Good News: Landmark New Adult Stem Cell Trial for MS Raises Hopes

Mark S. FreedmanA new stem cell clinical trial for Multiple Sclerosis (MS) in Canada is raising hopes amongst patients and researchers.

According to the Ottawa Citizen, the trial will be led by Dr. Mark S. Freedman (pictured, photo from Ottawa Hospital), director of the multiple sclerosis research unit at The Ottawa Hospital and “The Canadian trials which are funded with a $4.2-million grant from the Multiple Sclerosis Society of Canada and the Multiple Sclerosis Scientific Research Foundation.”

This clinical trial will use a type of stem cell called MSCs isolated from bone marrow.

You can learn a lot more by reading the official ClinicalTrials.gov listing here.

From the Citizen:

“This is the first major stem cell trial that is going on in MS right now around the world,” he said. “There is so much noise about stem cells in general and the hype that surrounds them, we are doing this study properly so we can answer the question for once and for all.”

I see this trial as real reason for hope. I asked my colleague and leading MSC scholar, Dr. Jan Nolta, for her thoughts on the trial:

“The well-established ability of human mesenchymal stem/stromal cells to reduce inflammation, blunt the immune system and to produce growth factors and small parcels of intracellular components- exosomes and microparticles, to deliver to damaged cells makes this a highly promising trial for patients with MS. I wish the investigators and patients the best of luck with this clinical trial.”

Like any clinical trial, this one will have certain risks, but for the discussions I have had with patients, many with severe relapsing-remitting MS, being part of a rigorous clinical trial is worth it and is a way they give back to other patients including in the future by participating.

To be clear, this trial is fundamentally different than many of the pseudo-trials of stem cell clinics that we see sprouting up in the US using stem cells to “treat’ MS and whose main goal is to make money.

In this new trial, the investigators do not charge the patients simply to be in the trial, the investigators do not personally profit directly from patient participation in the trial, the team includes highly respected physician researchers who have extensive published track records and experience in these areas, and the data from the experiment will benefit everyone.

I’m excited to see the results.

51 thoughts on “Good News: Landmark New Adult Stem Cell Trial for MS Raises Hopes


  1. I am particularly excited for this trial, having previously worked on the immunomodulatory effects of MSCs in the nervous system, although in this case I am thinking that the proposed neural effects may also be mediated indirectly through systemic immunoregulation. One interesting thing to note is the high amount of cells being injected- probably 50-150 million per patient given that they are putting in 1-2 million per kg; I think that this will give higher chances of success. However, I would also be interested in knowing how much ex vivo expansion is required to reach these numbers, especially because they are starting from an autologous harvest, and what the passage number is of the cells being implanted; I hope that they carefully characterize the cells they implant. Also, given that the cell product they are injecting contains 10% DMSO, I am also guessing that they will be expanding the cells first, then freezing/storing them and then directly infusing them from the cryovials after thawing; I can’t think of any other reason why the injection solution would contain 10% DMSO. This is really interesting to me because at least in my experience with cell transplantation, the thawing of the cells is a crucial quality control checkpoint, and also because I was under the impression that thawed cells do not like to remain in the cryopreservation medium for long after thawing. Any thoughts? I am hoping that they also check the viability of the cells immediately before implantation, and not just by Trypan Blue. In any event, it will be great for those suffering from this terrible disease, which has debilitated one of my closest friends and labmates, to finally get some answers from a controlled trial.


    • Shinsakan – thankyou for this valuable insight

      Picking up on the immune perspective of stem cell-based therapies, I have recently discussed the potential “Friend versus Foe” role of T cells, drawing attention to immune regulatory checkpoints that may be influenced by stem cell-derived growth factors and cytokines (Stem Cells 22 Feb DOI: 10.1002/stem.1863). Your comments on expansion and viability of the therapeutic cells are highly relevant to the profile of growth factors/cytokines linked to the graft – as indeed is the level of cell-derived, or media supplement-derived, growth factors at the time of grafting. Could DMSO support prolonged bioactivity of growth factors perhaps …. ? The clinical trial may well be recording these details.


      • Su,

        Thanks for your response! I read your letter to the editor of Stem Cells and appreciate your nuanced view of immunomodulation by secreted molecules. Regarding DMSO, though, I am wondering how it could support the prolonged activity of the growth factors; DMSO is an organic solvent that, if anything, is used to denature proteins and other biological molecules. Any ideas?


        • Hi Shinsakan

          Thanks for getting back. Regarding DMSO, I was referring to the 10% DMSO in the cell product and my thought was – DMSO being both a polar and non-polar solvent – those cytokines and growth factors with four-helix bundle hydrophobic cores, when in the presence of 10% DMSO, will tend to be preserved with retained structural integrity.

          But, as others have said, the whole DMSO issue here may be in fact an error in the trial protocol text: perhaps the trial personnel can check and let us know.

          Su


          • Su, that is a really interesting idea! But I am thinking that the hypothesized effects are probably derived from cytokines/growth factors secreted de novo after the cells are infused in the body and less so from cytokines/growth factors already present in the injection medium of the cell product. I think that as soon as the infusion is performed, the DMSO concentration will decrease from 10% to probably around ~0.1% because the infused solution will be diluted by the blood, so I wonder whether such a low circulating concentration of DMSO would still be able to exert a stabilizing effect on de novo secreted molecules in the circulatory system.

            Regardless, I agree that this aspect can be easily clarified. I am just very curious about it.

            Regarding the immunomodulation that you discussed in your letter to the editor of Stem Cells, do you think that a similar cocktail of growth factors, perhaps from the conditioned medium of stimulated stem cells, could be developed as a potential biological drug to stabilize Tregs and exert a therapeutic effect without requiring cell transplantation? Are there small molecules out there that induce and/or stabilize Tregs?


            • HI Shinsakan,

              Following up on your query can immunomodulation be achieved using growth factors alone to exert therapeutic effect – the answer is yes. We have proof of concept that LIF targeted to CD4 cells in vivo using biodegradable nano particles as a carrier (i) promotes Treg and (ii) suppresses TH17 maturation (e.g. Mol Pharm 8(1):143-52). Also Cao et al in an EAE model showed that conditioned medium from NPC suppresses TH17 differentiation – an effect that was lost when anti-LIF antibody was added to the conditioned medium. Cao et al found recombinant LIF (given daily i.p.) per se could replace the therapeutic effect of NPC in reducing EAE.

              Looking to the future, the concept of nano particle (NP)-mediated targeted delivery of factors, rather than cells, is clearly an attractive alternative. In addition to being defined both chemically and physically, and suitable for large scale production and storage in freeze dried form, the NP provide sustained paracrine-type delivery to specific cell types. Off target effects are reduced whilst the nano particle PLGA matrix protects the embedded cytokine cargo from degradation by serum proteases. In our own work we use the same platform of nanotechnology that is already approved by the FDA: others are using this platform in clinical trials for delivery of anti-cancer agents – see BIND Therapeutics.

              As to LIF in the context of MS, both resetting of self tolerance and enhancement myelin repair are anticipated to provide dual benefits.


              • Su, thanks for your response and insight! I agree with the great potential of NPs for controlled and targeted release. I actually postdoc’d in a lab that was one of the pioneers of using gelatin and PLLA microspheres for drug and growth factor delivery, and we have also used PLGA scaffolds for simultaneous cell engraftment and drug release. I now work extensively with NPs for drug and cytokine/growth factor release, but from the perspective of intellectual property rather than actual bench work. It is a very exciting time indeed!


    • Dr. Loring,

      Thanks for your comment!

      The approach of Bai et al. in the Nat Neurosci paper is to take the conditioned medium/supernatant from cultured MSCs and apply it, rather than the cells themselves, with the goal that the molecules secreted by the MSCs (HGF in this case) will exert a therapeutic effect. This approach has been extensively evaluated (although not for MS) by Martin Yarmush’s group at MIT/MGH. Personally, though, I think that one of the big advantages of MSCs (and NSCs and other stem cells) is their ability to respond to pathological conditions, so am not sure whether taking supernatants of unstimulated cells would provide the most effective growth factor cocktail for a given condition.

      I did find a paper from Dr. Miller’s group where they actually transplanted cells to treat the EAE model of MS.

      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706928/

      In this case, they infused 3 million cells intravenously into mice, which proportionally is actually a much larger amount than used in the clinical trial discussed here; assuming a weight of about 20 g per mouse, this would be a dose of 150 million cells per kg, or 75 to 150 times the dose used in the clinical trial! One other thing that is important to note is that the paper from Dr. Miller’s group used an allogeneic transplantation model, so they could have a higher number of starting cells from multiple donors, which would require less ex vivo expansion; also I think that it would be easier to scale up to 3 million cells from multiple rodent donors than it would be to scale up to 50-150 million cells from a single human donor.

