Is Advanced Cell Technology (ACT) on the road to cure Multiple Sclerosis (MS) using stem cells and specifically MSCs?
Some folks seem to think it’s quite possible, but I remain skeptical.
Still there have been some interesting developments.
ACT has a relatively new patent filing for a mesenchymal stromal cell (MSC) product that was just recently published.
The filing has 125 claims. Wow.
Mentioned prominently in the patent filing is MS as a target disease. In fact, there are rumors that ACT has already “cured” MS in mice leading to “dancing mice” that if not for a stem cell treatment should be paralyzed.
Talk of dancing mice in the stem cell field (as opposed to say the movie, Cinderella) should be viewed cautiously.
Still, one wonders what the back story is here and it turns out to be intriguing.
A member of the Investor Stem Cell Site named Patti apparently transcribed a recent talk by ACT CSO Bob Lanza in Boston, which contained the following section that seems relevant here:
We’re starting to now look in various animal models. So one of the first that we looked in was the experimental autoimmune encephalitis, the DAA model. A mouse is one of the best models we have right now for multiple sclerosis. So when you induce the equivalent of MS in these animals, you have a clinical score. So when you get to 2, these animals are unable to use their forward limbs, they’re paralyzed. By the time they’re up to 4, they’re completely paralyzed, all of their limbs are paralyzed. So what we were able to show is that we can go in with MSCs. In this particular model we’re using is very aggressive, severe clinical symptoms, when you go in with bone marrow MSCs, we see minimal impact on the course of the disease. By contrast, when you go in with the MSCs derived from the embryonic stem cells, completely knocks it out. The animals have clinical scores of less than 1; in many cases almost completely normal at 0. So these animals are jumping around, you know currently with no symptoms.
This is a surprisingly definitive statement, but I’ll wait to see the data before making any conclusions.
I would also note that recently some serious questions have been raised about how effective mouse models of inflammatory human diseases (the so-called EAE (experimental autoimmune encephalitis) mouse model would fit into this category) actually are given the big differences in how humans and mice react to these kinds of diseases.
Getting back to the MSC patent, an important question stands out: how is this patent filing unique and hence would not infringe on the scads of existing MSC-related patents?
The title of the filing gives a potential clue (emphasis mine):
METHODS OF GENERATING MESENCHYMAL STROMAL CELLS USING HEMANGIOBLASTS
It would seem that the sourcing of the MSCs from hemangioblasts is a key distinguishing feature.
Another question that then logically follows is that if MSCs are already so readily available from fat, bone marrow, and other sources, why should anyone get particularly excited about yet another source of MSCs?
In addition, since ACT’s way of making MSCs clearly requires more than minimal manipulation, their product is definitely a biological drug subject to relatively more lengthy FDA regulatory oversight. While I think that oversight is appropriate, it is important to mention this reality in the context of competitors using MSC products doing everything under the sun and moon to avoid such FDA regulation.
This makes for a difficult potential future market for ACT’s MSC product should this patent be awarded down the road.
I’m not trying to be a wet blanket here, but it’s important to place this in the appropriate context.
In the patent filing, ACT states (emphasis mine):
The hemangioblast-derived mesenchymal stromal cells of the instant invention retain a novel, youthful phenotype as defined by expression or lack thereof of specific markers.
This would seem to be the key element: ACT’s MSCs stay young for a long time, whereas generic run of the mill MSCs say taken from a liposuction aspirate do not.
Let’s see how this develops, but it seems to me that no dancing in the streets (especially on Wall Street) by humans or mice seems appropriate based on this.
Not yet at least.
Disclosure: I do not have stock or any financial interest in ACT.
I saw the presentation put up on youtube and found it very interesting.
If my understanding is correct hESC-derived MSCs are far more potent than adult derived MSCs and they have a longer duration of action as well as their replicative capacity is more than 30,000 times greater than that of adult derived MSCs.
MSCs are multipotent stem cells, while ESCs are pluripotent, so I am just wondering what are the characteristics of hESC-derived MSC in terms of carcinogenicity and tumor formation. Extensive experience with adult derived MSCs indicate that they are pretty safe; however, ESCs seem to be a bit of a concern.
The experiment was carried out with the mouse model of MS, so, it would be interesting to know whether the anti-inflammatory and immunmodulatory characteristics of the MSCs did mostly the job or these MSCs did really facilitate repair as well. This latter characteristics would be important for those progressive MS patients who have no gadolinium enhanced lesions and already incurred damages in their CNS.
Why are eMSC superior to adult MSC?
