Eyeing Stem Cell Therapies for Vision Loss

Back by popular demand (well, at least a handful of you demanded it!) we’re pleased to present the third installment of our Stem Cells in Your Face video series. Episodes one and two set out to explain – in a light-hearted, engaging and clear way – the latest progress in CIRM-funded stem cell research related to Lou Gehrig’s disease (Amyotrophic Lateral Sclerosis, or ALS) and sickle cell disease.

With episode three, Eyeing Stem Cell Therapies for Vision Loss, we turn our focus (pun intended) to two CIRM-funded clinical trials that are testing stem cell-based therapies for two diseases that cause severe visual impairment, retinitis pigmentosa (RP) and age-related macular degeneration (AMD).

Two Clinical Trials in Five Minutes
Explaining both the RP and AMD trials in a five-minute video was challenging. But we had an ace up our sleeve in the form of descriptive eye anatomy animations graciously produced and donated by Ben Paylor and his award-winning team at InfoShots. Inserting these motion graphics in with our scientist and patient interviews, along with the fabulous on-camera narration by my colleague Kevin McCormack, helped us cover a lot of ground in a short time. For more details about CIRM’s vision loss clinical trial portfolio, visit this blog tomorrow for an essay by my colleague Don Gibbons.

Vision Loss: A Well-Suited Target for Stem Cell Therapies
Of the wide range of unmet medical needs that CIRM is tackling, the development of stem cell-based treatments for vision loss is one of the furthest along. There are a few good reasons for that.

The eye is considered to be immune privileged, meaning the immune system is less accessible to this organ. As a result, there is less concern about immune rejection when transplanting stem cell-based therapies that did not originally come from the patient’s own cells.

The many established, non-invasive tools that can peer directly into the eye also make it an attractive target for stem cell–based treatment. Being able to continuously monitor the structure and function of the eye post-treatment will be critical for confirming the safety and effectiveness of these pioneering therapies.

Rest assured that we’ll be following these trials carefully. We eagerly await the opportunity to write future blogs and videos about encouraging results that could help the estimated seven million people in the U.S. suffering from disabling vision loss.

Related Links:

Stem Cellar archive: retinitis pigmentosa
Stem Cellar archive: macular degeneration
Video: Spotlight on Retinitis Pigmentosa
Video: Progress and Promise in Macular Degeneration
CIRM Fact Sheet on Vision Loss

Have your cake and eat it too: Stem cells without the risk of tumors


An unregulated stem cell treatment in 2001 led to tumor growth in the (A) brain stem and (B) spinal cord of the patient four years later. (Fig 1. PLoS Med. 2009 Feb 17;6(2):e1000029)

A real stem cell tourism story
Back in 2001, an Israeli boy suffering from Ataxia Telangiectasia, a genetic brain disease that affects movement, traveled to Russia for an unregulated stem cell treatment. His brain and spinal cord were injected with fetal stem cells though the exact composition of those cells was not known. Four years later, the boy complained of headaches and his doctors back home found tumors in his brain and spinal cord.

 Stem cells: a double-edged sword
As the BBC  and many other news outlets reported in 2009, a Plos Medicine report eventually confirmed the tumor cells originated from the donor stem cells. And here lies a double-edged sword of stem cell-based therapies. On one side, stem cells hold great promise to repair diseased or damaged tissue because they can morph, or differentiate, into a wide range of cell types.

 But on the other side, they have the capacity to remain unspecialized and continually self-renew.This is great for producing enough cells to treat many people. Researchers try to make sure only more mature cells are transplanted, but if any of these propagating, undifferentiated cells get carried along with a stem cell-based treatment, there’s a risk of introducing uncontrolled cell growth and cancers instead of remedies. Human pluripotent stem cells (hPSCs), which can form almost any cell type found in our body, are believed to be especially susceptible to this dangerous potential side effect.

Reporting this week in the journal, eLife, CIRM-funded researchers at UCSD found a way to dodge the risk of tumor growth by identifying a unique, alternate stem cell type that could be applied to kidney disease. To find this cell type, the research team focused on cells that were a bit further along a differentiation path compared to unspecialized hPSCs.