      Also, they do not mention the medium used to carry the cells for infusion, although I seriously doubt that they are directly infusing cells still in the cryopreservation medium. In every in vivo experiment I have performed or observed, low-passage MSCs are frozen for storage, then thawed and expanded for a couple of passages before transplantation to make they are healthy and to have a more exact idea of how many viable cells are being implanted, or at the very least washed and resuspended in an appropriate carrier medium. The only reason that I could think of why the clinical trial would directly implant the cells still in the cryopreservation medium would be that perhaps a clean bench, centrifuge, etc are not available in the place where they will be treating the patients, so it may be easier to just directly thaw and inject. Of course, I am making a lot of assumptions as to their method based solely on the presence of 10% DMSO in the injection medium, which I am assuming is there as a cryoprotectant. The actual method they use could be different, but it seems a little strange to me that the patient will be receiving a total of 5 ml of DMSO in the infusion (!).

      Whenever we injected MSCs (although I did not work with MS models), we used the culture medium or PBS as a carrier, which agrees with other studies similar to Dr. Miller’s group. For example, Nessler et al. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724887/pdf/pone.0069795.pdf) and Constantin et al. http://www.ncbi.nlm.nih.gov/pubmed/19676124 both injected MSCs intravenously to treat mouse models of MS, and the cells were injected in PBS.

      Karussis et al. transplanted autologous MSCs in MS patients (http://www.ncbi.nlm.nih.gov/pubmed/20937945); they put in around 60 million cells either intrathecally or intravenously, which is similar to the clinical trial described here. They required 40-60 days to obtain that many autologous cells, and although they evaluated surface marker expression before implantation, they did not perform any functional analyses. Additionally, the cells were resuspended in normal saline for injection. Notably, before transplantation the MSCs were “washed twice with normal saline solution to remove any residual dimethyl sulfoxide,” and they even attribute one case of meningitis to residual DMSO: “Aseptic meningitis was diagnosed and was most likely caused by residual dimethyl sulfoxide in the culture medium owing to insufficient washing of the cells.”

      Thus, in the clinical trial described here, I am wondering a little bit about the functionality of the MSCs after the high number of passages used to obtain high cell numbers, and I am especially wondering a lot about the presence of 10% DMSO in the infusion medium, which I have never heard of before.


  2. Given previous results treating aggressive MS (killed off the immune system and then rebooted it with hematopoietic stem cells) I’d say GO FOR IT!

    For BETTER and for WORSE, this sort of work is partly motivated by the growth of stem cell tourism:

    “Freedman said the growth of stem cell tourism makes such research in Canada crucial”

    Powers-that-be notice when patients shift their feet and dollars… Back in 2011 people were heading off for the Zamboni MS therapy. That caused the Canadian Government to cough up some loot for trials to test the Zamboni MS therapy. (Waste of money in my opinion.)

    Remember, in Canada, Healthcare is a Government monopoly. Medical tourism is the alternative…


  3. Thank you Paul for the heads up on this important Clinical Trial – indeed it will set a precedent for safety & outcome as the field develops. No greater responsibility than to responsibly try to push open new doors to possible patient treatments that have little or no options.

    My question would be on the issue of MSCs and their potential therapeutic action on the CNS, considering the Blood Brain Barrier.

    I read in the Clinicaltrials.gov overview in the “Detailed Description” that the expected “mechanism of action …. relies on their ability to modulate pathogenic immune responses and provide neuroprotection through the release of anti-apoptotic, anti-oxidant and trophic factors as demonstrated by in vitro and in vivo preclinical studies.”

    Given your, Dr. Nolta or a reader’s knowledge on the subject, is there a possible reduced opportunity for potential efficacy signals considering systemic IV administration of Adult MSCs have in the literature been inhibited from finding their way to the brain while other immune cell candidates have been shown in preclinical work to have the ability to modulate directly at the site, having crossed the blood brain barrier? Is that a consideration for the relatively large numbers of these MSCs, as a low hit % of distal trophic effect is the strategy?

    Irrespective a positive outcome will be a breakthrough and welcome news for patients. Thx.

    Cheers


    • One consideration could be that the BBB is known to be disrupted to some extent in MS, which may be why some MSC studies have shown therapeutic effects in the mouse EAE model (in which the BBB is disrupted) whereas effects were not observed in another CNS demyelination model without BBB disruption. DMSO is also known to increase the permeability of the BBB to some extent, although I doubt that’s why they are putting it in there.


      • Shinsakan:

        I’m thinking that the 10% DMSO might just be a stupid mistake in the description- but I haven’t read the details.

        Meanwhile, we’re following up on our work in a mouse viral model of MS using a very specific hPSC-derived cell type that we think is a neural precursor. I’m curious about what you think. http://www.ncbi.nlm.nih.gov/pubmed/24936469


        • Dr. Loring,

          Thanks so much for the comment! Regarding the DMSO, it could well just be a mistake; however, they describe it in detail, clearly stating that the patients will receive 5 ml of DMSO and also stating that the vehicle-only arm will also receive the same amount of DMSO, so I don’t know. It will probably be clarified when they publish their first report, although of course that won’t be for a few years yet.

          Thank you for sharing your study. I think it’s really exciting! The proposed mechanism makes sense, and the improvement of clinical scores is very dramatic. I like the use of a viral MS model rather than EAE for the likely greater clinical relevance and also the use of a fibroblast control rather than vehicle-only to really zero in on the effect of the NPCs. The cell injection seems to have been performed using the needle from the Hamilton syringe- was there any concern over potential damage to the spinal cord with that technique? I have typically used glass micropipettes for intraspinal cell injections. I think it’s really interesting that such extensive therapeutic effects were observed even though most of the donor cells died within a week; I think that this really gives hope to the idea of a one-time treatment to “reset” the immune system, which is especially important in this case because an intraspinal injection is not something that can really be performed as a repeated treatment. I also think it is interesting that the focus shifts to immunomodulation from other proposed mechanisms for neural stem cells in neurological disease, e.g., remyelination through differentiation of the NPCs into oligodendrocytes. These powerful immunomodulatory effects could have important implications for other types of neural trauma and disease such as spinal cord injury and stroke, in which neuroinflammation also plays a major role. What is the next step for your group on this project?


  4. $4,200,000 dollars to enroll 40 subjects is $105,000 per subject. Some one is getting paid big time. these trials are not free. Patient funded treatments would cost a lot less


    • Patient-funded treatments are treatments, not trials. They do not analyze the cells before implantation or use MRI and other tools to track clinical progress for years of follow-up after treatment or employ people to actually collect and analyze data. These things all cost money, and that is why what you are referring to is patient-funded treatments and not patient-funded clinical trials. There is a difference; the purpose of clinical trials is to collect data and obtain answers.


      • I agree that the treatment has to be scientific and leading to meaningful results, otherwise it’s a random aimless treatment that serves no one short or long term, irrespective of whether patients pay for it or not.


  5. I’ll take a stab at this Dr. Loring, as I’m trying to follow the biological mechanisms of action here, and would welcome your or the other experts’ feedback.

    From what I can gather there is still some healthy debate as to which are the varied possible avenues of influence and the most effective biological agents/cells to employ when seeking to interact on specific body systems to mitigate human disease states. Cellular trophic factors seem to be identified more and more as playing a fundamental role in regenerative pathways. The synthetic constructs or direct application of those biologics hold great promise as a means to restore function, albeit in some cases temporarily. Is homing & sustained release the challenge, given the mediating knowledge is fast being unlocked?

    In respect to MS the Treg data indicates modulation by all the discussion cells types – BM-MSCs, eMSCs and eNPCs – so one would assume that IV or spinal infusion is a cell specific/delivery matter, aside from ease of treatment and dose manufacturing considerations.

    The CD4+ versus CD8+ level differential is interesting as BM-MSCs show limited to no effect on the levels, while eNPCs reduce CD4+ levels while eMSCs reduce both. I wonder if there is more to the issue that Treg modulating capabilities, as your paper suggests growth factors play a positive role via eNPCs. In respect to increased IL10 in eNPCs wasn’t that caused by the viral induction methods and wouldn’t that have had a knock-on effect on the outcome data? Would it be worth conducting the same experiment with the EAE mouse model and compare? In the EAE model BM-MSCs showed increased IL6 activity while reduced IL6 levels in eMSCs seem to be the unique flag by which the Hemangioblast derived eMSCs perform in autoimmune diseases, other than the other cell trophic factors common among the groups.

    It could very well be that there will be any number of potential therapeutic routes to improve disease states & the critical test on all these topics I suppose is the successful translation to humans and as such the results of rigorous clinical trials to test the various cells/biologics & methods is vital, as a next step. I would only add here that cost effective commercial scale-up of any methodology in a safe, potent, replicable & standardized product is a prerequisite for consideration as patients need realistic solutions that are both effective & accessible. This is why I favor Allo Pluripotent cells programs – however not exclusively and support whatever works near-term as a driver (e.g. Emily).

    For general ref. the following eMSC Papers are material to the discussion – http://www.cell.com/stem-cell-reports/fulltext/S2213-6711(14)00127-1 & http://www.ncbi.nlm.nih.gov/pubmed/24650034 / https://www.ocata.com/uploads/scientific_papers/2014-03-20-Kimbrel-et-al-STEMCELLS-DEV-2014.pdf

    Alexey Bersenev referred today to a pertinent study on BM-MSC/MNCs via systemic delivery – http://www.celltherapyjournal.org/article/S1465-3249%2814%2900884-6/abstract. Certainly systemic delivery is the preferred route of administration.

