√ Japan Conditionally Approves New Ips Cell-Based Heart Study

Where do things stand with IPS cell translational research?

The newest development is that regulators in Japan just have given conditional approval to an Osaka University team to an induced pluripotent stem (IPS) cell-based study for ischemic heart disease.

Screenshot of Yoshiki Sawa slide on IPS cell approach for heart failure, which is similar to approach for ischemic heart disease.

For years IPS cell-based products have been on-again off-again in active clinical study for macular degeneration, work led by Dr. Masayo Takahashi. The new heart disease study is led by Yoshiki Sawa. This appears to be the third conditionally approved IPS cell study in Japan. I’m not clear on whether both other studies included in the total of 3 here are from Dr. Takahashi or not.

Here is information on the study design:

“The approved plan will cover patients with ischemic cardiomyopathy, or hearts weakened by narrowed or blocked arteries preventing blood from reaching parts of the heart muscle. Three people aged between 18 and 79 will have two round cell sheets made from the iPS cells of other people attached to the surface of their hearts. The sheets will each be 0.05 millimeters thick and several centimeters in diameter. Researchers will examine the safety of the procedure, checking for cancer, immunorejection and other such signs, and will also observe changes in the function of the patients’ hearts.”

It has a number of key differences with the previous conditionally approved studies beyond the organ of focus. Perhaps the most striking aspect of the new study is that it will use far more cells:

“This is the third case of clinical research involving transplants using iPS cells to be approved. In the previous two cases, groups including the Riken research institute are transplanting several hundred thousand cells in the treatment of intractable diseases. The number of cells in the latest research is far greater — at around 100 million. As there is a risk of iPS cells turning cancerous, it will be crucial for researchers to guarantee the safety of the process.”

Ideally, we don’t want any undifferentiated IPS cells in the transplanted product, but that’s a tall task with 100 million cells. Past studies have suggested that not all IPS cells have tumorigenic potential including in a transplantation context so a few amounts 100 million overall may not cause problems. This will have to be carefully monitored as stressed in the  Mainichi piece. From a second Mainichi article we have a quote on this issue from Dr. Sawa:

“Even if a tumor does develop, because the cells come from another person, it is expected that it will disappear after the suppressants are withdrawn and the person’s natural immune system kicks in.”

I hope he’s right about that.

This is exciting investigational work, but high-risk in my view. It will be interesting to follow.

You can learn more from a slide set from Dr. Sawa’s research here (and see image above from one such slide).

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√ Launch Of Jun Takahashi Ips Cell Trial For Parkinson’S Disease

A much-anticipated induced pluripotent stem (IPS) cell trial for Parkinson’s Disease reportedly will soon launch led by Professor Jun Takahashi.

The news broke on Yahoo Japan, which included an unusual number of appropriately sober statements regarding the trial, even though it is an exciting trial as well, compared to most media stories on stem cells.

Parkinson’s Disease is a result of a loss of dopaminergic neurons in the brain so it is a particularly attractive sasaran disease for stem cells, which can be readily used to produce dopamine neurons for transplant.

Here are some key details in the article on the Jun Takahashi IPS cell-based trial. It is anticipated that there will be some insurance coverage for this trial for patients. The sasaran patients generally will be those who do not have the most severe disease. This is an interesting choice as it potentially allows for patients earlier in the course of the disease to get the cells, but could have somewhat higher risks. Generally, early phase trials often treat the sickest patients to minimize risks.

Graphic from Yahoo Japan article

Here’s an example of the more sober aspect of the article, as translated by Chrome so forgive mistakes:

“Side effects must also be carefully judged. The nerve made from iPS cells is transplanted to a place different from the nigra that originally had dopamine nerve. Dopamine may overdone and cause side effects such as involuntary movements. Even though we confirmed the safety by monkey experiments, attention is required.

Even if this treatment method using iPS cells is established, it is not to become “dream medicine” that can return to a completely healthy state. While possessing the possibility of opening a new way of treatment, it is necessary to examine the significance properly together with other treatments.”

Overall, I think there’s real hope for stem cells for Parkinson’s Disease given the work on a number of fronts by a variety of international researchers conducting rigorous research.

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√ Some Stem Cell Good News, Stuff For Debate, Cool Pubs

Sometimes we could all use a jolt of good news and cool science.

Those of us in the stem cell field probably get tired at times of all the bad-ish, even if important news (like this from Michael Hiltzik of the LA Times) out there surrounding certain unproven stem cell offerings and also clinics that engage in all kinds of stuff ranging from off-beat shenanigans to really dark stuff.

Today’s post is focused mostly on the good news and exciting science. You can see past posts on good news in our stem cell arena here.

Evidence of in vivo reprogramming in skin. “…tissues were generated by converting one cell type (red: mesenchymal cells) to another (green: basal keratinocytes) within a large ulcer in a laboratory mouse model.” Quote from Salk Institute caption. Image from Salk Institute.

Below I’ve listed some upbeat headlines and also links to some intriguing research papers, but I couldn’t resist putting in a few more links to things that are not necessarily good news yet are interesting or spark conversations or debates.

