over the last 10 years:

  • FES, which is functional electrical stimulation. It can prevent or reverse disuse atrophy, substitute for orthotics . . .
  • Weight-bearing, which means loading weight on any joint. It promotes alignment, lessens bone stress, and normalizes input. It improves all kinds of things in your autonomic system (bowel and bladder, e.g.)
  • Locomotor training, which involves moving the legs and feet in an approximation of normal walking rhythm. It improves sensory, motor and autonomic function. It provides near normal sensory cues and comes with many benefits . . .
  • Massed practice, which is an intervention in which repeating a motion over and over is the primary factor. There’s a video of a man’s hand picking up ball after ball and dropping them into a plastic bucket. It promotes cortical reorganization; you have to do it multiple times for multiple hours and days.  In traditional rehab, the average duration was 36 minutes long — NOT enough. Not even close to what we ask of animals. Could high repetition training be done? They did 289 repetitions in each 47 minute session.
  • Task-specific practice is the last one; you’re train the task and not the impairment . . . video of a young man on a pt mat turning from back to side without help.

Aquatic therapy (pools!) can be a very effective way to work on all five. Most people don’t have access to fancy gyms or pools & therefore have to do home rehab programs. Best to have an FES unit, a standing frame of some kind, and an FES bike. That set of equipment would

Q: Is activity-based therapy now standard?

A: There are more of us, but . . .

Q: Are there hospitals using it for inpatients? What if I were somewhere else?

A: What we’re trying to do is incorporate the 5 principles WHILE training the self-care that has to be taught anyway. Transfer with no sliding board is one example.

Q: Something that scares all of us is the idea of becoming MORE impaired. Are there interventions that can prevent this?

A: Maintaining activity is how your body knows what to do, and that’s true for everybody, not just people in chairs. Your health literally depends on activity.

Q: What about the importance of nutrition and diet?

A: We have the luxury of having a nutritionist whom we can call in to address that — you’re correct that it’s vital. We’ve been looking at the correlation between BMI and skin scores . . . people who are slightly overweight seem to have some protection against skin breakdown.

Dr Ed Wirth: Early phase clinical trials of human embryonic stem cell-derived oligodendrocyte progenitor cells in patients with subacute SCI

Puts in a plug for an org called scope. Among other things, there’s a comprehensive list there of current clinical trials.

Start with early fetal tissue work overview. Dr Wirth works for Asterias, and IS biased, which he cheerfully admits up front.

Shows an image of a cross section of a damaged cord. There’s a massive hole. Short of brain injury, sci is the toughest problem in science. During the 80s and 90s there were many studies that involved fetal tissue . . . these were about transplants that happened in the subacute phase, between 2 and 10 weeks post. You can fill cavities with these cells, and you can do it safely, at least in rats. If you put the cells in too early, they all turn into astrocytes and you get not only no function but more pain.

We’ve made mistakes. We’ve put olfactory cells into the cord and grown nose tissue there instead of neurons . . .

Showing a video from 1992 that shows a cat with a compression injury — a couple of months post the cat has some recovery. They gave her some fetal tissue and she recovered a lot of weight bearing and coordination. (I can’t really stand to look at this cat, who was injured deliberately, unlike the dogs we saw earlier. I know that’s not how all of you will feel.)

So what else? They did a little study of 8 patients back in the 90s — gave them fetal cells along with immunosuppression. All of them had been injured for many years and had syrinxes developing. Their condition was getting worse, which is probably why they volunteered for fetal cell transplants. Ed’s talking about a guy who had been injured for 25 years when he started losing sensation in his arms.

So Ed’s team got rid of the syrinx that was causing the problem and while they were there, they added a whole bunch of fetal cells — using what they’d done with rats for the previous 15 years as a guide.

Another case was a woman who was 30 years post, but had begun to lose proprioception and feeling in her legs and feet. Again, it was a syrinx causing the problem. She got the cells, but they didn’t survive once the immunosuppression drugs stopped. She could walk almost 4 times as fast. He’s showing video taken in Andrea Behrman’s lab of this woman moving along pretty well.