(NK) Natural killer cells are a class of lymphocyte that recognize and eliminate tumors, foreign cells such as an invader (eMSC) and cells that are infected with microbial pathogens. My argument is specifically, the allogeneic eMSC could possibly override ( I do not know this yet but a theory, Bobby Lanza help me out here) the identify receptors on the cell surface of NK cells that enable these immune cells to interact with both adult stem cells and the immune system. Recently, Lewis L. Lanier lab have been studying two types of transmembrane adapter proteins expressed by CD8 cytotoxic T lymphocytes, natural killer (NK) cells and myeloid cells that activate these cells when their associated membrane receptors bind to ligands. One group of these adaptor proteins is characterized by immunoreceptor tyrosine-based activation motifs (ITAM) in their cytoplasmic domains that recruit and activate the Syk and ZAP70 protein tyrosine kinase pathway. This adapter protein family includes FceRIg, the CD3z, and DAP12. These ITAM-bearing adapters provide signaling for several distinct membrane receptors, some of which interact with ligands on virus-infected or tumor cells or in our case eMSC for treatment of autoimmune disease such as MS and activate the effector cells to produce cytokines and to kill the targets. The second type of adapter is DAP10, a transmembrane adapter protein that contains a YxxM motif in its cytoplasmic domain, which recruits and activates the PI3-kinase pathway. DAP10 is associated with the NKG2D cell surface receptor that is expressed on all CD8+ T cells, NK cells, gd-TcR T cells, and activated macrophages. NKG2D recognizes proteins encoded by the human MIC and mouse Rae-1 genes that are usually silent in normal adult tissues, but are induced by stress, viral infection or treatment of eMSC
My argument continues that these functions are neutralize by eMSC and therefore you get to the rescue and repair phases of the epithelium in the eye or pancreas for diabetes. A biofeedback mechanism that Lanza’s eMSC will and has prove out with mammal studies per his statements (Papers to be release hopefully any day now, since Lanza’s announcement in August 2012). I think the eMSC patent release opens the door for more communication to the scientific community
One of the more perplexing questions in biomedical research is—why does the body’s protective shield against infections, the immune system, attack its own vital cells, organs, and tissues? The answer to this question is central to understanding an array of autoimmune diseases, such as rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, and Sjogren’s syndrome, MS. When some of the body’s cellular proteins are recognized as “foreign” by immune cells called T lymphocytes, a destructive cascade of inflammation is set in place. Lanza’s eMSC cells will now providing new approaches to strategically remove the misguided immune cells and restore normal immune cells to the body
Why? Because of the early telomere and gene expression activity with eMSC cells. Stem cells have trouble assuming a specialized identity if their telomeres, the protective caps on the ends of their chromosomes, are short. Pluripotent stem cells can become any cell type in the body, and are known to require long telomeres to grow normally. Without telomeres, the genomes would progressively lose information and be truncated after cell division because the synthesis of Okazaki strands requires RNA primers attaching ahead on the lagging strand. Over time, due to each cell division, the telomere ends become shorter but not when you start with Lanza’s eMSC and reboot the immune system
From a gene expression point of view embryonic MSC cells promise a precious cell source for the treatment of various degenerative diseases due to their capacity for self-renewal and ability to differentiate along multiple cell lineages. IMO eMSC are more pluripotent because early telomeres. A lack of understanding surrounding the basic biology of stem cells, the stemness, continues to challenge the field and prevents successful clinical application of these cells. Gene expression analysis, both genome-wide and targeted at specific gene subsets, will played a key role in improving our understanding of the genetic attributes of stem cells through identification of molecular signatures that characterize normal stem cell function and Potency. Such approaches have facilitated the investigation of stemness in a subset of tumor cells, so-called cancer stem cells, and have started to unravel their roles in initiation and progression of tumors. A recent advance of gene expression analysis in stem cell research and also discusses critical issues that remain to be elucidated in the search for cancer stem cells markers. The overall goal is to define the immune mechanisms involved in the recognition of eMSC cells after they are injected
Hi Paul, thanks for your thoughts. After reading through the patent, I find it hard to believe that anyone would be threatened by your post. Along with your concerns and/or suggestions, the authors included a myriad of possibilities to test and manipulate further for clinical translation.
Dr. Lanza has faced this type of skepticism before, myself included. At UCLA, I asked him about a study that ACT pursued with respect to pre-clinical RPE. In the study, RPE were manipulated with bovine corneal epithelium….the results were a staggering 200% increase in cell survival/attachment. However, Lanza was adamant that this was not translatable, and in turn suggested RNP.