Repeat after me: endoderm, ectoderm, mesoderm

In the earliest stages of embryo development, three germ layers form. (image: Internet Science Room)

In the earliest stages of embryo development, three germ layers form. (image: Internet Science Room)

To explain, let’s take a brief detour into developmental biology. In the very early stages of specialization, the cells of the embryo form the three germ layers: ectoderm, endoderm and mesoderm. Each layer gives rise to specific set of cells and tissues. Endoderm forms, to just name a few, the lungs, intestines and pancreas; ectoderm develops into skin, the brain and spinal cord; mesoderm forms blood, muscle, bone and kidneys. Within each germ layer lie progenitor stem cells, that maintain the capacity to self-renew and can also differentiate into the adult cells formed by that germ layer.

Finding a mesoderm progenitor
While methods for growing ectoderm and endoderm progenitor stem cells from hPSCs had been previously developed, few, if any, labs had done the same for mesoderm. So the UCSD team systematically tested thousands of combinations of nutrients and chemicals for both growing and differentiating hPSCs into mesoderm. Using this approach, they successfully tracked down a recipe that gave rise to mesoderm progenitor cells with the potential to multiply and grow in population yet lacking the ability to form tumors when transplanted into mice.

Color tagged surface proteins indicate a kidney fate for activated mesodermal progenitors (Fig 7c Kumar et al. eLife 2015;4:e08413)

Color tagged surface proteins indicate a kidney fate for activated mesodermal progenitors (Fig 7c Kumar et al. eLife 2015;4:e08413)

The research team planned to work out the various conditions to specialize the progenitor cells into a wide range of mesoderm tissues. But to their surprise, when triggered to differentiate, the progenitors only gave rise to cells of the kidney. This very limited specialization is actually desired for clinical applications since purity of cell therapies is a requirement for testing in humans.

Our kidneys thank you
Putting it all together, the team has identified a cell source with unlimited self renewal capacity that can differentiate into a very specific cell type and doesn’t carry a risk of tumor formation when transplanted. These qualities make the mesoderm progenitor cell an exciting tool for developing future kidney repair or replacement treatments. And as Dr. Karl Willert, senior author and associate professor at UC San Diego, states in a UCSD press release, there is also reason to be excited about near-term applications:

“Our cells can serve as building blocks to generate kidneys that may one day be suitable for cell replacement and transplantation. I think such a therapeutic application is still a few years in the future, but engineered kidney tissue can serve as a powerful model system to study how the human kidney interacts with and filters drugs. Such an application would be of tremendous value to the pharmaceutical industry.”

New Video: Spinal Cord Injury and a CIRM-Funded Stem Cell-Based Trial

Just 31 years old, Richard Lajara thought he was going to die.


Richard Lajara, the 4th participant in Geron’s stem cell-based clinical trial for spinal cord injury.

On September 9, 2011 he slipped on some rocks at a popular swimming hole and was swept down a waterfall headfirst into a shallow, rocky pool of water. Though he survived, the fall left him paralyzed from the waist down due to a severed spinal cord.

Patient Number Four
At that same time period, Geron Inc. had launched a clinical trial CIRM helped fund testing the safety of a stem cell-based therapy for spinal cord injury (SCI). It was the world’s first trial using cells derived from human embryonic stem cells and Lajara was an eligible candidate. Speaking to CIRM’s governing Board this past summer for a Spotlight on Disease seminar, he recalled his decision to participate:

“When I participated with the Geron study, I was honored to be a part of it. It was groundbreaking and the decision was pretty easy. I understood that it was very early on and I wasn’t looking for any improvement but laying the foundation [for future trials].”

A few months after his treatment, Geron discontinued the trial for business reasons. Lajara was devastated and felt let down. But this year the therapy got back on track with the announcement in June by Asterias Biotherapeutics that they had treated their first spinal cord injury patient after having purchased the stem cell assets of Geron.

Getting Hope Back on Track
Dr. Jane Lebkowski, Asterias’ President of R&D and Chief Scientific Officer, also spoke at the Spotlight on Disease seminar to provide an overview and update on the company’s clinical trial. A video recording of Lebkowski’s and Lajara’s presentations is now available on our web site and posted here:

As Dr. Lebkowski explains in the video, Asterias didn’t have to start from scratch. The Geron study data showed the therapy was well tolerated and didn’t cause any severe safety issues. In that trial, five people (including Richard Lajara) with injuries in their back received an injection of two million stem cell-derived oligodendrocyte progenitor cells into the site of spinal cord damage. The two million-cell dose was not expected to show any effect but was focused on ensuring the therapy was safe.