So.

Fetal tissue comes from elective abortions and there are ethical issues that will never go away. That — plus the need to have multiple shots on goal — drove the development of oligodendrocyte precursor cells out of embryonic stem cells. That work was done by Hans Keirstead in the early 2000s.  In 2008 Geron (the company that had funded the research) filed a 21,000 page request for permission to test the cells. In 2010 permission was granted, and a few patients were enrolled . . . but then Geron ran out of heart and money for the project, and it folded.

In 2013 a new group started over. The FDA didn’t like the way the trial was designed . . . they weren’t convinced that the doses were safe as planned, and they made the scientists go back. These cells, by the way, are derived from a single donated blastocyst from a couple that had all the children they wanted after an IVF procedure.

And they could make all the cells they would ever need for the next 100 years from the the cells they have right now. That means once the cells are perfected, they’ll be not just plentiful but CHEAP to make. It’s hard, though, to make them 100% pure. What can OPCs do?

So glad you asked. They can make myelin sheaths, they can produce neurotrophic factors and stimulate axon growth, and they can stimulate growth of a new tissue matrix. By now they’ve evaluated these cells in a whole slew of animal models. Mice, shiverer mice, rats, African Green Monkeys, Gottingen minipigs — thousands of animals. . . the animals were shown to get all kinds of improvement — unfortunately NOT in chronic phases.

Meaning, these cells didn’t work unless they were delivered during the subacute window — and that means if humans work the same as all the animal models, human patients would need to get the cells sometime between 2 and 4 weeks post-injury.

Now he’s talking about the first 5 patients who got those cells back in 2012. None of them got infections related to the cells, none of them had more pain. In 4 of the 5 subjects, there’s evidence that tissue matrices formed to fill the cavities.

In August 2015, the company that took over from Geron got permission to test more patients, and were careful to name the outcome measures using the SCOPE standards. The plan is to inject 2 million, 10 million, then 20 million cells.  The first cohort (the 2 million cell people) have been done & we’re waiting for the FDA to evaluate safety before cohort 2 gets the 10 million.

Boom, the end. That, my friends, was a ton of words all in a row. I maybe captured the gist. Go to the video.

Steve Morin & Salina Prasad FDA: Developing Partnerships with Patients

This is about us engaging with the FDA, and them engaging with us.

Why do they care about our voices?

Because only we know what matters to us, because there’s variety in our opinions about that, because we have skin in the game, because we can report adverse events that might not get through, because we can carry information from them back to community as ambassadors and educators.

Slide up about history of patient engagement. It begins, natch, with the AIDS folk in 1988 and goes thru cancer & others until finally in 2011 they launched a patient network website. Between 2012 and 2014 the patient engagement thing was formalized by FDASIA 1137. And this year — 10 days ago — there was formed a patient engagement advisory committee, which is taking applications right now.

Okay.

So there’s a patient representative program, which exists to get our voices into their ears. They recruit into their program based on need . . if they have patient reps, they contact those people. There are 200 patient reps in the program, but none of them seem to be us. What?!

Patient reps are trained and prepared through a well-developed protocol that includes webinars and an interactive website and an annual workshop.

What do patient reps do? They can be on advisory committees, serving as temporary voting members, sharing experiences and informing the agency. OR the y can be in consultation directly with the decision makers, behind closed doors.

They’re involved all along the drug process: basic research, translation, pre-IND, clinical trials, NDA/BLA review, and post-marketing.

For getting medical devices through the system, the process is quie similar. The idea is that a device or a drug has a life cycle. There are patient-focused drug development meetings that are disease specific. At those meetings patients get a chance to speak in-depth about what they care most about . . .

Each meeting results in a report; there’s video. The reports are used by industry and in the larger community.

Why aren’t we in this list?

Muscular dystrophy is an example of a community that wasn’t part of this list — but they created their own materials and gave them to the FDA. We could do that.