As suggested in the patent, the MSCs(when injected systemically) may need to be mitotically inactivated and thereby reducing its efficacy and duration. However, it may be possible to isolate human cytokines from these models. Again, Im not sure how your lack of emphatic enthusiasm disembodies the scientific method that these scientists are currently pursuing in their EC50 experiments.
Truth be told, I am ultimately biased toward the capabilities of this team. Now that they have reached clinical trials and have shown unprecedented results in dryAMD; my question to you is: If ACT indeed takes MSC into the clinic with dramatic results, will you be skeptical on the next pre-clinical claims?”
granted, the first indication would have to be MS in this scenario…personally i think it will be uveitis…but a fun hypothetical?
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Hi Paul
Your opinion on balance is well placed – especially in respect to science and treatments for the ill. There are those in any community that take a prudent view and there are those that look to the future. That’s what makes us a community and in our case
a forum…
The MSC sector is moving fast and I wrote yesterday a piece on the leadership the Adult MSCs have taken in the stem field but I
also noted that there is a leap-frog technology phase in play which may see those advances obsolete sooner than many believe…
On the potency, replicative ability and immune privileged etc nature of hESC/iPS MSCs I’ll defer to Dr. Lanza to answer your
questions on the topics when you Interview him soon… Looking forward to that, as I believe he’ll fill in some of the missing data for you…
Safety is an issue in both Adult and Pluripotent cells that have been manipulated… As you know even Adult can suffer from lapses in Safety aka Pluristem… knock on wood ACTC will continue there 100% clinical trial safety record with their work…
Appreciate your Blog and what it represents – I come from the world of media and know it is hard work…
Cheers
Hi Paul – I recall you recently posted here in your blog that ACTC would within 5 years be a household name.
Having publicly said that, how can you then ignore the scientific progress that ACTC is making in their EYE, BLOOD and IMMUNE programs by doubting the pre-clinical data that backs up all these programs?? You even went so far as to recently doubt
the sight improvement of a legally blind trial patient who went from 20/400 to 20/40 as a result of ACTC’s RPE cells…
Investorstemcell.com provides factual real-time analysis of the news – it reports from the venues where the scientists are speaking, immediately and in their own words. We do not make things up for the sake of media attention.
I have personally interviewed the Management of ACTC and can assure you that they are real people not made up characters from a fantasy entertainment…
The word “jumping” mice was used not “dancing” and it’s quite clear from our correspondence with the University of Conn. that the MS model work was a success. How significant a data point we still need to determine from a report on the matter.
Dr. Lanza and Senior Mgt. of ACTC have confirmed large animal models have been underway using MSCs for some time and the overall data picture will be released on the program when it is compiled, submitted and approved by peer review.
If you read the Patent Doc. certain detailed mouse model study paragraphs were present which specifically addressed the success of the cell work, as are references to the large animals studies.
On the Patent itself this is an hESC and iPS Pluripotent Patent Technology and not from your common Adult sources such as the ones you describe. That is the BIG difference – Pluripotent cell derivation creates more powerful and plentiful MSCs for therapeutics. The fact that these are derived from Hemangioblasts is secondary but important as ACTC has a Granted Patent on deriving Hemangioblasts, so it’s a stacked Patent Family strategy which will be v.hard to compete with irrespective of whether ACTC is ultimately Granted the Patent for the MSC Patent App itself or not… It’s called a “Blocking Patent App” that fundamentally secures the field given the source material for the MSC derivation are Patented Technology already…
In April of this year the US changed it’s Patent Laws to move more towards a First to File system which the rest of the World uses. The important of this is in that we must first establish Patent protection before Publishing as it’s otherwise possible for International companies to copy the Published work and File a Patent on your scientific work thereby claiming first priority… This is an important fact that you need to appreciate before casting doubt on why the mouse model study hasn’t been Published… This is of course apart from the obvious of not wanting to expose the
science unnecessarily early into such a competitive sector and waiting for the Large Animal work to be completed.
I trust you have a better picture on this now.
Cheers
Thanks, msemporda, for the helpful background and perspectives! I have a lot to learn on some stuff and I try to keep an open mind. I do think that ACTC will be a household name in coming years.
As I mentioned earlier in the comments on this thread, I probably made some missteps in this post, but I think some level of caution is appropriate and pragmatic. Raising expectations so high that no one can meet them is a recipe for disappointment down the road, but at the same time we need energy and excitement and hope. The key is balance between these things.
I would also say that from talking with many of the key thought leaders in the field that MSCs made from pluripotent stem cells are not thought to be uniformly better than amplified endogenous MSCs. So we may disagree on that. One key challenge with MSCs made from pluripotent stem cells is culture heterogeneity. Another is safety. Clearly, as you said, MSCs made from pluripotent stem cell sources may also have important advantages too. Again, it’s important to take a balanced view of things. Every cellular product is a “package deal” of potential strengths and weaknesses.