Oligodendrocyte Precursors: Spinal Cord Healers
As the former Chief Scientific Officer at Geron, Lebkowski spoke first hand about why the oligodendrocyte precursor was the cell of choice for the clinical trial. Previous animal studies showed that oligodendrocyte progenitors, a cell type normally found in the spinal cord, have several properties that make them ideal cells for treating SCI: first, they help stimulate the growth of damaged neurons, the cell type responsible for transmitting electrical signals from the brain to the limbs.

Second, the oligodendrocytes produce myelin, a protein that acts as an insulator of neurons, very much like the plastic covering on a wire. In many spinal cord injuries, the nerves are still intact but lose their myelin insulation and their ability to send signals. Third, the oligodendrocytes release other proteins that help reduce the size of cysts that often form at the injury site and damage neurons. In preclinical experiments, these properties of oligodendrocyte progenitors improved limb movement in spinal cord-severed rodents.

Together, the preclinical animal studies and the safety data from the Geron clinical trial helped Asterias win approval from the Food and Drug Administration (FDA) to start their current trial, also funded by CIRM, this time treating patients with neck injuries instead of back injuries.

The Asterias trial is a dose escalation study with the first group of three patients again receiving two million cells. The trial was designed such that if this dose shows a good safety profile in the neck, as it did in the Geron trial in the back, then the next cohort of five patients will receive 10 million cells. In fact, Asterias reported in August that the lower dose was not only safe but also showed some encouraging results in one of the patients. And just two days ago Asterias announced their data monitoring committee recommended to begin enrolling patients for the 10 million cell dose.  If all continues to go well with safety, the dose will be escalated to 20 million cells in the third cohort of five patients. While two million cells was a very low safety dose, Asterias anticipates seeing some benefit from the 10 and 20 million cell doses.

Changing Lives by Increasing Independence
Does Lebkowski’s team expect the patients to stand up out of their wheelchairs post-treatment? No, but they do hope to see a level of improvement that could dramatically increase quality of life and decrease the level of care needed. Specifically, they are looking to see a so-called “two motor level improvement.” In her talk Lebkowski explained this quantitative measure with the chart below:

“If a patient is a C4 [meaning their abilities are consistent with someone with a spinal cord injury at the fourth cervical, or neck, bone] they will need anywhere from 18 to 24 hours of attendant care for daily living. If we could improve their motor activity such that they become a C6, that is just two motor levels, what you can see is independence tremendously increases and we go from 18 to 24 hour attendant care to having attendant care for about four hours of housework.”

Slide13 cropped

Small improvements in movement abilities can be life changing for people with spinal cord injuries.

It’s so exciting the field is at a point in time that scientists like Dr. Lebkowski are discussing real stem cell-based clinical trials that are underway in real patients who could achieve real improvements in their lives that otherwise would not be possible.

And we have people like Richard Lajara to thank. I think Dr. Oswald Stewart, the Board’s spinal cord injury patient advocate, summed it up well when speaking to Lajara at the meeting:

“Science and discovery and translation [into therapies] doesn’t happen without people like you who are willing to put yourselves on the line to move things forward. Thank you for being in that first round of people testing this new therapy.”

Don Reed Reflects on the California Stem Cell Initiative

StemCellBattlesCoverYesterday was stem cell awareness day. In honor of this important event, Don Reed held a book reading at CIRM for his newly released book, STEM CELL BATTLES: Proposition 71 and Beyond: How Ordinary People Can Fight Back Against the Crushing Burden of Chronic Disease.

Don has worn many hats during his life. He’s been a power lifter, a diver at Sea World, and is one of California’s most tenacious stem cell research advocates. His stem cell journey began when his son, Roman Reed, was seriously injured in a football accident, leaving him mostly paralyzed from the neck down.

Both Don and Roman didn’t let this tragic event ruin their lives or steal their hope. In fact, both Don and his son were instrumental for getting proposition 71 to pass, leading to the birth of CIRM and new hope for patients with uncured diseases.

At yesterday’s book reading, Don chronicled the early battles to get human stem cell research off the ground in California, the progress that’s been made so far and the promise for future therapies. It was truly an inspiring event, bringing together patients, friends of Don and his wife Gloria, and CIRM scientists to celebrate the stem cell research accomplishments of the past ten years.


Enjoy more pictures of the event below and a short video of Jonathan Thomas, Chair of the Governing Board of CIRM, who said a few words in praise of Don Reed’s efforts to fight for stem cell research in California.


Don Reed and his wife Gloria share a smile with CIRM’s Pat Olson.


Jonathan Thomas and Don Reed.