Headlines

Kyoto Univ. team eyes clinical test of platelets derived from iPS cells

To Heal Wounds, Cells Time-Travel Back to a Fetal State

Stem cells show promise as drug delivery tool for childhood brain cancer

Officials Hope Indiana Will Become Leader In Regenerative Medicine

The latest worker benefit: Freezing stem cells in case they’re useful. Is it worth banking your cells?

Adult Cardiac Stem Cells Don’t Exist: Study Do 4dukt hearts have stem cells?

Pubs

In vivo reprogramming of wound-resident cells generates skin epithelial tissue. For more on in vivo reprogramming see here. Also check out the cool image of in vivo regeneration sourced from the Salk, where this work was conducted.

Chromatin remodeling factor BRG1 regulates stemness and chemosensitivity of glioma initiating cells

Hoxc-Dependent Mesenchymal Niche Heterogeneity Drives Regional Hair Follicle Regeneration

Is there 4dukt neurogenesis? The debate continues here in Cell Stem Cell piece. My perspectives piece on this from this spring.

Special Series: Transplantation of Stem Cells into the Eye

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√ Japan’S Dangerous Gamble Approving Unproven Stem Cells For Spinal Cord Injury

MRI of cervical spinal cord injury. Open source image by Андрей Королев.

There is real hope for treating spinal cord injury with stem cell-based therapies in the future. However, unfortunately regulators in Japan have taken a major misstep in approving a not-ready-for-primetime mesenchymal stem cell (MSC)-based approach to spinal cord injury. Their decision is dangerous and unwise.

In a Nature piece (linked to above) by David Cyranoski we learn that the MSC therapy in question is still unproven. There are only limited data available to support it, which are not from rigorous studies. The claimed outcomes so far using this therapy are also puzzling and controversial. Thus, the approval is extremely high risk. I believe it is likely to do more harm than good to patients and the stem cell field.

Regulators gush

Some Japanese regulators are more than upbeat on this approach:

“This is an unprecedented revolution of science and medicine, which will open a new kurun of healthcare,” says oncologist Masanori Fukushima, head of the Translational Research Informatics Center, a Japanese government organization in Kobe that has been giving advice and support to the project for more than a decade.”

A phrase like “unprecedented revolution” is often a red flag for hype.

Many scientists are very concerned, while inventor is upbeat

Ten independent experts that Nature contacted were concerned about the approval:

“But independent researchers warn that the approval is premature. Ten specialists in stem-cell science or spinal-cord injuries, who were approached for comment by Nature and were not involved in the work or its commercialization, say that evidence that the treatment works is insufficient. Many of them say that the approval for the therapy, which is injected intravenously, was based on a small, poorly designed clinical trial.”

This doesn’t sound good. The approval seems like a recipe for trouble and sets a bad precedent. Of course, the inventors of this product now called Stemirac are very positive:

“One of the inventors of the treatment, neurosurgeon Osamu Honmou of Sapporo Medical University in Japan, says he is preparing to publish a scientific paper that will discuss the clinical-trial and safety issues. “I think it is very safe.” He says he did not do a double-blinded study because Japan’s regulations do not require it. “The most important point is that the efficacy is dramatic and definitive,” says Fukushima.

The unpublished results describe a trial of 13 people, who had experienced spinal-cord injuries in the past 40 days. The team found that infusions of stem cells extracted from the patients’ bone marrow helped them to regain some lost sensation and movement.”

You can see Dr. Honmou’s PubMed record here with many papers on MSCs including in rat models of CNS injury.

Concerns about the science and logic here

To me it doesn’t make a lot of sense that an IV infusion of MSCs would significantly aid spinal cord injury. For one thing these cells tend to accumulate in the lungs. They also mostly don’t survive more than a few days. How would this help an injury as severe as major spinal cord damage? There is also some claim that the MSCs turn into brain cells such as neurons, which is highly controversial.

I wonder if they ruled out cell fusion? In work by my lab in collaboration with my UC Davis colleague Veronica Martinez-Cerdeno where we transplanted undifferentiated hESC and hIPSC into mouse brain, we found a surprisingly high degree of fusion of the stem cells with resident brain cells including neurons.

Unfortunately, it seems likely that placebo effect played some major role in the study results related to this approval. Once patients start paying for it (which kicks in soon), the placebo effect is likely to be further amplified.

It also isn’t right for patients to have to pay for an unproven therapy.

Update: I asked Doug Sipp, who is an expert on the Japanese regeneration medicine framework, and he highlighted three areas of concern:

“Three of the things that should be raising eyebrows are 1) why no controls, randomization, blinding for study that just involves IV infusion in a non-fatal condition; 2) why such a small study size for a condition that is not particularly rare; 3) why was the study not published prior to conditional approval? “

Big potential negative consequences

Sadly, this controversial approval by regulators in Japan may end up having another negative consequence. It’s likely to be a big help to unproven stem cell clinics. Some of these for-profit clinics sell various kind of MSCs for spinal cord injury, autism, or other conditions that don’t make sense at this time.

More broadly, the relatively permissive regenerative medicine regulatory system in Japan has been controversial. I discussed it and also the RMAT system in the US in my recent piece in Cell Stem Cell, “Too Much Carrot and Not Enough Stick in New Stem Cell Oversight Trends.”

This new approval is by far the most controversial to date and is a step backward for regenerative medicine science.

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