What should we be doing that we’re not? There’s a website, which I just checked and is quite functional. You can submit comments through the Federal Register, every one of which is given to every member of the committee that’s focused on your area. You can go to an FDA-sponsored public meeting or sign up for one of their webinars.

(Okay, slightly frustrated at the moment. Dudes, this is what we want to know:

  • What is your job?
  • Who are the people who are in charge of drugs and devices for spinal cord injury
  • How do we get in touch with them?
  • What is the best way for us to have an effect on what happens with respect to decisions that affect our situations?)

Instead he’s talking talking talking about what other groups have or haven’t done.

The bottom line that I take from here is that if you go to the website I linked to above, you’ll be put in touch with these people. Their job is to take your phone call, answer your email, respond to your letter, whatever. They can’t move the process themselves, but — THIS IS IMPORTANT — they can help you figure out how and where to push and who to talk to.

Q: Do you maybe have too much paperwork? Couldn’t things be a little more streamlined?

A: We’re getting better . . . one thing that’s going to stop everything in its tracks is the shutdown of the federal government. Call your congressmember on that one. I think there are about 3,000 new drug applications that arrive at the FDA every year, with maybe 35 or 40 getting through.

Q: What’s the threshold for the FDA to pay attention to our community? What do you need to hear? How much do you need to hear?

A: They’re looking at what gets submitted . . . the original patient meetings were set up as a basis. He’s recommending that we think about what the Duchenne Muscular Dystrophy group did, (so I better go see what that was.) They actually got things done more quickly than they could have through the FDA.

Q: Earlier someone suggested that the FDA is quicker to approve interventions in acute conditions. Not chronic. Why?

A: We just review the applications we get. We don’t control what comes through, we just regulate it. There’s a language that we speak, and patient groups are learning more and more what that is . . . they can only do that by showing up and being in the conversation. In terms of acute/chronic things — they do eventually weave together. But you who live with chronic conditions,

Q: Clarification from Lyn Jakeman: are we (FDA and NIH) really putting priorities on acutes? A lot of the basis that helps us decide whether a therapy is ready to try in people is testing in animals. So, what she’s saying is that it’s not a matter of priority, it’s a matter of it being so very difficult to get anything to work in chronic animals. There’s very little data to support the idea that something will work in people. In other words, scientists don’t know how.

(My thought on this is that we do know of one thing that has actually worked and been tested and peer-reviewed. And that’s epidural stimulation.)

Dalton Dietrich: Current Progress on Neuroprotection and Repair following SCI

He’s from the Miami Project, which has a mission to discover and test new therapies that will improve function and quality of life issues in people living with paralysis. It used to be all about sci, but has expanded to include paralysis with other causes (stroke, ms, etc)

They run a bench to bedside/bedside back to bench research program that includes work with mice, rats, pigs, and non-human primates.

(He’s a super fast-talker, people . . . be sure to look at the video of this one if you want the full picture.) I’m letting him run through the basic intro slides, which are about things not that interesting to most of us — old approaches, acute interventions, like hypothermia.

For those who don’t know, that means cooling the body of the injured person within hours of the injury; it seems to be very safe and fairly effective in changing almost half of the ASIA A patients to a better outcome. There’s a major study underway right now. Other strategies for acute injuries include riluzole, minocycline, neither of which seem to work as well as cooling . . . another one is cethrin, also in trials right now.

On to regeneration: there are various helper cells: schwann cells, OECs, astrocytes, macrophages, genetically engineered cells like fibroblasts and schwann cells, stem cells including fetal, embryonic, adult, etc.

Why Schwann Cells? They promote regeneration of axons, they produce growth factors, they myelinate axons, they restore conduction, they enter the cord in big numbers, they’re already in your body . . . right now there are 6 FDA approved clinical trials being run out of the Miami Project, including Schwann cell transplantation for subacutes.

Wow, such a fast talker — I’m sitting here wishing he’d have chosen to talk only about CHRONIC injury intervention and done so at a reasonable pace. 

Boot camp for chronics, with a goal of getting people conditioned. It includes body weight supported training and then injection of Schwann cells.