    Cheers


    • msemporda, so nice to see you weighing in here with your insights and resources. These are exciting times. Jeanne, any thoughts on these ideas on mechanisms of action?


    • Just wanted to make a small correction here regarding the interpretation of Dr. Loring’s paper- actually, the IL-10 was upregulated in activated T-cells, not NPCs, and both groups were treated with the virus, so the observed increase of IL-10 in the NPC-treated group actually cannot be attributed to the viral induction method.

      Also, regarding the comparison of BM-MSCs and eMSCs, note that Wang et al. did not observe any amelioration at all of MS symptoms with BM-MSC treatment, which is different from the results obtained in other studies. Additionally, note that in Wang et al., the comparison of BM-MSCs and eMSCs in the EAE model was performed prophylactically and not therapeutically, i.e., before symptoms manifested, which is less clinically relevant. I am not trying to say that one cell type is better than another; rather, I am saying that it is difficult to come to general conclusions on what works and what doesn’t based on a single study or studies from a single group.


  6. I would like to know what Jan Nolta thinks about – http://www.cell.com/stem-cell-reports/fulltext/S2213-6711(14)00127-1 & http://www.ncbi.nlm.nih.gov/pubmed/24650034 / https://www.ocata.com/uploads/scientific_papers/2014-03-20-Kimbrel-et-al-STEMCELLS-DEV-2014.pdf

    With that is said by Esemporda and his points bioassays fro potency and toxicity are needed….I will focus on Potency…..

    Now understand, I am thinking out loud here: eMSC biology lesson 101 flow cytomerty to standardize treatment before therapy and assess the affects on the patients immune response or lack of with suppression of say IL-6….

    IMO from where I sit think of the following;

    Now if I were at a flow company BD, GE, Coulter, Sony, Thermo Scientific, I would develop a blood diagnostics immune monitoring kits to include:

    1. Activated CD 4 T-reg with IL-6, IL-2 and IL12p70.

    2. To follow the injections of eMSc I would see following the homing to nesting of eMSc with CD10/CD24/CD83 with Stro-1 as my negative anchor therefore I could watch the progress of Adult MSC vs. eMSC.

    3. Now the tricky part I would look at the epithelium micro environment from an indirect blood analysis of the epithelial to mesenchymal transition (EMT) pathway the literature states the loss of EMT is a direct relation to cancers and the progression of epithelial carcinomas and movement to metastatic to other parts of the body. I suspect this is true for the auto immune disease to a lesser extent, too. Since, Cancer is the most advanced auto immune disease that society does not want to label, like MS or diabetes……. because people see 2nd stage vs. terminally ill as not a good thing. EMT has 3 types – developmental (Type 1), fibrosis, rescue and wound healing (Type 2), and auto immune and cancer (Type 3).

    Why is this important because this is the part of the REBOOT mechanism and also in the calling of the T&B, NK from the bone marrow, spleen and other lymphoid organs at the right stage of differentiation response to help in the RESCUE.

    Once that is under way the REPAIR with epithelial cell surface & extracellular molecules such as integrin alpha, E-cadherin this leads to epithelial cell intracellular molecules which are claudins and cytokeratin filament proteins that work with collegen.

    Now I realize the this cascade is simplified to the most sophisticate aspect of signal transduction in organ homeostasis that leads to epithelial stem cell transcription factors which in turn control the epithelial stem cell functions of proliferation or differentiation.

    So now let’s look at epithelial stem cell proliferation or differentiation, since we inject the right amount of eMSC we have proliferation that shocks and awes the bodies to differentiation and REVERSE EMBRYONIC STATE (RES) also know as anti-ageing and you have REPAIR and healthy individual from any disease. RES first heard here at the Premium cause by eMSC injection and cellular therapy that is what is triggered. Lot’s of DNA as a percentage of the cell, in small bast cells, eMSC.

    Are you kidding me….. get out of here…… holy crap, my God, the man and his team is out of this world. ……but this is enough to chew on for now…..

    We will call all this REBOOT, RESCUE AND REVERSE EMBRYONIC STATE (RES) = REPAIR…LOL all the way to the bank.” Ocata therapeutics CSO, Robert Lanza’s work with Andy Hoffman at Tufts Vet School in dog trials on auto immunity diseases…..soon to be publish we all hope….


    • Hank, these are interesting questions and points. No offense intended to anyone, but it is funny how often we see scientists basically arguing “my stem cells are better than your stem cells”. This has been going on for a long long time.


    • Couple of quick comments:

      (1) How could flow cytometry of blood samples be useful to assess activated CD4 Tregs in MS, which are actually activated in the spinal cord? Indeed, various studies have suggested that CD4 Treg levels in the peripheral blood are similar in MS patients and healthy people. Furthermore, even if this was possible, wouldn’t it be more useful to directly evaluate effects on symptoms or MRI to assess effects on structure?

      (2) How could flow cytometry of blood samples be used to track the “homing to nesting of eMSc” when the “homing to nesting” is occurring in various organs and not the blood? Even if this were possible, wouldn’t in vivo tracking of the MSCs using contrast-enhanced MRI be more useful?

      (3) What does the the EMT, which is involved in fibrosis (including the fibrotic aspects of autoimmunity) and cancer (especially metastasis) have to do with MS, which is a CNS demyelinating disease and does not involve fibrosis or tumorigenesis/metastasis? What cells would it be monitored in, and how would this have anything to do with MS?

      Also, just out of curiosity, how are you defining cancer as an autoimmune disease? Part of the way that cancer grows is that cancer cells evade immunosurveillance; this is actually the opposite of autoimmunity. If anything, the triggering of autoimmunity against cancer by cancer neoantigens may actually help the body to naturally suppress cancers (see, e.g., Joseph et al., Science 10 January 2014: 152-157).


  7. Handy are you aware that Dr. Loring & many others are in their labs working with Pluripotent cells today? Genetic modifications of the underlying expression patterns can be achieved to enhance performance of all cell types IMO.

    Paul I agree that the debate continues and one aspect which is important to discuss openly is the outcome data in a clinical setting and comparitive analyse. This is something the sector as a whole will benefit from and therefore should be the prime motivation for the selection process in scientific translation.

    I believe CIRM and other important players in the industry recognise the importance to produce results given the need and public awareness of the sector’s long published developments. This is apart from the International movement outside the US which is driving change already.

    Highlighting dubious practices and exploitive commercial activities is important and oversight is absolutely necessary. However, the most effective mechanism in my opinion to thwart snake-oil predatory practices, other than pushing for clinical outcome data, as you correctly point out, is to focus on the Priority #1 of advancing the leadership programs/cells/science.

    All too often the public are presented with medicore at best clinical results after years and years of press. More of the same is not a receipt for broadbased acceptance and sector progression – including from the investor community.

    Gene modification technology became “hot” as a result of success not because it was around for a long time and was due. It hit its mark by way of pioneering efforts, innovation in the sector and risk taking.

    40+ years of stem cell work and the science needs a current breakthrough in overcoming a serious autoimmune issue on the same level and as important as CAR-T has made in Cancer … The database is full of cell trials dating way back but how many have shown significant trial data that points to actual cures that are simarily repeatable across sites, in numbers & cure ratio %s? Emily was a marketing phenomena as much as she was a clinical success – stem science needs an Emily+ for each lead indication.

    By getting behind the naturally potent therapeutic candidates in indications that can realistically be delivered the industry will be able to move things forward in the public eye and with much greater success. It has been said before – the sector needs undisputed clincal successes, not rivalry.

    That is not to say Pluripotent cells are the only answer, not at all, and there is certainly not only one company’s programs in the game (even if they have great potential). What I’m referring to is the need to identify from within, publically target, and support them to deliver a handful of curative stem cell treatments that are powerful in addressing serious conditions as swiftly as possible. Everyone needs to get behind those types of programs for the entire field to benefit.

    I’d welcome Dr. Loring or Dr. Nolta’s feedback, in addition to yours and the other experts that are today active in their stem labs.

    With respect.