This is Patti, the “apparent” transcriber of your quote in your article. For the record, I did personally transcribe Dr. Lanza’s presentation at Brigham Women’s Hospital presentation in May, as well as record and transcribe parts of Dr. Lanza’s presentation at Georgia Tech Regen Med conference in Hilton Head in March this year. You can find all of this information in public domain (Youtube), and investorstemcell.com.
I found your article above poorly researched and disrepectful of Dr. Lanza. I appreciate science types “want to see the data”, but how can you not think the data will support Dr. Lanza’s public statements is beyond me.
It is public knowledge the mice treated with adult stem cells from bone marrow had very modest improvement in paralyzed limbs compared to the eSC-derived treated mice. But I guess you will have to wait for the data since you will not give Dr. Lanza any credibility while speaking to rooms full of medical professionals and science researchers in cell biology at prestigious university settings.
I don’t quite understand your “wet blanket” approach and negativity in this article.
Patti (the apparent transcriber)
Hi Patti,
Thanks for the comment.
I apologize for the clunky way I handled this.
No offense was intended generally or by the “apparent” adjective. I just felt I didn’t know the facts of this directly. I should have dug deeper before posting. As I said in response to Steve’s comment earlier, part of what surprised me is that Dr. Lanza would make such a bold forward looking statement regarding MS. I meant no offense to him either.
Yes, I am a “science type”. Admittedly, we tend to be a little obsessed with data.
The bit of wet blanket-ishness may stem from more than a dozen years in the stem cell field seeing excitement lead to disappointment down the road. I’m not saying that’s going to happen here necessarily, but it happens more generally all the time. I think the field benefits from enthusiasm, energy, and excitement, but at the same time one has to carefully manage expectations so as not to make them so high that it is difficult to meet them in the future.
Paul
Thank you for your reply Paul. I had the distinct honor to meet and chat with Dr. Lanza in Hilton Head last March for 30 minutes, this after sitting through his 45 minute presentation and Q&A. Full disclosure, I am also an investor in ACTC. Because I transcribe every public meeting and conference call available publicly, and read and re-read them, I am very familiar with ACTC’s research and trials. The strongest impression I got from my Hilton experience and one-on-one time with Dr. Lanza was his excitement about the eSC-derived and iPS-derived MSC research and the “paper in process” that we are all dying to see published with a video of the treated mice. I have no science background, just a ton of personal research and due diligence, which includes getting the opportunity to chat with Dr. Lanza in person. I hope you get to do that some day and get to experience his enthusiasm about this research.
I appreciate your caution of building hopes up too high, but I cannot deny that the hopes of the followers of ACTC are very, very high with the safety and progress of the RPE trials. The 20/400 to 20/40 vision improvement of one of our patients was a shocking slip by Dr. Lanza that the company was not ready to announce. We were excited BEFORE this news slipped out.
I just wanted to share the perspective I am coming from having followed this company so closely for 17 months.
I want to thank you for having a stem cell blog and for all you do to educate the public. Thank you for your past (and future) support of ACTC. I think you are onto something, that ACTC will be a household name in five years time.
All is forgiven….I can be pretty “clunky” in my communication at times as well.
All the best,
Patti
As as scientist, I would think that of all people you would be the most impressed with this discovery. A new source for a msc? It seems a little odd that you are surprised that Dr Lanza or any other pioneer might try to improve upon the science.
Hi Steve,
Thanks for the comment. I may not have made myself clear on what I meant. I’m not surprised that Dr. Lanza or any other pioneer is trying to improve on the science. I love that and that’s why I’m in science myself. What is surprising to me is to see such a bold forward looking statement made by a company leader in public. Also I was commenting on how crowded and competitive the MSC field is with hundreds if not thousands of existing already awarded patents. That doesn’t mean people shouldn’t try to improve things. They should, but there is a fine line between energy and excitement vs overexuberance. That’s all. I like ACT by the way and support what they are doing.
Paul,
You missed the fact that ACTC has a huge production advantage over adult cell from donation–on the order of 30000 to one. Also ACTC cells retain their vibrancy far longer than adult cells that lose efficacy after 2-3 passages. No comparison in technology.
Ron Allen MD
Paul,
You missed the point that ACTC’s cells have a massive advantage in availability compared to adult mesenchymal cells from donation–on the order of 30,000 times more from ACTC. In addition ACTC cells do not lose vibrancy after a few passages as do adult cells.There is no comparison between ACTC cells and current adult cell technology.
Ron Allen MD
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