They’re building a $130 million hospital right next to the project . . . they’ve started a neuro-engineering department, led by Monica Perez.

Talking about using Deep Brain Stimulation to target neuropathic pain. Done two patients, and both of them are getting relief. THAT’S BIG NEWS TO ME. Where can we learn more about this, please?

He invites questions and communication! write to him at ddietrich@miami.edu

Q: You have a lot of things planned and ongoing for acutes and subacutes. What drives an organization like yours to spend so much time and money and energy on acutes instead of chronics?

A: If you look at those 25 trials I mentioned on that last slide, we’re looking at all kinds of things for chronics. (Names a few things)

Q: (same person) no, no, no . . . we’re always told when we ask that things are being studied for chronics, it’s like, someone is doing a psychological study to find out how you are feeling! We want to get up.

A: I hear you loud and clear. Keep in mind that we can learn from these studies. We can only do what the FDA permits, and that often does mean — as in the case of Schwann cells — they wanted us to do acutes only at first.

Q: It’s very important to keep a balance, though. There’s a big imbalance in how much of your work is aimed at acutes v. chronics! There are no acutes in this room, are there? I’m not saying you shouldn’t do that work at all, but you might have a better balance between acutes and chronics.

A: I think if you go into emergency rooms you’ll see plenty of acutes . . . Thank you very much.

Q: About chronics getting Schwann cells & procedure vis a vis surgery & rehab

A: We’re using technology developed in other trials to do the surgery, are adding more cells to the chronics as we demonstrate safety, and yes, for chronics there’s a very serious rehab to maximize return.

Q: Are you collaborating with others across the planet?

A: Yes.

Q: How close are you to developing a cell that you think will work?

A: Schwann cells could work (for a variety of reasons). I think we’re getting close. Some people are showing robust regeneration but it’s not leading to functional improvement. We’re working with StemCellsInc and Neurostem on their programs, because we’re going to need industry.

Q: What’s the main mechanism you expect from Schwann cells?

A: Remyelination, plus growth factors. Creating a more permissive environment by addressing inhibitory molecules . . .

Dr. Nick Jeffery: How pet dogs can help us understand the value of new therapies for spinal cord injury

Causes of human SCI in the USA

  • car crashes -37%
  • violence- 28%
  • falls- 21%
  • sports-related-6%
  • other – 8%
  • Of course, what we all want is to reverse the effects of the injury and restore ourselves back to where we were.

How do we do that? Traditionally, with lab rats. Why use rats? because you can’t test therapies directly in people, and in animal models you can pretty much make all the injuries exactly the same. And that makes it easier to figure out if some intervention worked.

This is great BUT with artificial injuries, you’re missing a lot of factors that vary the outcome in human injuries, which are radically different.

The question is always, will this therapy be effective in a person? You can look at statistical differences to guess what might be meaningful, but you’re always guessing.

So, that’s where working with pet dogs can help. SCI is very common in dogs, especially in certain breeds. Also dogs are a lot bigger than rats, which makes it simpler to guess whether or not a treatment will scale up, so to speak. What works in a tiny rat cord hardly ever works in a person.

But the best thing is that the disease process is similar — it’s a real life injury. And scientists have access to both acute and chronic patients. There’s a lot of variation in age, weight, lesion nature, severity, and genetics — just like in humans.

So, how do dogs with sci show up at the vet? In the acute phase, just like us — their back legs don’t work. In the chronic phase, they use these little “chairs” attached around their middle with wheels to help them get around. (It looks uncomfortable in exactly the same way a wheelchair does . . . )

(Image of a fracture in the spine of a coon hound that was chasing a coon up a tree and fell) They use MRI to diagnose dog SCI just like they do with humans.

ACK. Showing video of them testing sensory function with a pair of pliers applied to the tail and the feet . . . he’s saying that it’s the very best way to figure out the prognosis very soon after injury. There’s a scale for dog injuries that’s analogous to the one we use (ASIA); it’s called TL. The first four categories have about a 95% recovery rate. The fifth has less than 5% recovery after 3 months.

You see where this is going, right?