    Cheers
    Michael


    • I agree with the need to promote successful therapies at the fastest possible pace, but I would also like to point out that by its nature, scientific research is an incremental process. The notion of “breakthroughs” that suddenly lead to miracle cures is largely manufactured by the media and members of the public who seek hope. Success in this (or any?) field does not come overnight, not for lack of trying; it’s not as though for the last 20-30 years researchers have been putting off trying to develop clinically effective therapies. That has been the goal since day one. Going off of the example of gene therapy that you mentioned, yes, it became “hot” as a result of success, but in reality, that success actually first required many years of basic investigation and even clinical failures. The pioneering, innovation, and risk taking actually started at day one when the first hypothesis was formed, not just when the public saw the train emerging from the tunnel. Even iPS technology, which has seen relative whirlwind development, took 8 years from the first paper to the first clinical trial, and that first paper would not have been possible without the many years of ES and other basic cell biology research that preceded it. I would argue that the more complicated the science, the longer it takes to figure it out to the point that it can actually be clinically applied, and stem cells are about as complicated as they come. This is why it is so important to go after the fraud and the snake oil; with so much overexaggeration and repeated hype but no definitive cures, the public eventually gets the impression that 40+ years have gone by with no real progress, when that is not really the case. The progress is there, but it is incremental, and this is the aspect that really has to be made clear to those who have not worked at the lab bench (especially those who want to cut government funding for basic research). That being said, I think that all of the incremental progress over the last few decades has finally brought us to the point where clinically effective stem cell treatments may conceivably be at hand, as evidenced by the recent profusion of clinical trials with various types of cells. It is just important to remember that in this field, the effective clinical translation of innovation will not occur overnight, no matter how much we want it to.


        • Thanks, Dr. Loring. I was reminded of when Prop 71 was on the ballot and Mel Gibson came out saying that it shouldn’t be approved or funded because stem cells have been researched for 40+ years without yielding any clinical therapies.


  8. I appreciate the reply & opinion and it’s probably a fair assessment from the lab looking out. That is what we need, more engagement and something I believe has been identified by Paul even as a key element in the outreach education process. All too often the perception and reality are blurred by inaction, rivalry and distance. In today’s connected culture the old school notion that the walls exist to protect the people are fast being modified to adapt to the new age we live in. Open access is a prime example. Patient advocacy has an important role to play in the development of the science that is for them. The dollars spent in large part by academics are dollars provided by the people. Accountability comes with the responsibility to develop and deliver solutions in a timely manner and within a supportive patient driven system.

    I’m the first to acknowledge the need and requirement to expand the resources approved for the sciences – you’re on the wrong tack there. Look to the other side for those reductions and ask why. It’s for that very reason of support we are communicating. There is a difference however between your view of the need to focus on basic science and my opinion on finding a middle ground whereby the science can flourish in a step wise manner and deliver the results the public and industry can get behind. A lot of attention is spent courting the media by scientists announcing development results. I agree this is a constant and the flow is getting wider and deeper.

    No one’s doubting it’s complicated, takes time and a stepwise process. Neither should it be overly rushed or any corners cut. However, the public are being marketed to and have been forever as a means to get attention to the programs the scientists are developing. Why is that? This reality isn’t the public’s doing btw. Media exists to service a market and it’s wise to understand the mechanics of it and participate in the process rather than believing the perception will occur by itself on its merits – as it hasn’t worked like that for a long time and especially now when everything is connected. Both are needed today more than ever. On the marketing of success – it is important IMO to ensure the best science is showcased to the public not the reverse.

    It’s a bit of a double edged sword when the science itself has pursued and promoted adult cellular products from within into countless applications & sponsored clinical trials while on the other hand it wishes to stop & regulate the use of them when the results generally are so so. Isn’t there an issue with standards here? I think anyone who knows my opinions knows I’m a proponent of Safety first but I’m also in favor of the patient’s rights as a priority beyond a basic regulatory framework to protect. Potency & results are what matter for Industry & Patients.

    Let me add here that science innovation doesn’t equate with regulatory barriers to entry nor successful licensure. There is an underlying reason for the new “Breakthrough” designation and emerging pathways to Expanded Access, not to mention the Right to Try movement.

    This isn’t about discovery it’s about translation and the countless stellar research & proof of concept studies done that don’t see the light of day as a result of a system that is poor at translating & communicating and which would benefit from some improvements here and there. The marketing of & support for leading programs is one aspect only but one which if done properly will provide the “heat” needed to drive more forward.

    Cheers


    • Actually, I am not in the lab looking out. I left the lab and currently work in a position with a more “big picture” role in innovation, policy, and clinical development, from start to finish.

      That being said, it is incorrect to attempt to separate discovery from clinical translation because in reality, that is not how research works; they constantly inform each other. This is why research is an incremental and iterative process; ongoing basic discovery informs the iterations of clinical development, especially with something as complicated as stem cells. For example, clinical trials with adult stem cells in spinal injury were performed almost 10 years ago but obviously did not result in a cure; current approaches may offer more hope because they have been informed by the ongoing basic and mechanistic research that continues to be performed alongside the translational work. I am not saying that basic research should be the only focus. Rather, I am saying that it is important to not underestimate or discount the importance of the basic science that makes clinical therapies possible.

      It is important to note that the dollars spent by academics that come from the people are often spent to support basic research because the fact is that most basic research cannot directly result in clinical translation and is thus not directly profitable (my basic point that research is incremental), even though without the overall progress in the field, the clinical translation cannot occur. This is why such research has traditionally been supported by the government (i.e., the people), because starting out and even up to clinical translation, there is no way to know what will work except to test hypotheses and also learn from negative results. That is how research works. If we already knew what kinds of basic phenomena could be effectively translated to therapeutics and exactly how to do it, there would be no need for research or clinical trials in the first place. However, there seems to be an increasing misperception among the public and some elected officials that all or most basic studies should be directly and rapidly translatable into a clinical therapy, otherwise they are not worth performing and money/time is being wasted, and an incorrect assumption that innovation and progress occur on some direct, predictable path that can be scheduled, hence your suggestion on the “accountability to deliver solutions in a timely manner” and assumption of “a system that is poor at translating.” As a result, members of the public wish to only focus on research for which they can perceive obvious and immediate merit, hence your comment on “a middle ground whereby the science can flourish in a step wise manner and deliver the results the public and industry can get behind.” However, research and innovation do not actually work that way. Such a perspective is taken by those who do not actually do research or innovate, based on hindsight and only looking at the last few steps of the process. Again, it must be recognized that many iterations and a basic determination of how biological phenomena actually work is necessary to “deliver the results the public and industry can get behind,” and that this takes a winding path that requires both time and negative results. A good example of this is siRNA, which is finally hitting the clinic after years of misfires in clinical development and was based on initial observations of basic phenomena in worms and plants that members of the public would have likely have not seen value in because it was too far removed from applications that they could perceive. If public funding for basic research is reduced or cut off, such innovation will not occur.

      The public is indeed at least partially responsible for the “marketing” as a means to get attention to programs that scientists are developing. By creating a demand for “results” and calling for restriction of funding to programs for which they cannot perceive merit (even though they do not work in the field and thus may not be qualified to actually judge the merit), the public creates a need for scientists and universities to “sell” and market their results to secure funding, which can then lead to misintepretation of findings and of the state of the field by the public. The media exists to serve the market (not to educate the public or report facts in a balanced manner) and makes money with big headlines and more clicks on news stories describing “breakthroughs”, which further contributes to this problem. The problem with the marketing of “success” is the definition of success. Those who actually work in research know that the findings of a single study or by a single group are interesting but not accepted until they are independently replicated and become part of the scientific consensus, again going back to the concept of an incremental process and not “breakthroughs.” The “best” science can only be distinguished after this process, not before. However, the “marketing of success” and showcasing of the best science that you advocate often prematurely highlight not-yet-validated concepts (like what happened with STAP cells last year). This would be fine if the public understood exactly what the results represent and their tentative nature and then used such reports as a springboard to generate excitement for further investigation as scientists do (again going back to the concept of an incremental, iterative process); however, the public instead tends to treat such “breakthrough” reports as fact without critical analysis and also as the end rather than just part of an ongoing process, which results in hype. They then think that the “best science” and “breakthroughs” have failed when they turn out to not be real or clinically ineffective, which in reality this is just a necessary and natural part of the long-term, iterative research process. I think that more than “marketing success,” it is important to educate the public on how research actually works so that they are better equipped to support the process, and I see the forum in this blog as a great asset in this regard.

      Promoting the development of adult stem cell products and simultaneously regulating them are actually not incompatible or two different edges of a double-edged sword. Rather, they go hand in hand, just as they do for any other drug or medical device, or indeed any other technology. Indeed, lack of regulation could actually hurt innovation in the field by causing rigorous approaches with potential clinical efficacy to be drowned out by noise. No one is trying to stop the usage of adult stem cell products; rather, the purpose of regulation is to ensure that as the field grows and more products become available that patients and consumers are protected. Simply put, it is necessary to know that people are being injected with what they think they are being injected with and that it is manufactured/prepared safely and correctly, and that what they are being injected with has a reasonable expectation of benefit that outweighs the risks. Or are you also suggesting that the current supplement scandal where many nutritional supplements have been found to not contain any of the ingredients they claim to contain (a consequence of the lack of regulation in the nutraceutical/supplement industry) is also acceptable? Patients’ rights are important, and patients have the right to not be defrauded or taken advantage of because they are in a desperate medical circumstance. Regulations can help prevent this. Potency and results matter for everyone, not just industry and patients, but they cannot be achieved by just wishing for them; potency and results require careful study, mechanistic understanding, and basic investigation. This is an important point known to those who work in research but often lost to the public. Perhaps the improvement of communication between researchers and the public that you mention should focus on this disconnect.

