√ 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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√ Japan Stem Cell Clinical Studies Rapidly Piling Up

Shibata, et al. Cell reports 2018, corneal structures made from hIPSCs

Japan is a leader in stem cell and regenerative medicine research, and in particular in clinical translation toward the bedside. Induced pluripotent stem cell (IPSC)-based investigational therapies are rightly an area of focus in Japan given their invention by Nobel Laureate Shinya Yamanaka. Small clinical studies based on IPSC have been initiated there for several diseases including related to vision loss and Parkinson’s Disease.

David Cyranoski over at Nature reports on a new, different stem cell clinical effort in Japan for vision loss with “Japan poised to allow ‘reprogrammed’ stem-cell therapy for damaged corneas.” Readers are probably much more familiar with the efforts of Masayo Takahashi‘s team working with IPSC-based retinal pigmented epithelial cell therapy being studied for macular degeneration. The Takahashi work is focused on the retina in the back of the eye, whereas the new work led by Kohji Nishida is studying stem cells for the cornea at the front of the eye (see some of their data at left from a 2018 Cell Reports study on making corneal sheet-like structures from human IPSCs). Note that in this figure the term ICEC means “hiPSC-derived corneal epithelial cells.”

I expect authorities to give the go-ahead for this new clinical study.

Another new article points to an additional area of novel work. See the piece Ministry OKs 1st iPS cell therapy trial for spinal cord injuries in The Asahi Shimbun. The team leaders are Hideyuki Okano and Masaya Nakamura. The study will begin with low doses (2 million cells) to assess safety.

Over at The Scientist, there’s also this opinion piece Ethical Challenges in Using iPS Cells to Treat Paralysis on the new trial raising questions as well. In the piece, Professors John Loike and Martin Grumet raise what I think are some legitimate concerns about the new IPSC-based spinal cord injury trial. They argue this hasn’t been enough transparency about this study and also they note that in preclinical work some cells exhibited abnormal proliferation.

This is the 2nd stem cell therapy study for spinal cord injuries recently in Japan. The other one, where an approach was actually approved for marketing to patients, spurred a lot of debate because there wasn’t much published data to support it and the premise based on infusion of MSCs seemed puzzling.

Overall, Japan is taking more regulatory gambles on innovative stem cell-based therapies. It’s a high-risk, high-reward approach. I’m very curious to see where things will stand there in five years. Here in the U.S. the newish Regenerative Medicine Advanced Therapy (RMAT) designation program is also trying to speed along stem cell clinical trial work, but doesn’t involve actually approving still-investigational products for marketing to patients.

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