They did a trial on that fifth group — the “hopeless” dogs. They looked at particular lesions in the thoracolumbar region, and they chose to work with small dogs, mostly because it’s too hard for people to take care of big paralyzed dogs.

They randomized the dogs into two groups — one that got the treatment and one that served as a control . . . the controls got a sham injection; the treatment dogs got a real one. The people who worked with the dogs after that didn’t know which was which.

Showing video of a para dog on a treadmill, which can’t move its feet unless you hold its tail up high and pinch it . . . the dogs hind legs then move right along in a stepping pattern.

Image of a dog with digital markers on its limbs that can be captured with infrared light and used to measure movement & coordination in really precise ways. They also measure electrophysiological outcomes (signal getting to muscle through the injury), and urodynamics with plain old catheters.

They’ve already published one study, which used autologous olfactory mucosal cell transplants (OECs) . . . you can find it in Brain here.

One of the cases was a 7 yr old male dachsund with a compression injury. (His name is Henry.) Henry didn’t recovery spontaneously . . . he got the OEC injection after being randomized to the treatment group. There were 34 dogs in this study, and Henry was one of 23 who got the cells.

They followed the dogs for six months afterwards . . . and saw gradual improvement. At six months the video shows him walking (with difficulty) along the treadmill. This was good, but it was “cumbersome” to get the cells out of the dogs’ noses, culture them for several weeks, and then inject them. They wanted to try something better & simpler.

Image of the glial scar, full of CSPGs that inhibit axon growth. We know that ChABC (chondroitinase) tends to eat up CSPGs. They’re using a form of ChABC that’s heat-stabilized so that it k

They’ve so far recruited 42 cases and are aiming for 60 by the end of the trial, probably about a year from now. There’s a PT component that involves swimming . .. can’t give us results until they’re finished, GAH — I really wanted to hear at least a hint!

Credit for funding to Spinal Research of the UK. You can follow them on their facebook page.🙂

Q: about that dog who could walk with his tail pinched and held up high. how did that work?

A: the lesion would have been around t-13 . . . the part that deals with back leg reflexes is below that. the reason is supposed to be plasticity in the remaining healthy bit of the cord . . it reverts back to some neo-natal reflexes–stepping movements not controlled by the brain.

Q: are all the dogs in the ChABC trial motor and sensory complete, and do they get PT before?

A: yes, they’re all motor/sensory complete. they’re also a long way out from injury, so many of them have had other things tried . . . we do require that their joints are still functional

Q: are the OECs terminally differentiated? or are they precursors (stem cells)?

A: yes, they are. they’re not stem cells. the biggest problem we have is that the source of them contains other types of cells, so we have to sort them very precisely, which is challenging . . . and while there was improvement, it wasn’t life-changing enough to justify the procedure

Q: if chABC was shown to be effective by your studies, would it come on the market for dogs, i.e., without all the protocol required for human trials?

A: ah, my knowledge of the US protocol isn’t complete enough to answer that question . . . (he’s British) . . .

Q: any anecdotal or owner stories about the controls getting better?

A: at the end of the trial we ask the owners, and at least 90% say their dogs got better. BUT the lab tech could guess with much better accuracy.

Day Two: Marilyn Smith

She’s saying that yesterday was incredible, both in terms of information presented and in the quality of questions and comments from the audience. (I felt that, too, for the record. We’ve learned a lot over the last 10 years.)

Also, if anybody wants to donate a buck or two to keep U2FP (organizer of this event) breathing and healthy, You can do it easily at their website. There’s a little red flag at the top right of every page.

Housekeeping details re cell phones, parking, schedule changes . . . and now recognition of people who helped with Rally #1, way back in 2005. Here’s the list:

  • Marilyn Smith
  • Betheney Gaines
  • Susan Maus

(sweet moment with the 3 of them together on stage)

  • Tricia Brooks
  • Michael Manganiello

(both of whom were working at the Reeve Foundation way back when & showed up to fill in the many gaps )

Literally true that these five people are why we’re here right now.unnamed

David Brafman: Engineering Human Pluripotent Stem Cells for the Study and Treatment of Neurological Disorders and Diseases: History, Opportunities, and Challenges

Oh, good — a tutorial about stem cells.