      Science innovation is not blocked or reduced by regulation or licensure; the ones actually doing the innovating are not the ones primarily affected in a negative way by regulation. The notion that the “the marketing of & support for leading programs is one aspect only but one which if done properly will provide the “heat” needed to drive more forward” is faulty because (1) it assumes that only certain end-stage programs should be supported when in reality innovation comes from the collective knowledge provided by advances in the overall field, and it further creates the public misperception that only a few “leading programs” exist and that other programs and more basic/fundamental work are not valuable or worth focusing on. If only a handful of approaches/programs are supported, then innovation will not occur. The field as a whole needs to be supported. Also, (2) it assumes that marketing is the problem. I believe that education is a bigger issue because more sustainable interest the field can be generated by educating the public on how research actually works than by marketing particular approaches to them, especially considering that they are already receiving extensive marketing for “breakthroughs” that may be hurting the field rather than helping it by building false expectations. Finally, (3), it assumes that there is some magic “heat” factor that will suddenly result in the deployment of successful therapies because presumably such heat is currently missing. This assumption ignores the reality that the field has been hot for a long time but that stem cell biology is only now beginning to be understood to the point that effective treatments may be developed, i.e., that an extensive foundation was necessary to bring us to where we are. Again this goes back to my original point that even though the public usually only focuses on the development of clinical therapies when the train is already emerging from the tunnel, i.e., in the last few steps where the therapies are almost developed, the reality is that an extensive and time-consuming basic foundation with a winding path and many dead ends is required for the successful deployment of any clinical therapy, particularly for biologically complicated ones like stem cells. I suppose that what I am saying is that the current clinical progress and any future clinical success will be the natural outcome of the continuing efforts that started with the laying of the initial foundation, and that it is important to recognize the process as a whole because we can then understand why it takes so long to see actual clinical implementation. Furthermore, although I agree that attracting public attention to the field through marketing is important to continue to generate excitement, in this context it is most important to educate the public so they understand how research actually works, what results actually mean, how investing in basic research and not only end-stage translational research is critical for therapeutic development, and how the entire field has to be supported for meaningful innovation to happen, such that they get an accurate and balanced view; otherwise, such marketing can backfire.


  9. Appreciate your feedback and I can understand your interest in explaining and desire to educate – that comes across… It does seem however that the perspective you take is from a viewpoint trained and seasoned in the finer details of the basic sciences – at least that’s what it comes across as.

    The educational process we speak of as a common thread requires a fluid communication free of assumptions I agree – and as such I’d suggest the bigger picture is the focus free from the apparent need to emphasise basic research values, as no one has questioned the merit and interdependency of such. Less defense and more team work would be welcome. Results & success are what we are speaking to I believe and how best to support the process to make that a reality for the stem field – not funding, not the importance of basic research and not who’s fault it is that the media and public are in the mix. If it was me that phrased my comments incorrectly, please forgive me.

    You speak of siRNA, which is a good topic to address and one which I’m well aware of having been there during the dark days. The bandwagon approach to the early years of RNAi led to many disappointments and dead-ends – you’re right. Then the money & many many scientists abandoned the field en masse for new discovery topics while the hard core carried on and prooved their science. This is a prime example of how not to manage difficulty and challenges in the cycle. It happened with Gene Therapy and has with Stem Cell Science….

    I hope you wouldn’t say that it’s necessary to abandon a line of research even if there is great promise as the support ebbs and flows? I don’t think that should be the lifeblood cycle of the research & development community. Is it reasonable to expect criteria for applicable clinical program selection as a fundamental requirement in the earliest possible stage of translational research development? Is there more need of a business filter in the process? For example aren’t manufacturing and commercial issues an important component of decision making during the earliest possible stage in program selection and if so shouldn’t the entire ecosystem of the development process revolve around perfecting those criteria elements as a standard? I’ve run ISO studios and managed creative staff needing freedom to express, so the concept of innovation & experimentation within a deliverable isn’t foreign – some of the projects took many years also.

    On STAP I was never into it and Paul knows that very well. It was just another researcher’s announcement, like so many others, albeit more newsworthy. I have stated that Sasai was a brilliant contributor to the field and should be remember as such. How many retracted papers have there been and how many more errors have been published by the sector’s researchers with problems? Peer review? Publishing is a media business but researching & authoring is a science business. Both need to improve IMO. Just as you say independent repeatability is required for scientific validation – I agree.

    My issue with Adult cells is why are there thousands of programs in that space with so so results and only a small number of potentially more important Pluripotent programs in development? It’s not that there isn’t value in Adult nor need for regulation. Decades of research and only a handful of hES programs?

    Nutritional supplements? How about cosmetics? What about chemicals in food? Vaccines? Toxic drugs? Labelling? The list is long and frankly I’ll pass on that as I prefer to focus on the science of cellular therapies in respect to translation > robust science shown to work in animals that require clinical translation to verify human safety & effect with industry & public support.

    iPS was slated to be trialed in the USA, alongside pioneering efforts in Japan, however the reality is another story on clinical translation.
    Are the federally funded US iPS lines for research able to be freely accessed by research groups yet?

    The 1st Parthenogenesis trial is slated to be done in Australia, not in the US, as a result of the cited regulatory issues?

    Is there an obstacle to the redefinition on embryonic stem cells to included Blastomere for federally approved funding? Why? Is that the reason so few programs exist today? Politics? How many years?

    Are you suggesting that the Japanese and UK governments with their own world class regulatory systems are wrong to push forward with new efforts to modernize the development & use of novel cellular, genetic & biologic drugs?

    The point I’m trying to make, perhaps not as well as I’d like, is that the sector requires deft management of the success factor required to develop. It’s clearly a leadership & communication issue and how best to market the industry to propel things forward. I don’t believe you honestly think that CIRM are interested in starving research? The entire foundation of the sector depends on a supportive infrastructure. The NIH and US Govt. have and continue to prioritize research and innovation in the sciences. There is no lack of fundamental support as I see it but it has to do with optimization, bottlenecks and a unified approach.

    Selecting & broadly supporting the most promising translational ready & early clinical stage programs is what matters at the moment as a priority.

    I’ll state this again so I don’t run the risk of misdirecting you – all phases of the science cycle require full support. The above is not a zero sum game.

    So you are aware I do not represent the public. A layperson reading an article wouldn’t be interested in the topics I’m discussing – all they’d be interested in is restoring their elderly parent or saving their sick child/family member from disease. The hope for that with new science is what the sector is responsible to nurture.

    My family have for almost a century cared for the sick as medical practitioners & specialists, performed all forms of surgery in battle zone deployments and treated the fallen heroes of those trying to save others in 9/11. Our extended families have set up charitable foundations and funded the basic sciences and arts. We care and have an interest in helping our own as a result of personal genetic weaknesses.

    Thank you for your communication S and I’ll keep it shorter next time, I promise.

    Cheers
    Michael


    • I apologize for mistaking you for a layperson; I just got that impression and made that assumption from your comments on Wang et al. and Dr. Loring’s paper.

      I appreciate the response and agree with you on many points; however, having worked in preclinical and some translational research in both Japan and the US, I am not sure I would say that there is a particular bottleneck here for cell therapies as opposed to other countries. For example, the first ES clinical trials were initiated here (with actually rather premature approval by the FDA in the opinion of many working in the spinal cord injury field), and at least in my experience, Japan is actually more strict on ES cell research than the US and generally has a poorer system than we do for clinical translation and commercial development of basic science research.

      As for iPS trials, I believe you may have confused iPS cells with ES cells regarding “federally funded iPS lines for research;” typically in iPS cell research and development, people create their own iPS cells, and kits are commercially available so that any researcher can do it. Additionally, for clinical transplantation, the general idea is to use autologous iPS cells generated from the patient (as in the current trial in Japan), not pre-existing cell lines. The only time iPS “cell lines” are really considered for use is when they are prepared from people with genetic diseases and then used in vitro as cell models of the disease to find new mechanisms or drug targets. Also, with iPS cells, you have to understand that for Japan, iPS cells are a mark of national pride and touted by the government and even laypeople as the premier example of Japanese innovation, which is why they are so intent on pursuing iPS research (often to the detriment of other programs, as so much of the funding goes towards iPS work). In terms of commercial and clinical development, though, there seem to be more companies working on iPS or iPS-based technologies in the US than in Japan (much to the chagrin of many Japanese that I know), but it is important to note that direct transplantation of first-generation iPS cells is not the only goal for these companies; some companies are working on ways to generate the cells using small molecules rather than viral overexpression of genes, and some companies are working on using the cells to make in vitro disease models as I mentioned above to identify novel drug targets; the development of such disease models is actually considered by many to a primary application of iPS cells, over transplantation and cell therapies. Additionally, direct reprogramming from one terminally differentiated lineage to another without having to go back to the stem cell stage is another concept (made possible by iPS) that is attracting attention in basic research that, if clinically feasible, would be simpler than transplanting cells. Also a big thing to remember is that much of the intellectual property on iPS cells is owned by Kyoto University, which may affect clinical translation in terms of the direct transplantation clinical trials you are thinking of by companies in the US. All of these factors may have contributed to the lack of iPS trials in the US thus far.

