Interview with Bob Lanza on new ACT stem cells for MS paper

Robert-LanzaI did a brief email Q&A interview with Dr. Bob Lanza of Advanced Cell Technology (ACT) on their new hES-MSC 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.

Advanced Cell Technology (ACT) Revs Up Pre-Clinical Studies for MS

There is more good news from leading stem cell biotech Advanced Cell Technology (ACT) on preclinical rodent studies using stem cells to treat mice with an MS-like condition.

They published a new paper in the journal Stem Cell Reports entitled “Human ESC-Derived MSCs Outperform Bone Marrow MSCs in the Treatment of an EAE Model of Multiple Sclerosis” by Wang, et al. Note added: there’s a related interesting paper from Jeanne Loring and Tom Lane’s groups in the same issue using neural progenitors made from hES cells.

Mesenchymal stem cells (MSCs) derived from human embryonic stem (hES) cells, termed hES-MSCs by the authors) were able to substantially reduce symptoms of a Multiple Sclerosis (MS)-like disease in mice.

While the control mice were severely disabled by the MS modeling condition including paralysis, those treated with the hES-MSCs were significantly healthier. In some cases this difference was dramatic as shown in the video above (Courtesy of Dr. Xiaofang Wang and Dr. Ren-he Xu, ImStem Biotechnology, Inc.) where we see a hES-MSC-treated MS model mouse running around and a control severely ill.

Interestingly, the transplantation of the hES-MSCs appeared to greatly aid the MS model mice even though all the injected cells died, suggesting an indirect mechanism through secretion of trophic factors. This notion was further supported by the fact that non-lethally irradiated (and hence non-mitotic) hESC-MSCs were still therapeutically beneficial.

HES-MSCs

They also demonstrate fairly convincingly that the hES-MSCs were better at aiding the mice than MSCs derived from bone marrow (BM-MSCs). This difference was traceable to the unique ability of hES-MSCs to readily extravasate (crawl through blood vessels) into the central nervous system (see Figure 6C above). The inability of BM-MSCs to do much therapeutic benefit may be linked to their secretion of high levels of IL-6.

This paper is exciting and important. As with pretty much all papers in the biomedical field, there are some limitations here as well and room for future studies to further clarify things. For example, there is a growing realization that for a number of conditions, especially those involving the inflammatory and immune-related illnesses such as MS, the unique physiology of mice may yield results not entirely translatable to humans. Further, more specifically the MS model here, called experimental autoimmune encephalitis (EAE), has some limitations as a model of MS in humans. Still, this work represents a significant advance and provides hope for future treatments of MS based on stem cells.

Top 5 challenges for SCNT cloned human embryonic stem cells

It was intriguing last week to read about another advance in somatic cell nuclear transfer (SCNT)-based therapeutic cloning of human embryonic stem cells (hESC). The first such work was published last year by Mitalipov’s group from OHSU.

Knoepfler Diagram Human Cloning

This second paper to produce so-called nuclear transfer hESC (NT-hESC) made the important advance to show that it could be done using adult and even old human somatic cells. This is a reproducible technology, which is very important.

However, key challenges and concerns remain for human therapeutic cloning and for potential clinical application of NT-hESC. Below is my list of the top 5 challenges.

  • NT-hESC must be indisputably better than human iPS cells and IVF hESCs to be relevant clinically: NT-hESC face very high hurdles. They must be demonstrably better in some key way than induced pluripotent stem (iPS) cells or traditional hESC made from IVF blastocysts or there’s no point in making them. If NT-hESC are only about the same as these other human pluripotent stem cells in terms of most key attributes then given the difficulty of making NT-hESC (even factoring in some anticipated improvements in technology) there would be little reason to make NT-hESC from a clinical perspective. Thus, their production would be limited to intellectual inquiries. While NT-hESC have the potential benefit of being used for autologous therapy (as opposed to IVF hESC being limited to allogeneic use), the other issues uniquely facing NT-hESC including some mentioned below make this trait of NT-hESC probably not enough alone to carry them forward.
  • The head start of other human pluripotent stem cells. Human iPS cells were first reported in 2007 and thus have a 7-year head start on NT-hESC.  The first clinical trial using cells derived from human iPS cells began enrolling patients in Japan in August 2013. Traditional hESC made from left over IVF blastocysts have been around much longer and their clinical trials started even earlier (ACT’s trials for MD). So in a sense NT-hESC could are starting far behind from a translational medicine perspective. On the other hand, one might say that the regulatory and scientific hurdles cleared by both hESC-based products and human iPS cell products might pave the way for NT-hESC and speed their translation to the clinic. Perhaps, but perhaps not. It’ll be fascinating to watch how this develops.
  • Human egg procurement challenges. The efficiency of making NT-hESC is very low. The legal and regulatory challenges of human oocyte procurement means NT-hESC production must either boost efficiency or find a new source material. For example in the latest paper only 2 lines were made from 77 oocytes. Some have said this is no big deal since the efficiency of making iPS cells is also inefficient. However, there’s a critical difference. When making iPS cells we start with proliferative somatic cells and can essentially use as many as we want (e.g. tens of millions), while in contrast when making NT-hESC each line must be derived using a separate human egg. Therefore, the efficiency of making NT-hESC must either be boosted at least say 5-10-fold or a substitute for human eggs must be found. In regard to the latter possibility, Mitalipov’s group has shown that at least in mice, two celled embryo cells can mediate successful SCNT.
  • The dual use dilemma for human cloning. One of the headaches for the advocates of NT-hESC is that potentially each advance in making NT-hESC (therapeutic cloning) could unintentionally also make it easier for some crazy folks to try to actually clone a person (reproductive cloning or “Star Wars” type cloning). Think that reproductive human cloning is impossible? Unfortunately, that challenge is not going to stop people from trying. Further, even failed attempts at human reproductive cloning (and it’s very likely the first attempts at human repro cloning would be horrible failures potentially producing deformed or dead humans) could unfairly, but rather quickly sink therapeutic cloning. I personally do not believe that there is any insurmountable technical obstacle to human reproductive cloning as it has worked for many mammals in the past and animal cloning is more common now than ever.
  • Cloning confusion and public opinion. Cloning is a confusing topic for the public. It is not always so easy for people to differentiate between therapeutic and reproductive cloning. Many folks may already think that “cloning” is bad as they conflate all types of cloning together. It is sort of like when people use the umbrella term “stem cells” to refer to all types of stem cells together. Unfortunately some of the people thinking in these overly simplistic ways are powerful political leaders. This remains a practical challenge for NT-hESC. Above is a picture from my book, Stem Cells: An Insider’s Guide explaining the differences between reproductive and therapeutic human cloning.