Related links:

Seeing is believing: using video to explain stem cell science

People are visual creatures. So it’s no surprise that many of us learn best through visual means. In fact a study by the Social Science Research Network found that 65 percent of us are visual learners.

That’s why videos are such useful tools in teaching and learning, and that’s why when we came across a new video series called “Reaping the rewards of stem cell research” we were pretty excited. And to be honest there’s an element of self-interest here. The series focuses on letting people know all about the research funded by CIRM.

We didn’t make the videos, a group called Youreka Science is behind them. Nor did we pay for them. That was done by a group called Americans for Cures (the group is headed by Bob Klein who was the driving force behind Proposition 71, the voter-approved initiative that created the stem cell agency). Nonetheless we are happy to help spread the word about them.

The videos are wonderfully simple, involving just an engaging voice, a smart script and some creative artwork on a white board. In this first video they focus on our work in helping fund stem cell therapies for type 1 diabetes.

What is so impressive about the video is its ability to take complex ideas and make them easily understandable. On their website Youreka Science says they have a number of hopes for the videos they produce:

“How empowering would it be for patients to better understand the underlying biology of their disease and learn how new treatments work to fight their illness?

How enlightening would it be for citizens to be part of the discovery process and see their tax dollars at work from the beginning?

How rewarding would it be for scientists to see their research understood and appreciated by the very people that support their work?”

What I love about Youreka Science is that it began almost by chance. A PhD student at the University of California San Francisco was teaching some 5th graders about science and thought it would be really cool to have a way of bringing the textbook to life. So she did. And now we all get to benefit from this delightful approach.

Funding a clinical trial for deadly cancer is a no brainer

The beast of cancers
For a disease that is supposedly quite rare, glioblastoma seems to be awfully common. I have lost two friends to the deadly brain cancer in the last few years. Talking to colleagues and friends here at CIRM, it’s hard to find anyone who doesn’t know someone who has died of it.


Imagery of glioblastoma, a deadly brain cancer,  from ImmunoCellular’s website

So when we got an application to fund a Phase 3 clinical trial to target the cancer stem cells that help fuel glioblastoma, it was really a no brainer to say yes. Of course it helped that the scientific reviewers – our Grants Working Group or GWG – who looked at the application voted unanimously to approve it. For them, it was great science for an important cause.

Today our Board agreed with the GWG and voted to award $19.9 million to LA-based ImmunoCellular Therapeutics to carry out a clinical trial that targets glioblastoma cancer stem cells. They’re hoping to begin the trial very soon, recruiting around 400 newly diagnosed patients at some 120 clinical sites around the US, Canada and Europe.

There’s a real urgency to this work. More than 50 percent of those diagnosed with glioblastoma die within 15 months, and more than 90 percent within three years. There are no cures and no effective long-term treatments.

As our President and CEO, Dr. Randy Mills, said in a news release:

 “This kind of deadly disease is precisely why we created CIRM 2.0, our new approval process to accelerate the development of therapies for patients with unmet medical needs. People battling glioblastoma cannot afford to wait years for us to agree to fund a treatment when their survival can often be measured in just months. We wanted a process that was more responsive to the needs of patients, and that could help companies like ImmunoCellular get their potentially life-saving therapies into clinical trials as quickly as possible.”

The science
The proposed treatment involves some rather cool science. Glioblastoma stem cells can evade standard treatments like chemotherapy and cause the recurrence and growth of the tumors. The ImmunoCellular therapy addresses this issue and targets six cell surface proteins that are found on glioblastoma cancer stem cells.

The researchers take immune cells from the patient’s own immune system and expose them to fragments of these cancer stem cell surface proteins in the lab. By re-engineering the immune cells in this way they are then able to recognize the cancer stem cells.

My colleague Todd Dubnicoff likened it to letting a bloodhound sniff a piece of clothing from a burglar so it’s able to recognize the scent and hunt the burglar down.  When the newly trained immune system cells are returned to the patient’s body, they can now help “sniff out” and hopefully kill the cancer stem cells responsible for the tumor’s recurrence and growth.

Like a bloodhound picking up the scent of a burglar, ImmunoCellular's therapy helps the immune system track down brain cancer stem cells (source: wikimedia commons)

Like a bloodhound picking up the scent of a burglar, ImmunoCellular’s therapy helps the immune system track down brain cancer stem cells (source: Wikimedia Commons)

Results from both ImmunoCellular’s Phase 1 and 2 trials using this approach were encouraging, showing that patients given the therapy lived longer than those who got standard treatment and experienced only minimal side effects.