      As for pluripotent cells vs. adult stem cells, they are completely different animals used for different things. Pluripotent cells are much more complicated because they harder to prepare and culture, and must be differentiated to a desired lineage before transplantation; therefore, more basic cell biology knowledge and experimentation is required before they can be used. Because they can be differentiated into various lineages, therapeutic approaches with pluripotent cells usually involve a cell replacement strategy, with overall loftier goals in terms of the diseases treated. Adult stem cells, on the other hand, are much more easily obtained and cultured, and no differentiation protocols are necessary; they can just be injected as-is. They are mainly used for applications based on their secretion of growth factors and cytokines to decrease inflammation and enhance regeneration (but not generate completely new tissue, except in bone/cartilage/fat tissue engineering) because they do not really differentiate into cells other than bone, cartilage, or fat. Pluripotent cells are more complicated, and a lot more work and basic knowledge is required to use them in therapies, in addition to more resources. In contrast it is easy to extract and use adult stem cells, so it is easier to at least initiate clinical programs using them, although I think it will take a deeper biological understanding before they can really be used effectively. The difference in complexity and usage strategies (i.e., cell replacement with cells that must engraft for pluripotent cells where specialized knowledge is required vs. injection of cells that secrete factors for adult stem cells that almost anyone can do) may be why there are fewer pluripotent programs, although it may also be useful to separately consider adult stem cell programs that rigorously characterize the cells and then sort them or apply some other manipulation to enhance their efficacy vs. programs that simply extract them and then re-inject them; such consideration may decrease the apparent disparity between pluripotent and adult stem cell programs a bit. Note that I am not saying that one approach is better than another; although I spent most of my research career working on adult stem cells, I am also an Ocata fan. I think that there are individual applications where each approach could potentially excel.

      What I am trying to say is that sometimes, bottlenecks can come from the technology and research process itself and not necessarily from regulatory agencies or from lack of market appeal, and these bottlenecks are intrinsic to the research process and can only be removed by time and further research that brings new discoveries. The point I have been trying to make is that stem cells are complicated enough, that yes, it takes decades for them to be understood to the point that they can start to be clinically applied. We can’t effectively develop and use technology, especially something as complicated as stem cells, if we do not sufficiently understand it, and this is an iterative process that simply takes time and further experimentation to reach the critical stage where we actually know enough to make an effective therapeutic.

      On initial filters when starting preclinical/translational work, to some extent such filters are already being applied by the government and private investors when they decide whether or not to fund a technology. For further filtering beyond what is already done, it is simply not possible to know what will work and what won’t to that extent when starting out, or to define what is the “most promising.” To suggest that some kind of further filter beyond what is already applied can be initially applied to select the “best” technologies again seems to me to be a hindsight perspective not compatible with biological research. Of course nobody starts out a study thinking “this isn’t going to be clinically translatable” or “this isn’t the best approach.” The determination of the “best” approach can only be made after the fact, when the data are in. Attempting to even further winnow down “promising technologies” would result in an overt focus on things that may not work at the cost of things that may be highly effective, and also limit other research necessary to inform the continuing development of the “promising technologies.” Also, a focus only on what is translatable now means detracting from ongoing research into next-generation products that may have even higher efficacy in the future, and also basic research that will inform the translation of current products. That is why the whole field, at all stages, needs to be supported; even the process of finding out that something doesn’t work informs future iterations of the research in the field.

      I agree with you about the need for improvement in the publication process; I think that outright fraud (like with STAP) is fairly rare, but nonreproducible studies are common. I think that one reason may be the intense pressure to publish and publish rapidly; I am not sure how this situation can be changed.

      Anyway, thanks for the discussion. I don’t mind reading long posts, as I tend to write them myself!


  10. Appreciate the feedback & apologies for the tardy reply – flu here. An observation Paul, this comment template doesn’t display well for long conversations… perhaps a tweak needed or another venue for such?

    Teams of diverse people are required in all fields. Qs and observations require clarification I agree as needed. I’ll assume now that IL10 expression in the NPC arm is definitely not a viral phenomena and that it’s a unique method of action of NPCs generally. Is that a fair assessment? Pls. excuse me but my general observations on the viral model in relation to the EAE model speaks to the inability to accurately compare – hence my comment about why not do an EAE study to allow for such?

    Wouldn’t studying various cell source prodigy to see which is more effective in a given model be valuable? Unrealistic? I’m sure there are probably many reasons one could cite for not doing that but by doing so it would make it that much clearer to analyse, wouldn’t it? This is important even if the main thrust of one’s work is to prove a certain cell. This is an example of an area where the science can add color and improve IMO, along the lines I was speaking about and which can be based on preclinical data. Data is only one of a number of criteria to determine viability of utility in commercial science…

    I relayed Wang et al.’s actual study review comments which referred to general MSC modulation. I’d welcome some feedback on the more important queries on cell source expression in BM MSCs and eMSCs as there seems to be some fundamental differences which may prove material (IL6 being one I noted but also added now that eMSCs “can inhibit CD83 up-regulation and IL-12p70 secretion from dendritic cells and enhance regulatory T-cell populations induced by interleukin 2 (IL-2)”). Not sure if this has any bearing but CAR-T IL6 modulation is being used effectively to control the adverse effects of the occasional cytokine storm reaction.

    Many in the hands-on arena have noted they don’t know How or Why in many cases or even If one aspect of the mechanism of action being explored is responsible. Communicating what is known and what isn’t clear adds clarity.

    The general unknown here does reinforce your point about the iterative process of discovery and I would agree it’s central to the development of the science. I would only point out that the never ending search for answers shouldn’t take precedence over the practical translation of effective treatments that are proven to be safe but work in ways that the science of the day doesn’t fully grasp. Patients are waiting, suffering and dying.

    This brings me to the point I was attempting to make about regulatory hurdles. The UK and Japan have/are adapting their regulatory systems to meet the new realities of Cellular Therapeutics & Regenerative Medicine. The openness to explore all forms of next generation science is important, as is the concepts that streamline the process and make it a faster and a more effective process. I don’t believe you are saying the system can’t be improved. I’d like to see that aside from the tighting of controls in certain exploitive areas that there is a priority focus to facilitate faster and more effective routes to deliver safe & effective patient treatments.

    It may very well be that Japan considers iPS their domain and will look to defend its IP positioning but as far as I understand they have licensed their IP rights to a number of international parties for translational programs, apart from the standard for-research-only type. Using one of those developed lines would circumvent any perceived restriction. However, having said that the recent lawsuit challenge to Japan’s iPS IP is a flag that someone or group believe the IP held by Japan in this area isn’t valid. Aspects of Dedifferentiation and Transdifferentiation were earlier Priority dated technologies btw. Aside from those doubts there are various other “methods” to derive iPS cell lines which precludes exclusivity IMO. I would hazard a guess that the reason iPS hasn’t progressed to the clinic in the West isn’t due to secure a future “commercial” use license to specific IP, it’s due to the science & the current regulatory environment.

    On the hESC first clinical trials, I believe the common perception that the translational efforts were first initiated in the US by Geron, is evidentially in doubt as it seems that Dr. Geeta Shroff in India was the first to transplant hESC derived therapeutics – without Immunosuppression btw. As the story goes, evidentially there were many who didn’t believe her and her attempts at publishing her work were turned down, along with the willingness to accept her as a presenter at international scientific forums. I have no doubt there are still probably many that question the credibility of her work, as her trials aren’t controlled nor documented. However, if true the concept of a mixture of embryonic cells & es derivatives alone or in combination with adult cells may be a window to explore… She has now been granted US Patents for her hESC work.

    The US is indeed very progressive and retains the lead in innovation for a reason but perhaps is too cautious at times and would benefit from getting behind the initiatives that Congress are currently pushing for. Maybe the new FDA Director will take things forward with a renewed mandate & perspective.

    Adult cells being easier to access and use is true but that to me doesn’t mean that they should be the overly dominate focus of the industry. I understand there are commercial reasons to offer solutions that help and to expand and enhance those basic offerings to fill a niche in the market but I must say that stem cell science would benefit far more from potency than from a quantity of offerings. Pluripotent cells exist or can be made by calling BioTime’s ES Cell Int. sub for that or another hESC provider – this has been the case for a long time. To say that Pluripotent cells are mainly for cell transplantation completely misses the mark when looking at the unique cell expression profiles of some of the cell types being researched. I referred above to the eMSC unique issues with regard to its expression profile and these are transient non-engrafting cells by nature and not a cell replacement treatment. There are over 200 auto-immune diseases – some of which are incredibly important to solve as they are unmet needs. In respect to other biologic factors expressed by unique derivatives of Pluripotent cells I would say watch that space. Manufacturing boat loads of biologic factors may very well be the next big thing for Pharma. Synthetic variants of immortal cell lines also will be valuable for a host of delivery & therapeutics indications.

    I’ve gone way over my intended short reply – sorry about that and I agree it’s not a problem for me either if you wish to continue in the same vein.

