I did a brief email Q&A interview with Dr. Bob Lanza of Advanced Cell Technology (ACT) on their new hES MSCs pre-clinical data for Multiple Sclerosis. I discussed the paper itself in a concise review yesterday here.
Thanks to Dr. Lanza for doing the interview.
1. Were you surprised at the fact that the therapeutic benefit did not require engraftment or even the use of proliferative hES-MSCs?
No, not at all. MSCs usually persist for only a few days or weeks, and exert their therapeutic effects during that short time period
2. Any thought on the mechanism by which the hES-MSCs are beneficial? Trophic factors?
MSCs have myriad functions. They can, of course, modulate B and T cell function and impact the autoimmune process itself. But extravasation also seems to be very important, so release of trophic factors at the local site of inflammation and damage may also be a critical part of the mechanism by which they are beneficial.
3. Why inject intraperitoneally? Have you done any studies based on IV injection or direct transplantation into the CNS itself?
The cells have homing receptors and migrate to the site of injury regardless of the route of administration. Although we haven’t looked at it in this particular model, IV works quite well in the other autoimmune models we’ve examined. I suspect direct transplantation into the CNS itself would work equally well, if not better. However, that would obviously be a less desirable route for clinical application.
4. What are the steps between where these studies stand today and getting a therapy based on this product into clinical trials?
We need to complete IND enabling studies—i.e. dosage, safety, tumorigenicity, and biodistribution studies etc.
Thanks, Paul for the interview with Lanza and the article on hESC-MSC. These are good stuff as always.
You are fully right when you stated in your writing that EAE model has limitations as a model of MS in humans. I would go even further, EAE has nothing to do with MS. Most neurolgists specializing in MS are saying that there is no such general disease as MS. They say that there are at least 4 different types of illnesses that we call MS today.
Different proccesses are going on in these diseases and the most devastating part of long-term paralysis might have nothing to do with autoimmunity and systematic inflammation. A neurodegeneration must be going on with unknown origin even when the BBB is intact and no autoimmune cells trafficing accross it. It sometimes is parallel with an autoimmune process but sometimes it is there alone.
70% of the patients are already progressive MS patients (either SPMS and PPMS). This is the most devastating part of MS and here autoimmunity and inflammation do not play a major role. So, I am very sceptical if Lanza’s hESC-MSC has any benefits for these patients that is the majority of MS patients and those who are most in need.
great interview, paul!
special thanks for the comments, X.W.
I am wondering if the “careful i.v. injection” entail two or more smaller dosages after days or weeks?
…had no idea that large doses could cause embolism, yikes!
so it seems that IP would be a necessary administration for serious acute inflammation(e.g. sepsis)–in theory, would require a larger dose? Maybe chronic inflammation treated with careful and periodic i.v. injections, and perhaps subdural injections for CNS indications?
would also be curious how hESC-MSCs could benefit from mRNA transfection as BM-MSCs did in the inflamed tissue(O. Levy 2013)
looking forward to additional papers, keep them coming!
I agree with most answers of Dr. Lanza. For the 3rd question, a few more point: i.p. injection is usually good enough for small animal model since these cells have good migration abilities. i.v. injection of large amount of MSCs is harder because it will cause lung embolism. However, we did try some careful iv injections and the result seems better than i.p injections.
Dear Dr Wang,
first, let me congratulate for this great achievement. It is a great step towards the right direction.
I was just wondering if you had made any experiments with other animal models that mimic better the progressive MS or if anything can be inferred from these experiments for PPMS. As there is a huge unaddressed progressive MS patient population (much greater than RRMS), treating these patients would be both a great business opportunity and an excellent help for society.
I am not sure if these stem cells can enter the CNS of PPMS patients and halt the progression of their disease and induce some repair. As far as I know in progressive MS not only the white matter but the gray matter is also damaged. So, is there any indication that hES-MSCs might benefit PPMS patients as well?
Thanks,
Cukuru
As I know, the PPMS are not much related to inflammation and autoimmunity. And the efficacy of MSC in this type of MS is unknown. PPMS only account for 10% of all the MS patients. There are PPMS animal models available, we will explore the potential of hES-MSC in those models as well with our collaborators. However, I think specific neural cells may be better for that type of disease but not MSC.