Turning the corner against glioblastoma
There’s a moment immediately after the Board votes “yes” to fund a project like this. It’s almost like a buzz, where you feel that you have just witnessed something momentous, a moment where you may have turned the corner against a deadly disease.

We have a saying at the stem cell agency: “Come to work every day as if lives depend on it, because lives depend on it.” On days like this, you feel that we’ve done something that could ultimately help save some of those lives.

Stem cell stories that caught our eye: new CRISPR fix for sickle cell disease, saving saliva stem cells, jumping genes in iPSCs and lung stem cells.

An end run around sickle cell disease with CRISPR
The CRISPR-based gene editing technique has got to be the hottest topic in biomedical research right now. And I sense we’re only at the tip of the iceberg with more applications of the technology popping up almost every week. Just two days ago, researchers at the Dana Farber Cancer Institute in Boston reported in Nature that they had identified a novel approach to correcting sickle cell disease (SCD) with CRISPR.

A mutation in the globlin gene leads to sickled red blood cells that clog up blood vessels

A mutation in the globlin gene leads to sickled red blood cells that clog up blood vessels (image: CIRM video)

Sickle cell anemia is a devastating blood disorder caused by a single, inherited DNA mutation in the adult form of the hemoglobin gene (which is responsible for making blood). A CIRM-funded team at UCLA is getting ready to start testing a therapy in clinical trials that uses a similar but different gene editing tool to correct this mutation. Rather than directly fixing the SCD mutation as the UCLA team is doing, the Dana Farber team focused on a protein called BCL11A. Acting like a molecular switch during development, BCL11A shifts hemoglobin production from a fetal to an adult form. The important point here is that the fetal form of hemoglobin can substitute for the adult form and is unaffected by the SCD mutation.

So using CRISPR gene editing, they deleted a section of DNA from a patient’s blood stem cells that reduced BCL11A and increased production of the fetal hemoglobin. This result suggests the technique can, to pardon the football expression, do an end run around the disease.

But if there’s already a recipe for directly fixing the SCD mutation, why bother with this alternate CRISPR DNA deletion method? In a press release Daniel Bauer, one of the project leaders, explains the rationale:

“It turns out that blood stem cells, the ultimate targets for this kind of therapy, are much more resistant to genetic repair than to genetic disruption.”

Whatever the case, we’re big believers in the need to have several shots on goal to help ensure a victory for patients.

Clinical trial asks: does sparing salivary stem cells protect against severe dry mouth?
I bet you rarely think about or appreciate your saliva. But many head and neck cancer patients who undergo radiation therapy develop severe dry mouth caused by damage to their salivary glands. It doesn’t sound like a big deal, but in reality, the effects of dry mouth are life-changing. A frequent need to drink water disrupts sleep and leads to chronic fatigue. And because saliva is crucial for preventing tooth decay, these patients often lose their teeth. Eating and speaking are also very difficult without saliva, which cause sufferers to retreat from society.

Help may now be on the way. On Wednesday, researchers from University of Groningen in the Netherlands reported in Science Translational Medicine the identification of stem cells in a specific region within the large salivary glands found near each ear. In animal experiments, the team showed that specifically irradiating the area where the salivary stem cells lie shuts down saliva production. And in humans, the amount of radiation to this area is linked to the severity of dry mouth symptoms.

Doctors have confirmed that focusing the radiation therapy beams can minimize exposure to the stem cell-rich regions in the salivary glands. And the research team has begun a double-blind clinical trial to see if this modified radiation treatment helps reduce the number of dry mouth sufferers. They’re looking to complete the trial in two to three years.

Keeping a Lid on Jumping Genes
Believe it or not, you have jumping genes in your cells. The scientific name for them is retrotransposons. They are segments of DNA that can literally change their location within your chromosomes.

While retrotransposons have some important benefits such as creating genetic diversity, the insertion or deletion of DNA sequences can be bad news for a cell. Such events can cause genetic mutations and chromosome instability, which can lead to an increased risk of cancer growth or cell death.

To make its jump, the DNA sequence of a retrotransposon is copied with the help of an intermediary RNA (the green object in the picture below). A special enzyme converts the RNA back into DNA and this new copy of the retrotransposon then gets inserted at a new spot in the cell’s chromosomes.

Retrotransposons: curious pieces of DNA that can be transcribed into RNA, copied into DNA, and inserted to a new spot in your chromosomes.