    Cheers

    PS – Paul I hope you don’t mind I’m going to copy the exchange over to your Blog on iCell tomorrow unless you object, as the formatting is getting tough for people to read the earlier posts. We can carry on here if this has more legs in it but the archive would be worth having a readable copy somewhere.


    • Hi msemporda,
      Do you mean how the comments get narrower as they are nested or the fact that only a certain number of nested comments are allowed per original comment?
      I can work on those issues.
      I’d prefer that folks not copy and paste content in its entirety to other sites please as that’s a copyright issue.
      Paul


  11. Let’s try this out. If you are responding to someone else’s early comment just quote them and/or mention their name (e.g. in reply to: )


  12. Lookin better Paul – thx. Helps to be able to read the earlier comments, some seem to have appeared now that I can see them properly! Pls. note that by submitting content to your Blog it doesn’t mean assignment of the copyrights to such material to you, only contextual usage.

    One point I forgot to relay to S regarding the iPS lines I was referring to which he doesn’t seem to be aware of – it had to do with the NIH disease lines which was noted by Bernard Siegel’s 360 Editor’s commentary recently:

    “While it is commendable that President Obama is proposing this ambitious initiative, it is perplexing that in the “here and now” there is a bottleneck at the NIH holding up research on reprogrammed cells- potentially useful to personalized medicine. Since 2013, the NIH keeps a seemingly iron grip on at least 400 induced pluripotent stem cell (iPSC) lines created by the Institute from orphan and rare disease disorders. Scientists say the cell lines could be of immense value to research. Contrary to prior NIH pronouncements, and for unknown reasons, the cells created in 2013 are not being made available to outside researchers.Further, resources generated by NIH sponsored research are meant to be accessible to other researchers. It is a NIH requirement for funding. Thus, it is extremely frustrating that the reportedly 20,000 iSPC lines generated with NIH funds to the extramural program have not
    been distributed to researchers, despite a process enabling such distribution. The cell lines are being generated with NIH funding from
    NHLBI, NINDS, NIMH, NIGMS and other institutes. To date, we have no clarity on how these lines will be made widely available. Certainly,
    bureaucratic delay, indifference and neglect are not valid excuses when fighting chronic disease. So, what is the reason? Dr. Collins, it’s
    imperative that all these valuable cell lines be made available to researchers now.”

    http://us1.campaign-archive2.com/?u=513b92eb0bf6c17f06cca149d&id=b5a54eebb0&e=d58538bac1


  13. msemporda,

    Regarding models, the IL-10 is not expressed by the NPCs; it is expressed by the T cells in response to the NPCs. As for comparison of models, it depends on the reason for the comparison/hypothesis. It would be more useful if you are comparing two clinically relevant actual mechanisms of injury, e.g., penetrating vs. contusion for spinal cord injury. However, for MS, I think that although the EAE model is the traditional model and has been used to develop therapeutics for MS, it is currently considered by many to have various shortcomings in terms of clinical relevance because it does not completely reflect the human pathology. In this sense, some viral models such as the one used by Dr. Loring’s group are considered by some in the field to be more clinically relevant to human MS and perhaps to even better represent the etiology of the disease. I do think that comparing different cell types and preparation techniques for different conditions is useful; this is actually a popular theme for studies in the tissue engineering field and has been for a long time.

    For Wang et al., my point was that the comparison between eMSCs and BMSCs was made prophylactically and not therapeutically, i.e., the cells were administered before the onset of symptoms. That makes the data interesting but less clinically relevant (it is usually rare to treat a disease before the patient actually presents symptoms). Also, again note that they observed no effect at all for BM-MSCs, which goes against what many other studies have published for effects of BM-MSCs in MS models and if true would then seem to invalidate the rationale for the BM-MSC clinical trial that was the original topic of this thread (and thus suggest that $4.2 million is being invested for no reason). That is why I was making the point that it is necessary to look at the results of multiple studies from multiple groups before coming to any conclusions, and also that it is best to use the most clinically relevant model (e.g., in this case, not prophylactic administration, and perhaps not EAE if a better model is available).

    As for Japan and iPS, licensing of technology by itself could enable trials to be performed but would be unlikely to provide sufficient financial motivation without some other IP, especially because iPS Academia/Kyoto University is not giving out exclusive licenses (i.e., you and your competitor could both license the same technology). Companies generally want to generate their own IP as a core and then maybe license other technology as needed rather than operate off of a model whose entire basis depends on non-exclusive licensing. I believe that other companies will have to find their own “hook” before iPS clinical trials become commonplace. I am not saying that there is a failure to obtain a commercial use license; I am saying that having one alone (i.e., without having some other exclusive IP unique to the company) would probably be insufficient to make someone want to invest in running a trial. The trial in Japan is being supported by Japan’s government, not industry, and I explained their nationalistic motivations for doing so above. In terms of the place to actually run the trial (regardless of the location of the company producing the product), also note that trials cost more to run in the US because of higher staff and facilities costs, although of course compared to developing countries, our regulations will also be more severe. As for the recent iPS lawsuit challenge, I personally don’t expect it to go anywhere; it may even be thrown out by the PTAB before being reviewed (at this point, it is only in the petition phase). In my opinion after reading it, the lawsuit seems to be groundless and without merit; I seriously doubt that the patent will be invalidated. As for direct reprogramming, I was not talking about transdifferentiation or dedifferentiation. Direct reprogramming is conceptually different, and came after the discovery that cells could be “reprogrammed” to pluripotency (i.e., iPS); see the work of Dr. Melton’s group at HMS as an example. As for regulatory issues, I doubt that regulatory stinginess is the main reason why iPS trials have not been initiated in the US; I think part of it could be the current status of the science as you mention, and I also think that the IP issues and lack of an “angle” for companies could also play a role, in addition to the fact that as I mentioned, transplantation of iPS cells is not their only promising use, and companies are also focused on using them for drug screening, which could have better short-term payoffs.

    As for translational work, I am sorry but if it is not controlled or documented, then it does not count. That is why I was referring to Geron’s work when talking about initiation of ES clinical development in the US; also what I was responding to was your comparison to regulatory framework in Japan and the UK/Europe, and the idea that our regulations hold us back compared to those countries. As for pluripotent vs. adult cells, the main difference is indeed that pluripotent cells can be differentiated to many different lineages, which is why the focus for them has been on cell replacement therapies, because that is something that cannot be done with adult stem cells. Of course, the pluripotent cells can be partially differentiated to precursor cell lineages similar to those of adult stem cells (e.g., eMSCs) and then used in the same way, i.e., transiently for factor secretion and physical modulation of the environment, but I doubt that there would be a dramatic difference in potency. You mention watching out for biological factors secreted by stem cells- I agree, as I have actually been working in that exactly that space/field for almost 10 years. Adult-derived MSCs secrete many useful factors as well; factor secretion is not unique to pluripotent-derived MSCs.

    I do agree with you that there is always room for improvement at the FDA and any other regulatory agency, especially considering the evolution of the field, but I don’t think that regulatory stinginess is the primary reason for the dearth of cell therapy products on the market. My original point was that the status of the science itself and the complexity of stem cells also have to be considered. The field is finally coming of age.

    It seems that I have also again left a long response. Anyway, I hope that you are feeling better.


  14. I actually liked the previous format more because it was easier to keep track of conversations. I think that even if we respond to people by name, this format will make it difficult to follow conversation threads if multiple comments/conversations are in play at the same time.


  15. You said that about IL10 already. Viral microenvironment then NPCs enter the picture and IL10 goes up – I see.

    EAE model of no value to many in the field. Sort of sounds like someone I know when the Wang paper came out. Tell that to the scientists that use that model as the “traditional” way to work.

    No use in comparing different cell types for diseases? Seriously?

    You said that already on the Wang et al. paper issue with BMMSCs. If it shows prevention of disease onset I would say that’s very useful as the whole point is not to get sick. On the repeat issue you should read the Lupus & Uveitis study from Kimbrel et al. & note the Turfs Dog trial data as it gets published.

    I’m not surprised on the variations of effect from BMMSCs that exist in studies – they typically are expected to do more than they can and age of the donor and passage are highly correlated to potency, evidentially. Trust the Canadian trial will do it’s best with what they have to work with – high cell count dosage seems a stretch…

    So you know the Law on Patents doesn’t prevent anyone from doing research – including clinical trials.

    Getting to a ground state of Pluripotency via iPS is only one part of the puzzle, as you know. If a License to do it yourself via a patented method helps and secures your commercial positioning moving forward then yes that would make strategic sense but getting to ground zero isn’t the problem nor is it the IP you need to create your own Product protected by your our IP. That is where you need to innovate and create. Obviously your know that.

    The challenge to Japan’s iPS positioning may or may not amount to anything. Reminds me of the WARF issue – far too long and drawn out a process legally to mean anything practically, especially considering when the science moves faster than the process.

    Direct reprogramming doesn’t have it’s roots in transdifferentiation? Perhaps you’d like to clarify that for me, considering the Prior Art in the archives if I recall dates back to 2000 if not earlier for Transd.