What makes a cell a stem cell? One, it can make more of itself, and two, it can differentiate into other kinds of cells.

What are the basic types of stem cell? There are multipotent, which can only turn into a few other kinds of cells, and the other is totipotent, which can turn into anything.

That’s the basic info.

Now we get a quick history . . . 1860s: Ernest Haeckel came up with the ideal. In 1890s, a little progress . . . then nothing until 1963, when we got the beginnings of bone marrow transplants. Idea-to-therapy took about 80 years.

There are lots of stem cells in our bodies — the brain has neural stem cells, there are lung progenitor cells, and satellite cells . . . in humans, what we really want is pluripotent stem cells (that can become anything at all), which have two sources. One is the blastocyst, which makes human embryonic stem cells. The other what they call induced pluripotent stem cells, which work just like embryonic stem cells but don’t come from blastocysts — they come from skin cells that have been re-engineered back to the “origin state.”

The source of blastocysts is leftover embryos from in vitro fertilization. The process of fertilizing a woman’s eggs to aid a couple in getting pregnant almost always results in more viable embryos than the couple is able to bring into the world . . . which means that many of those embryos end up being destroyed. When couples choose to donate them to science instead of having them disposed of, the blastocysts become the source of stem cells.

The other option for pluripotent stem cells is to use a process called induced pluripotency. It’s literally turning the clock back. Every cell in every human begins as pluripotent cell, and it goes through a series of changes to get sorted into lung, heart, blood, skin, whatever. Inducing pluripotency means walking it back down that path, all the way to the original stem cell, where it’s just like the ones in the blastocyst.

(There’s also something called direct reprogramming, which takes one kind of adult cell and turns it directly into another kind of adult cell. We heard about that this morning from Jan-Eric Ahlfors — he’s going to speak again tomorrow about his data gathered after using these cells clinically.)

In David’s lab, he’s been working with induced pluripotent cells in dishes to see if it might be possible to use them to help people with neurodegenerative diseases and conditions. Like schizophrenia.

Slide title: Stem Cell Therapies of Snake Oil?

There are people who are preying on the unsuspecting public, promising that they have a stem cell therapy that can cure anything and everything. This is happening not just overseas but here in the USA. One thing the clinics are selling is based on taking fat, processing it, and injecting it into patients. The number of clinics keeps rising; they’re not selling FDA-approved products; they’re charging between $600 and $20,000 for their “treatments.”

How do you know when you’re looking at snake oil? Claims will be something like, it works for every kind of illness, or the process will involve minimal manipulation to get the cells into shape for you. There are cases all over the world and in the USA of people dying after these treatments. But don’t these companies have lots of testimonials from former patients? They do, but they don’t have any followup from independent reviewers.

Can’t the government stop them? It’s difficult because they’re popping up quickly. So how can a person tell what’s legit and what’s not? Look for this:

  • Claims based on patient testimonials
  • Same cells for multiple diseases
  • Source of the cells not clearly documented
  • Treatment not documented with protocol
  • Claims of “no risk”
  • High cost

Look at A closer look at stem cells for more info.

Lyn Jakeman: SCI Research Support from the National Institutes of Health (NIH)

I have a hard act to follow, because I’m from the government, but I’ll do my best to keep you engaged.

Do any of you know how the NIH gives away money for SCI? (couple of hands raised)

Okay . . . I work at the NIH, about a block away from this hotel. I work in what’s called the extramural office. So, there’s a cabinet position called Health and Human Services. She oversees a whole raft of organizations, including the NIH.

The NIH itself is led by Francis Collins . . . who’s busy because he’s got 27 different institutes to manage. Every one of the 27 has its own culture, budget, etc.

FACTS: NIH invests about $3.3 billion annually

About 80% of this is awarded in the form of competitive grants to institutions and small businesses.