The duplication and insertion of transposons into our chromosomes can be bad news for a cell

Most of our cells keep this gene jumping activity in check by adding inhibitory chemical tags to the retrotransposon DNA sequence. Still, researchers have observed that in unspecialized cells, like induced pluripotent stem (iPS) cells, these inhibitory chemical tags are reduced significantly.

So you’d think that iPS cells would be prone to the negative consequences of retrotransposon reactivation and unleashed jumping genes. But in a CIRM-funded paper published on Monday in Nature Structural and Molecular Biology, UC Irvine researchers show that despite the absence of those inhibitory chemical tags, the retrotransposon activity is reduced due to the presence of microRNA (miRNA), in this case miRNA-128. This molecule binds and blocks the retrotransposon’s RNA intermediary so no duplicate jumping gene is made.

The team’s hope is that by using miRNA-128 to curb the frequency of gene jumping, they can reduce the potential for mutations and tumor growth in iPS cells, a key safety step for future iPS-based clinical trials.

Great hope for lung stem cells
Chronic lung disease is the third leading cause of death in the U.S. but sadly doctors don’t have many treatment options except for a full lung transplant, which is a very risky procedure with very limited sources of donated organs. For these reasons, there is great interest in better understanding the location and function of lung stem cells. Harnessing the regenerative abilities of these cells may lead to more alternatives for people with end stage lung disease.

In a BioMedicine Development commentary that’s geared for our scientist readers, UCSF researchers summarize the evidence for stem cell population in the lung. We’re proud to say that one of the lead authors, Matt Donne, is a former CIRM Scholar.

Related links

The Ogawa-Yamanaka Prize Crowns Its First Stem Cell Champion

A world of dark

Imagine if you woke up one day and couldn’t see. Your life would change drastically, and you would have to painfully relearn how to function in a world that heavily relies on sight.

A retina of a patient with macular degeneration. (Photo credit: Paul Parker/SPL)

A retina of a patient with macular degeneration. (Photo credit: Paul Parker/SPL)

While most people don’t lose their sight overnight, many suffer from visual impairments that slowly happen over time. Glaucoma, cataracts, and macular degeneration are examples of debilitating eye diseases that eventually lead to blindness.

With almost 300 million people world wide with some form of visual impairment, there’s urgency in the scientific community to develop safe therapies for clinical applications. One of the most promising strategies is using human induced pluripotent stem (iPS) cells derived from patients to generate cell types suitable for transplantation into the human eye.

However, this task is more easily said than done. Safety, regulatory, and economical concerns make the process of translating iPS cell therapies from the bench into the clinic an enormous challenge worthy only of a true scientific champion.

A world of light

Dr. Masayo Takahashi

Dr. Masayo Takahashi

Meet Dr. Masayo Takahashi. She is a faculty member at the RIKEN Centre for Developmental Biology, a prominent female scientist in Japan, and a bona fide stem cell champion. Her mission is to cure diseases of blindness using iPS cell technology.

Since the Nobel Prize-winning discovery of iPS cells by Dr. Shinya Yamanaka eight years ago, Dr. Takahashi has made fast work using this technology to generate specific cells from human iPS cells that can be transplanted into patients to treat an eye disease called macular degeneration. This disease results in the degeneration of the retina, an area in the back of the eye that receives light and translates the information to your brain to produce sight.

Dr. Takahashi generates cells called retinal pigment epithelial (RPE) cells from human iPS cells that can replace lost or dying retinal cells when transplanted into patients with macular degeneration. What makes this therapy so exciting is that Dr. Takahashi’s iPS-derived RPE cells appear to be relatively safe and don’t cause an immune system reaction or cause tumors when transplanted into humans.

Because of the safety of her technology, and the unfulfilled needs of millions of patients with eye diseases, Dr. Takahashi made it her goal to take iPS cells into humans within five years of Dr. Yamanaka’s discovery.

Ogawa-Yamanaka Stem Cell Prize

It’s no surprise that Dr. Takahashi succeeded in her ambitious goal. Her cutting edge work has led to the first clinical trial using iPS cells in humans, specifically treating patients with macular degeneration. In September 2014, the first patient, a 70-year-old Japanese woman, received a transplant of her own iPS-derived RPE cells and no complications were reported.

Currently, the trial is on hold “as part of a safety validation step and in consideration of anticipated regulatory changes to iPS cell research in Japan” according to a Gladstone Institute news release. Nevertheless, this first iPS cell trial in humans has overcome significant regulatory hurdles, has set an important precedent for establishing the safety of stem cell therapies, and has given scientists hope that iPS cell therapies can become a reality.