    If you followed the iPS trial planning in the US the FDA required a validated GMP Clinical Grade iPS cell line to start the trials.

    The iPS technology has evolved and presents another potential source for Pluripotent cells – however, I would agree it’s main use is for research.

    My opinion generally on reprogramming is it adds more complexity when there is perhaps more straightforward ways to derive Pluripotent cells, including patient specific cells.

    Doesn’t count! LOL Point was Geron may not have been the first as you were saying. You can be dismissive but it doesn’t change the fact.

    The US regulators are falling behind the movement to speed discovery and delivery of treatments to the public. That was this issue and that is clearly apparent by way of the Cures2015 initiative, amongst other regulatory work-in-progress…

    I wouldn’t put such certainty on the doubt that eMSCs will show a dramatic difference versus Adult MSCs… You could be very very wrong about that – even considering your years in space…

    The evidence to-date suggest that eMSC posses unique expression patterns as evidenced by the USPTO Science Examiners report.

    Glad to hear you’re so generous to believe there is always room for improvement…

    Still under the flu here but better thanks.

    Cheers


  16. msemporda,

    Regarding the NIH-funded/developed iPS cell lines, you were originally talking about clinical trials with iPS cell transplantation, so that’s what my comments were addressing. The NIH-funded sponsored iPS cell lines you mentioned are not for transplantation or clinical trials; they are used for better understanding of basic disease mechanisms and identifying drug targets. One big draw of using iPS cells for transplantation is their preparation from patients for autologous transplantation (like the current ongoing clinical trial in Japan). As I mentioned, kits are available so that any researcher can generate iPS cells in the lab. If we are talking about transplantation applications, then the distribution of NIH-funded/derived cell lines is irrelevant.

    Regardless, if we are talking about the NIH-funded disease lines, I don’t think they are quite as difficult to obtain as you suggest. Note that the quote that you cited appears to confuse 400 iPS cell lines generated by NIH with the 20,000 iPSC lines generated extramurally with NIH funds. At least the extramurally generated cells (and perhaps also the intramurally derived cells) could be obtained by directly contacting the lab/PI that generated them; this is how other cell lines generated by individual labs are often distributed. My lab and neighboring labs never had trouble obtaining iPS cells from other labs/collaborators, although we were using cells from healthy donors, not disease model cells. For the disease model cells, though, what about, e.g., the Coriell Institute, which keeps a repository of NINDS-funded disease iPS cell lines (e.g., Parkinson’s disease and Huntingon’s disease) and has distributed over 200 cell lines to outside researchers to date? Have you actually cultured iPS cells or tried to obtain iPS cell lines and had difficulty, or are your opinions solely based on a single quote from someone who himself is also not a researcher?


  17. msemporda,

    I believe that you did not read my post closely.

    I said that the EAE model is of value but has shortcomings that have to be accounted for. This is well known to those who work in the field. I never said there was no value to comparing different cell types; in fact, I said the opposite.

    Regarding prophylactic use vs. therapeutic use, if you peer reviewed for journals you would know that this is an issue that comes up. “Prevention of disease onset” is not as clinically relevant for MS because it represents treatment before even receiving a diagnosis, or are you suggesting that all people, even those who will never develop the disease, should be pre-emptively treated with stem cells for MS to “prevent disease onset?” I am not saying that the data do not have value; I am just saying that this caveat has to be considered. Also, out of curiosity, why did they use a therapeutic model for their other experiments but then a prophylactic model only for the BM-MSC/eMSC comparison?

    Given that you acknowledge the variations of BM-MSC effects in studies, then why are you yourself discounting the potential effect of BM-MSCs in MS or making assumptions based on the findings from a single study?

    Yes, patent law does not prevent anyone from performing a clinical trial, but people are less likely to perform a clinical trial and development unless they can eventually commercialize the product, which is where IP comes into play.

    If you read the challenge to the iPS patent (and took the patent bar and worked in patents), you would probably also expect that the challenge to the iPS patent will probably not amount to anything. Do you really think, though, that the science moves faster than the patent litigation process to the point that the iPS patents will irrelevant when the decision is rendered? I think otherwise, at least based on the kits to make iPS cells currently being sold based on that patent.

    As for direct reprogramming, yes it is conceptually different from transdifferentiation, and the concept of reprogramming to pluripotency is part of where it came from. Direct reprogramming refers to the direct reprogramming of one terminal lineage to another by chemical treatment or factor overexpression (similar to that used to make iPS cells) without any dedifferentiation or involvement of stem cells. To those working in the field, transdifferentiation is a term usually used to refer to when progenitor cells from one germ layer differentiate to a lineage considered to be in a different germ layer (e.g., when mesodermal MSCs are theoretically differentiated to ectodermal neurons).

    Regarding requiring a GMP clinical grade line for trials- this is a bad thing?

    Reprogramming may add complexity for development of pluripotent cells, but it also adds advantages, such as the use of autologous cells.

    The fact that proper control and documentation is required for clinical development is obvious. I am not being dismissive; only realistic. Or are legitimate ES clinical treatments actually now available in India as a result of the initial “clinical trials”?

    As for dramatic differences between eMSCs and adult MSCs, do you have any actual mechanistic reasoning that would support such a hypothesis, especially considering other approaches in development to increase the potency of adult MSCs? Do you actually work with these cells? I am not discounting the possibility; I just have doubts as to whether the difference will be as dramatic as you seem to expect.

    Also, the people at the USPTO are called patent examiners, not “science examiners,” because they primarily evaluate patentability from both a factual and legal perspective. The reasons for patentability may or may not be related to unique expression patterns, and even when unique expression patterns exist, that does not automatically translate into clinical efficacy or dramatic clinical differences. Indeed various other types of adult MSCs and also techniques to change the behavior of MSCs also show “unique expression patterns.” Time and clinical development will tell whether there really is one approach that shows clear superiority.

    I hope that you recover soon; I had the flu a few years ago in the winter when I was still living in Boston and it was terrible.


  18. My iPS quote from my post above on the subject:

    “iPS was slated to be trialed in the USA, alongside pioneering efforts in Japan, however the reality is another story on clinical translation.
    Are the federally funded US iPS lines for research able to be freely accessed by research groups yet?”

    If you wish you can address your reaction to Mr. Bernard Siegel directly, I’m sure he’ll be interested in your feedback.

    Personally I’ve had the pleasure to meet Mr. Siegel and respect his opinions.

    This was about the lines not being available, evidentially, as I first mentioned.

    Cheers


  19. msemporda,

    The original discussion was about the perceived slow rate of progress in the development of clinical therapies using transplanted cells and laying the blame on the regulatory system. How does the availability of cell lines for basic research have anything to do with that?

    You have not responded to the fact that cell lines are actually available, e.g., through the Coriell Institute. Have you actually worked with these cells or tried to get access and had difficulty, or actually known someone who has?


  20. I’d be happy to carry on the chat if you wish, as I agree there is more to explore. Multiple topics in this format here isn’t that effective for all to engage with IMO nor allows us to go into more detail, as we may wish – so I suggest you register on iCell where we can start dedicated Threads in the Science section on an individual Topic and carry on the healthy debate, which I have enjoyed. Thx.

    If you don’t wish to engage further I’ll understand.

    http://sco.lt/5rJmj3

    Cheers


  21. I agree and it’s going to be interesting how the alignments will occur given Ocata’s Mgt. having indicated they are interested in Partnering moving forward… Lot’s of possibilities given the proprietary cell types in the Blastomere to Hemangio > derivatives…

    If you haven’t seen this I wrote up a Blog on the subject recently: http://msemporda.blogspot.com.es/2015/01/the-hemangioblast-prodigy-ocatas-blood.html

    I’d be interested to hear more of your thoughts on the “unique” aspect to the cells per Dr. Lanza & Mgt. and the application to Cancer targets (immune regulation & eDendritic for example)

    Cheers


  22. I agree with Dr. Knoepfler’s analysis. I am also impressed by how broad the allowed patent claims are. As for how unique the cells are, the criteria for sufficient uniqueness to establish patentability are typically different from those I would consider as representing a discernible physiological/clinical difference (I think that the bar is lower for getting a patent). I think that more data are required before I would consider these cells really different from MSCs or other pluripotent-derived cells in terms of biological or therapeutic capability. However, I think that the discovery and application of an intermediate hemangioblast step before differentiation to other lineages like MSCs and DCs is interesting. I suppose the big question is really whether it makes such a huge difference in the resulting cells that actual clinical differences will occur. I am very interested and excited to see what they do with this and how their pipeline develops.


  23. Paul I believe has indicated he’s going to review the patents and feedback further. I’d agree that the Patents are Broad and the potential for human impact needs to be studied in the clinic for assessment. To-date we have the lab cell comparative analysis and positive animal work, most recently at Tufts. The Hemangio intermediate stage does seem to be a key contributing aspect to the lineage expression but again it’s early still and agree further data & work needs to be done & presented. We should continue the chat on the topic when Paul has a chance to feedback or more information is available. 3rd party study of the Hemangio line & derivatives would be useful I would imagine.

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