Adult human therapeutic cloning of embryonic stem cells by SCNT

An international team of stem cell scientists has replicated human therapeutic cloning to make embryonic stem cells via somatic cell nuclear transfer (SCNT).

The team was led by Drs. Dong Ryul Lee of CHA Stem Cell Institute in Korea and Robert Lanza of Advanced Cell Technology (ACT) and reported the advance in the Chung, et al. paper today in the journal Cell Stem Cell entitled “Human Somatic Cell Nuclear Transfer Using Adult Cells”. The cells expressed pluripotency markers (see Figure 1A at left) and had normal karyotypes.

Human SCNT

The research has replicated the human therapeutic cloning work reported last year by Mitalipov’s group and has advanced the field’s knowledge further in some ways.

One major important element of the new paper is the successful use of adult and elderly somatic cell nuclear donors (ages 35 and 75). Therefore, this new work indicates that SCNT may become a viable option for production of ES cells from in principle almost any person. Further, the new paper suggests that a slightly longer period of incubation prior to activation following SCNT may yield better results.

Some questions and challenges remain, which is not surprising for such a new technology. For example, why is it still relatively speaking so difficult to make SCNT work to make NT-ESCs in humans compared to other animals? An additional hurdle is that efficiency remains a challenge. In the current paper, 2 lines were made from a total of 77 human oocytes.

Again, it is early days for human SCNT and we can be almost certain that further refinements to the technology will boost efficiency.

For perspective, production of iPS cells is also an inefficient process, but the key difference here is that to make human iPS cells one can easily start with an almost unlimited numbers (easily in the 10s of millions) of say skin cells. In contrast, the low efficiency of human SCNT is much more of a challenge because every attempt involves a unique, difficult to obtain human oocyte. In specific countries and states in the US, oocyte procurement faces complicated regulatory and legal hurdles. In this regard, it is worth noting that Mitalipov’s group has just recently reported in Nature successfully conducted mouse SCNT to make ES cell lines using 2-cell embryo cells generated from fertilized eggs rather than naive oocytes. If this works in the human context, egg procurement may become less of a challenging issue.

As with the Mitalipov group paper, this team also did not mention the broader context whereby human SCNT technology could be misused by rogue scientists to pursue human reproductive cloning. As with many powerful technological advances, dual use ethical issues can arise and that is certainly the case here with therapeutic human cloning.

Some interesting questions that remain open include why this SCNT process is relatively inefficient in humans versus other species and also why certain human donors produce eggs that have the “right stuff” for successful SCNT.

Overall, I think this paper is an exciting, important, and technically convincing. SCNT ES cells may give us another potential tool to help patients via stem cells. Mouse studies hint that SCNT ES cells may have some advantages over iPS cells, but the jury is still out on that.

 

Big Changes Unfolding at Advanced Cell Technology (ACTC)

rp_advanced-cell-technology.jpgStem cell biotech, Advanced Cell Technology (ACT; stock symbol ACTC), has started off 2014 with indications that it is in a phase of rapid evolution.

Some changes, such as today’s announced departure of now former CEO Gary Rabin (see my 2013 interview with him here), are already in the public domain, but other big developments are likely based on private conversations.

ACT’s CFO and executive VP, Edward Myles, will serve as interim president during a search to replace Rabin, according to WBJournal.

Miles is quoted as follows:

“I look forward to working closely with our board of directors, executive team, and all of our employees and partners to achieve our corporate objectives,” said Mr. Myles. “Our core programs, the ongoing Phase I clinical trials for dry-Age Related Macular Degeneration (AMD) and Stargardt’s Macular Degeneration (SMD), continue to progress according to plan and we expect to release interim, top line data from the trials in the very near future.”

More data coming out is a good thing.

Update (hat tip to commenter Brad): A probable reason for Rabin’s exit seems to be related to an SEC investigation of possible improper transaction disclosures.

It is also notable that it was announced about a month ago that the company had settled a civil SEC action from stock issues from years ago with a payment of more than $4 million. It’s good to put that in the past.

In addition, rumors are now flying that this year ACT may receive the coveted “breakthrough status” for a product (its hESC-derived RPE product for macular degeneration) from the FDA.

The stock is up 4% today.

Recently I have been contacted by folks who think that quite a lot of other important developments are at play for the company at the moment as well. Stay tuned. I think 2014 will overall be a good year for the company.

Disclosure: this blog is not intended as financial or medical advice. All financial decisions such as stock-related choices should be made with a qualified financial planner, not based on a blog.