About 10% goes to research right on the campus at Bethesda, including the labs and the hospital there.

What we’re about: ensuring quality research, seizing opportunities to improve health, maintaining a diverse portfolio, considering the burden of disease, constructing and supporting research infrastructure.

We mostly fund research grants, but also fellowships to students and training grants. We fund cooperative agreements and contracts. We fund program projects and the centers themselves.

Okay. How does an idea get NIH $$$$?

A researcher gets an idea. She finds collaborators, and they develop a grant proposal, which gets delivered to us electronically. The grant gets sent to a review panel, who read it super-carefully to see if it merits further attention. Everygrant will get scored. Is it a serious question? Is it new? Are these the right people to investigate? Is the plan they have going to likely result in information not currently known?

The ones that get really high scores are the ones that the reviewers were super enthusiastic about. Eventually the institute director gets a suggestion pile from us that says what we think ought to be funded.

She’s showing a graph that shows what happened to biomedical funding between 1994 and 2012. There was a bump in 2008 (stimulus $$) and then a collapse in 2010, and it’s been flat since then. The graph also shows other sources for biomedical funding. Big contribution from pharma, and from the foundations.

What does NIH spend on SCI? $80-90 million, usually through NINDS, but also through NICHD, NIBIB, NHLBI, NIGMS, NIDDK  . . .

What does NIH spend its SCI money on? Big portion on repair and regeneration, like cell therapies and scaffold therapies. They also fund a lot of bioengineering. Okay, a couple of examples.

First is model systems, looking at those places where axons do or don’t regenerate. In the ringworm (C. elegans) there are scientists who can look at a single axon and manipulate a single gene to make it grow/not grow.

Another is the kind of nerve transfers that Justin Brown was talking about earlier today . . .

They’re interested in fundamental research, disease mechanisms, discovery therapy, preclinical work . . . very, very few clinical studies. What NIH is good at is helping to plug new ideas. But many of them fail, because that’s how science works. There’s a HUGE need to fund Phase III studies, which are the one and only way to get therapies to market.

Why that gap? Because things that happen in rat models don’t work in people. Out of 18 studies that were examined, not one of them was perfectly replicated in a big evaluation project about SCI research. Replicating a study is super-difficult, a little like trying to make biscuits exactly like your grandma’s. You don’t know what you don’t know until it doesn’t work.

She’s recommending we read an editorial in Experimental Neurology called Replication and reproducibility in spinal cord injury Research. (Okay, that paper is behind a paywall, but if you’re interested here’s a link to a slide show that was presented at the Reeve-Irvine Research Center. The authors are very heavy hitters: Os Steward, Phil, Popovich, Dalton Dietrich, and Naomi Kleitman.

What can we do together? Focus on ability, whatever you do best, do it. Increase representation; stop fighting for just accommodation — fight to be heard everywhere [use the RFI process from NIH and every other place in the federal government]. Try new approaches for research, which includes reverse translation — and that means taking the successes back to animals to find out what you can that you couldn’t/didn’t look for the first time. Share data. Form teams and centers without walls. Collaborate relentlessly. Stretch $$ through sharing efforts, and widen the circle of ideas.

Q: How can we fix the way the peer review system works? What about new types of science?

A: Well, it’s slow, but it does protect taxpayer dollars . . . we have to be cautious, but peer review lets us continue. One new type of science is data sharing, which is a big priority for us right now.

Q: How much money is going to neuroprotection?

A: Very little . . .

She’s at lyn.jakeman@nih.gov — ask your questions!

Gregoire Courtine: Neuroprosthetic Technologies to improve motor recovery after spinal cord injury

I want to talk to you about activity-based therapy combined with neuroprosthetics.

He’s giving a little history of how we got to epidural stimulation. Harrington, Grillner, Serge Rossignol, Reggie Edgerton . . . in 1984 they did an experiment with a transected cat that could learn what it was trained to learn. Train to step? It could step. Train to stand? It could stand. But it couldn’t do what wasn’t trained.