Dr. Deepak Srivastava presents Dr. Takahashi with the Ogawa-Yamanaka Prize.

Dr. Deepak Srivastava presents Dr. Takahashi with the Ogawa-Yamanaka Prize.

For her accomplishments, Dr. Takahashi was recently awarded the first ever Ogawa-Yamanaka Stem Cell Prize and honored at a special event held at the Gladstone Institutes in San Francisco yesterday. This prize was established by a generous gift from Mr. Hiro Ogawa in collaboration with Dr. Shinya Yamanaka and Dr. Deepak Srivastava at the Gladstone Institutes. The award recognizes scientists who conduct translational iPS cell research that will eventually be applied to patients in the clinic.

In an interview with CIRM, Dr. Deepak Srivastava, the Director of the Gladstone Institute of Cardiovascular Disease and the Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, described the prestigious prize and the ceremony held at the Gladstone to honor Dr. Takahashi:

Dr. Deepak Srivastava

The Ogawa-Yamanaka prize prize is meant to incentivize and honor those whose work is advancing the translational use of stem cells for regenerative medicine. Dr. Masayo Takahashi is a pioneer in pushing the technology of iPS cell-derived cell types and actually introducing them into people. She’s the very first person in the world to successfully overcome all the regulatory barriers and the scientific barriers to introduce this new type of stem cell into a patient. And she’s done so for a condition of blindness called macular degeneration, which affects millions of people world wide, and for which there are very few treatments currently. We are honoring her with this prize for her pioneering efforts at making this technology one that can be applied to patients.

The new world that iPS cells will bring

As part of the ceremony, Dr. Takahashi gave a scientific talk on the new world that iPS cells will bring for patients with diseases that lack cures, including those with visual impairments. The Stem Cellar team was lucky enough to interview Dr. Takahashi as well as attend her lecture during the Gladstone ceremony. We will cover both her talk and her interview with CIRM in an upcoming blog.

The Stem Cellar team at CIRM was excited to attend this momentous occasion, and to know that CIRM-funding has supported many researchers in the field of iPS cell therapy and regenerative medicine. We would like to congratulate Dr. Takahashi on her impressive and impactful accomplishments in this area and look forward to seeing progress in iPS cell trial for macular degeneration.


Related Links:

CIRM-funded team traces molecular basis for differences between human and chimp face

So similar yet so different
Whenever I go to the zoo, I could easily spend my entire visit hanging out with our not-so-distant relatives, the chimpanzees. To say we humans are similar to them is quite an understatement. Sharing 96% of our DNA, chimps are more closely related to us than they are to gorillas. And when you just compare our genes – that is, the segments of DNA that contain instructions for making proteins – we’re even more indistinguishable.

Chimps and Humans: So similar yet so different

Chimps and Humans: So similar yet so different

And yet you wouldn’t mistake a human for a chimp. I mean, I do have hairy arms, but they’re not that hairy. So what accounts for our very different appearance if our genes are so similar?

To seek out answers, a CIRM-funded team at Stanford University used both human and chimp induced pluripotent stem cells (iPSCs) to derive cranial neural crest cells (CNCCs). This cell type plays a key role in shaping the overall structure of the face during the early stages of embryo development. In a report published late last week in Cell, the team found differences, not in the genes themselves, but in gene activity between the human and chimp CNCCs.

Enhancers: Volume controls for your genes
Pinpointing the differences in gene activity relied on a comparative analysis of so-called enhancer regions of human and chimp DNA. Unlike genes, the enhancer regions of DNA do not provide instructions for making proteins. Instead they dictate how much protein to make by acting like volume control knobs for specific genes. A particular volume level, or gene activity, is determined by specific combinations of chemical tags and DNA-binding proteins on an enhancer region of DNA.

Enhancers: DNA segments that act like a volume control know for gene activity (Image source: xxxx)

Enhancers: DNA segments that act like a volume control knobs for gene activity (Image source: FANTOM Project, University of Copenhagen)

The researchers used several sophisticated lab techniques to capture a snapshot of this enhancer tagging and binding in the CNCCSs. They mostly saw similarities between human and chimp enhancers but, as senior author Joanna Wysocka explains in a Stanford University press release, they did uncover some differences:

“In particular, we found about 1,000 enhancer regions that are what we termed species-biased, meaning they are more active in one species or the other. Interestingly, many of the genes with species-biased enhancers and expression have been previously shown to be important in craniofacial development.”

