Good stem cell news as Takahashi IPS Cell Trial to Resume

Masayo TakahashiSome good news today as the pioneering induced pluripotent stem (IPS) cell trial led by Dr. Masayo Takahashi will resume.

This clinical study with a focus on macular degeneration has been on hold for quite some time due to regulatory changes in Japan. There had also been concerns over mutations in the 2nd patient’s IPS cell product.

As previous signs had indicated, the new clinical work will have an allogeneic focus, most likely drawing IPS cells from a bank.

According to a Japan Times article:

For the second trial, the CDB will develop retinal tissues from iPS cells supplied by Kyoto University’s Center for iPS Cell Research and Application, headed by Nobel laureate Shinya Yamanaka, the creator of the pluripotent cells.

Transplants of CDB-developed retinal tissues will be conducted at Kobe City Medical Center General Hospital and Osaka University Hospital.

This is exciting and I’m very curious to see how this clinical work develops.

In 2014, Dr. Takahashi won my Stem Cell Person of the Year Award.

This may also signal a door opening for other IPS cell trials in Japan including one for Parkinson’s Disease by Jun Takahashi.

New Paper on IPS Cell Immunogenicity, Clinical Insights, & Possible Solutions

打印Can cells produced from autologous induced pluripotent stem cells (IPSC or IPS cells) sometimes be immunogenic in patients?

This key question has remained somewhat unsettled due to varied findings over the years (e.g. see here), but many of us had generally felt in the last couple years that immunogenicity in an autologous context wouldn’t be a major problem.

This is a big deal because if human IPSC (hIPSC) and in particular their derivatives are immunogenic (sparking a major immune response once transplanted that destroys them) even in an autologous setting that could necessitate the use of immunosuppression with their clinical use. In turn this would substantially reduce their potential advantage over human embryonic stem cells (hESC) for various clinical applications. Immunosuppressive therapy can be expensive and has its own potential side effects too for patients.

A new, very important Cell Stem Cell paper from a team led by Professor Yang Xu sheds significant new light on this key issue, but interestingly leaves the question answered so far at least as both “yes” and “no”. In short, autologous hIPSC derivative immunogenicity is present in some instances and not in others. The researchers used an innovative humanized mouse (Hu-mice) immunological model system. You can see a summary in image form from the paper above. They found that hIPSC derivative immunogenicity depends on the type of differentiated cell that is produced and the specific, associated antigens.

For instance, while hIPSC-derived retinal pigmented epithelial cells (RPE) were not significantly immunogenic in this system, smooth muscle cells (SMC) make from hIPSC did spark a substantial immune response. The rejection of the hIPSC-derived SMC was thought to be due to misexpression of immunogenic peptides that sparked a T cell response. The immunogenic factors are not normally expressed in SMC suggesting that tweaking hIPSC production protocols could be helpful here as the authors indicate:

“While SMCs differentiated from hiPSCs exhibit functionalities and global gene expression profiles highly similar to those of normal human counterparts, the finding that the immunogenic antigens expressed in hiPSC-derived SMCs are not expressed by normal human SMCs suggests that further improvement of the robustness of the differentiation process of hiPSCs could help to reduce the immunogenicity of hiPSC-derived cells.”

Therefore, how IPSC are made will impact their immunogenicity.

The data in this paper on RPE is encouraging, but the observations with SMC raise broader awareness that hIPSC derivatives cannot simply be assumed to be non-immunogenic in an autologous setting. What about liver, kidney or neural derivatives of hIPSC? Lung, heart?

It is also possible, since everybody’s immune system is different, that immunogenicity of any given hIPSC-derivative will vary depending on the patient.  If the immunogenicity of every patient’s hIPSC-derived cells ideally would be tested prior to transplantation, how would we do that? We’d need some kind of robust, high-throughput system like the teratoma and gene expression assays that are now used to screen human pluripotent stem cells for potency. Could the Hu-mice be used for this? The Hu-mice used here are indeed an elegant system, but how things play out in actual human patients with their own immune system could be different. Still they or some adaptation of that technology could prove very effective as an initial screening system.

Overall the findings of this new paper along with the recent news of the halt on the hIPSC trial for macular degeneration, together are signs of a more complicated road ahead to the beside for IPSC. They are not insurmountable hurdles, but rather indications of the IPSC field maturing to have a clearer understanding of the challenges facing it. This is a good thing, even if a bit bitter sweet, because it means we can find solutions and move forward.

Landmark IPSC clinical study on hold due to genomic issue

IPSC RPE sheetThe pioneering induced pluripotent stem cell (IPSC) clinical study in Japan led by top stem cell clinical researcher Dr. Masayo Takahashi has been stopped reports the WSJ in Japan. This development is confirmed by other sources and in a PDF report by RIKEN (in Japanese here).

One patient was transplanted in September 2014 with their own IPSC-derived retinal pigment epithelial cells (using an innovative RPE sheet, see image) for treatment of macular degeneration.

The study then moved on to a possible second patient, whose IPSC did not pass a genomic validation step. Reportedly, these IPSC contained a mutation, potentially in a known oncogene, which is a serious concern. Thus, the team decided to at least temporarily suspend the trial pending a possible redesign. The new plan could involve a change in how the IPSC are produced. For example, the team is reportedly considering the possible use of allogeneic IPSC as well, which could come from CiRA (Center for iPS cell Research and Application, Kyoto University).

It remains unclear at this time whether the mutation in the second patient’s IPSC was pre-existing in the patient’s skin cells or if it occurred during the reprogramming process itself. This is a critically important question to resolve. If the mutation was caused by/associated with reprograming then that would be a deeper issue.

Overall, this situation is of course a concern, but it also reflects the very rigorous and appropriate degree of caution that this team was using in validation studies. Notably, the first transplanted patient is apparently doing well.

I hope to learn more details from Dr. Takahashi and will pass that along on the blog when possible. She has also been tweeting about this development (you can follow her at @masayomasayo). Until we learn more it is advisable to take a cautious approach in interpreting this development.