Gregoire began by working with astronauts to help them learn how to walk again after being in space, and then he went to Reggie’s lab at UCLA. They started with rats, chronic, complete injuries and trained them with a suspended gait system.

And got nada. Zip. Nothing. But it had worked in cats! At about that time Yuri Gerasimenko came to the lab with his epidural stimulators, developed in Russia.

After that was the first time he got to know people with spinal cord injury, starting with Christopher Reeve himself — and since that day hasn’t worked on anything else.

He published the successful rat work in Nature Neuroscience in 2009. With just a 2-electrode stimulator, the rats could walk. He went to Zurich and began his own lab. They developed a robot that allowed them to very precisely train and support the rats.

“At the beginning it was a complete failure.”

“We had forgotten something critical . . . motivation.” (image of chocolates on the screen, laughter). “We were focusing on the leg, but not the animal.” He’s showing a video now of a rat with a double-hemisected cord walking along in its little treadmill, basically chasing chocolate being dangled in front of its nose.

And then they take away the chocolate and that little critter quickly collapses. The spinal cord is part of the brain, not its servant. 

In Zurich they’ve working a sort of matrix: chemical, electrical, robotic, training across the top and mouse, rat, primate, human down the side. I can’t make the image with this technology, but picture the grid that’s formed. Four models of animals, four types of interventions. Each square needs to be understood and the last ones on this particular bingo card will be Human/Chemical, Human/Electrical, Human/Robotic, Human, Training.

Giving the cord below the injury a jolt of energy is the Model T (Model T is Reggie’s phrase for the Louisville epidural stimulators) way. Giving it the exact amount of energy needed under dynamic conditions is a super difficult challenge. They built a stretchy electrode array to solve that and it took them six years to do it. So how do you figure out how much energy to deliver and where exactly to put it? They built computer simulations to answer that question. And now they can deliver what they call “spatiotemporal” electricity — exactly how much is needed and exactly where it’s needed and exactly when it’s needed.

The next step would need to be primate research — not possible in Switzerland, very difficult in the USA. So, he moved to China (murmurs of appreciation).

He convinced Medtronic, after years of working on them, to allow him into the “vault” — the mothership. By August of 2014, they had a product ready to test on a monkey in China. And there is a video on the screen right now of a monkey walking along with that thing embedded. And he’s responding with specific movements to specific instructions that they’re giving him. Step higher, slow down, that sort of thing.

They’re developing a wireless platform right now that takes advantage of a brain implant. They can decode the animal’s intent. LET ME SAY THAT AGAIN. They can use their software/hardware to decode the animal’s intent and use the information to deliver that intent wirelessly to the animal’s muscles.

They can read the motor cortex activity in the brain. 7 years of technology development. Incredible.

An injured monkey (lateral hemisection) after 5 days post with this technology can walk. I’m looking at it. Gregoire says that when he saw this he wept.

He’s talking about a patient named Maria . . . at first she needed 70% body weight support plus stimulation. After 34 weeks, she’s walking across the room behind a walker with no support and no stimulation. They’re looking to work with ASIA C patients.

Beautiful black and white images of dozens of young scientists in his lab, all of whom, he assures us, are dedicated to making this work in humans as fast as they can.

Q: Did your primates get the same drugs as the rodents? And can humans get them, too?

A: We haven’t even started the drugs with our primates yet.

Q: This feels like you’re using a scalpel compared to the thing that was delivered in Louisville . . . why isn’t the lab in Louisville doing what you’re doing?

A: (pause) There are people here from the NIH and from Neilsen Foundation who funded that first work . . . I agree that at this point this is bigger than ego and countries and we should be collaborating.

Q: (couldn’t hear, it was about pharmacology)

Q: Please expand about the nature of the stimulator experimentation, especially about motor intent and how that drove your parameters

A: (A long, involved answer that boils down to using the brain’s natural plasticity to fix itself).

Q: You told me in an email that only ASIA C patients will be eligible for your trials. When will others be included?

A: We’ve got to do this step by step.

Man. I was pretty excited about the prospect of hearing Courtine speak, and I wasn’t wrong.