PAX Humana: A genetic basis for our smaller jawline and snout?
For example, their analysis revealed that the genes PAX3 and PAX7 are associated with chimp-biased enhancer regions, and they had higher levels of activity in chimp CNCCs. These results get really intriguing once you learn a bit more about the PAX genes: other studies in mice have shown that mutations interfering with PAX function lead to mice with smaller, lower jawbones and snouts. So the lower level of PAX3/PAX7 gene activity in humans would appear to correlate with our smaller jaws and snout (mouth and nose) compared to chimps. Did that just blow your mind? How about this:

The researchers also found a variation in the enhancer region for the gene BMP4. But in this case, BMP4 was highly related to human-biased enhancer regions and had higher activity in humans compared to chimps. Previous mouse studies have shown that forcing higher levels of BMP4 specifically in CNCCs leads to shorter lower and upper jawbones, rounder skulls, and eyes positioned more to the front of the face. These changes caused by BMP4 sound an awful lot like the differences in human and chimp facial structures. It appears the Stanford group has established a terrific strategy for tracing the genetic basis for differences in humans and chimps.

So what’s next? According to Wysocka, the team is digging deeper into their data:

“We are now following up on some of these more interesting species-biased enhancers to better understand how they impact morphological differences. It’s becoming clear that these cellular pathways can be used in many ways to affect facial shape.”

And in the bigger picture, the researchers also suggest that this “cellular anthropology” approach could also be applied to a human to human search for DNA enhancer regions that play a role in the variation between healthy and disease states.

CIRM CAP Kickoff to New Clinical Trials

Alisha Bouge is the project manager for CIRM’s Clinical Advisory Panels (CAPs)

On the cusp of the official kickoff to football season, CIRM has had its own kickoff to celebrate.  The first Clinical Advisory Panel (CAP) meeting took place on August 18, 2015 in Irvine, CA with Caladrius Bioscience, Inc.  And just as every NFL team starts the season hopeful of a Super Bowl win, all our CAPs start out with equally lofty goals. That’s because under CIRM 2.0, the role of the CAP is to work with the clinical stage project teams we fund to help accelerate the development of therapies for patients with unmet medical needs and to give these projects the greatest likelihood of success.

In the case of Caladrius, the work is focused on treating metastatic melanoma, an aggressive and deadly form of skin cancer. You can read more about this clinical trial here.

Obstacles and challenges are inevitable in the lifecycle of research. CIRM hopes to help its grantees navigate through these hurdles as quickly and positively as possible by providing recommendations from expert advisors in the field.  The intention is for the CAP meeting process to be that navigating vessel throughout the lifetime of each clinical stage project.

The CAPs will include at least three members: one CIRM science officer, a patient representative, and an external scientific advisor.  The CAP will meet with the project team approximately four times a year, with the first meeting taking place in-person.  Consider the CAP as the grantee’s special team, doing all they can to get that two-point conversion at the end of an already successful outcome, giving the grantee and their team just a few more points in their pocket to reach the ultimate success.


CIRM CAP on a tour of Caladrius’ facility in Irvine, CA.  The CIRM CAP can be seen in the far right of the photo (left to right) Randy Lomax (Patient Representative), Ingrid Caras (CIRM Sr. Science Officer), and Hassan Movahhed (External Scientific Advisor).

As the lead Science Officer on this first CAP, CIRM’s Ingrid Caras stated: “This is our opportunity to be good stewards of the taxpayers’ money.”

The mission and the message of the CAP was well received by Caladrius.  After the CAP meeting, Anna Crivici, VP of Operations & Program Management at Caladrius, had this to say about her experience:

anna crivici

Anna Crivici, Caladrius

I thought that the meeting was very productive.  Everyone on the Caladrius team appreciates the collaborative approach CIRM is taking on the program, as amply demonstrated during our successful first meeting.  The discussion on every agenda topic was helpful and insightful.  The opportunity to better understand the patient perspective will be especially beneficial and increasingly important as the Phase 3 program progresses.  We are confident that this and future CAP meetings will help us advance and refine our strategic planning and execution.


CIRM CAP and members of Caladrius discussing operational strategies for success.

CIRM is looking forward to the 2015/2016 CAP season. And while there is no Super Bowl incentive at the end of our season, there is the hope that CIRM’s efforts, both financially and collaboratively, will contribute to successful treatments for so many out there in need. That’s something well worth cheering for.