Creating partnerships to help get stem cell therapies over the finish line

Lewis, Clark, Sacagawea

Lewis & Clark & Sacagawea:

Trying to go it alone is never easy. Imagine how far Lewis would have got without Clark, or the two of them without Sacagawea. Would Batman have succeeded without Robin; Mickey without Minnie Mouse? Having a partner whose skills and expertise complements yours just makes things easier.

That’s why some recent news about two CIRM-funded companies running clinical trials was so encouraging.

Viacyte Gore

First ViaCyte, which is developing an implantable device to help people with type 1 diabetes, announced a collaborative research agreement with W. L. Gore & Associates, a global materials science company. On every level it seems like a natural fit.

ViaCyte has developed a way of maturing embryonic stem cells into an early form of the cells that produce insulin. They then insert those cells into a permeable device that can be implanted under the skin. Inside the device, the cells mature into insulin-producing cells. While ViaCyte has experience developing the cells, Gore has experience in the research, development and manufacturing of implantable devices.

Gore-tex-fabricWhat they hope to do is develop a kind of high-tech version of what Gore already does with its Gore-Tex fabrics. Gore-Tex keeps the rain out but allows your skin to breathe. To treat diabetes they need a device that keeps the immune system out, so it won’t attack the cells inside, but allows those cells to secrete insulin into the body.

As Edward Gunzel, Technical Leader for Gore PharmBIO Products, said in a news release, each side brings experience and expertise that complements the other:

“We have a proven track record of developing and commercializing innovative new materials and products to address challenging implantable medical device applications and solving difficult problems for biologics manufacturers.  Gore and ViaCyte began exploring a collaboration in 2016 with early encouraging progress leading to this agreement, and it was clear to us that teaming up with ViaCyte provided a synergistic opportunity for both companies.  We look forward to working with ViaCyte to develop novel implantable delivery technologies for cell therapies.”

AMD2

How macular degeneration destroys central vision

Then last week Regenerative Patch Technologies (RPT), which is running a CIRM-funded clinical trial targeting age-related macular degeneration (AMD), announced an investment from Santen Pharmaceutical, a Japanese company specializing in ophthalmology research and treatment.

The investment will help with the development of RPT’s therapy for AMD, a condition that affects millions of people around the world. It’s caused by the deterioration of the macula, the central portion of the retina which is responsible for our ability to focus, read, drive a car and see objects like faces in fine details.

RPE

RPT is using embryonic stem cells to produce the support cells, or RPE cells, needed to replace those lost in AMD. Because these cells exist in a thin sheet in the back of the eye, the company is assembling these sheets in the lab by growing the RPE cells on synthetic scaffolds. These sheets are then surgically implanted into the eye.

In a news release, RPT’s co-founder Dennis Clegg says partnerships like this are essential for small companies like RPT:

“The ability to partner with a global leader in ophthalmology like Santen is very exciting. Such a strong partnership will greatly accelerate RPT’s ability to develop our product safely and effectively.”

These partnerships are not just good news for those involved, they are encouraging for the field as a whole. When big companies like Gore and Santen are willing to invest their own money in a project it suggests growing confidence in the likelihood that this work will be successful, and that it will be profitable.

As the current blockbuster movie ‘Beauty and the Beast’ is proving; with the right partner you can not only make magic, you can also make a lot of money. For potential investors those are both wonderfully attractive qualities. We’re hoping these two new partnerships will help RPT and ViaCyte advance their research. And that these are just the first of many more to come.

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Three people left blind by Florida clinic’s unproven stem cell therapy

Unproven treatment

Unproven stem cell treatments endanger patients: Photo courtesy Healthline

The report makes for chilling reading. Three women, all suffering from macular degeneration – the leading cause of vision loss in the US – went to a Florida clinic hoping that a stem cell therapy would save their eyesight. Instead, it caused all three to go blind.

The study, in the latest issue of the New England Journal of Medicine, is a warning to all patients about the dangers of getting unproven, unapproved stem cell therapies.

In this case, the clinic took fat and blood from the patient, put the samples through a centrifuge to concentrate the stem cells, mixed them together and then injected them into the back of the woman’s eyes. In each case they injected this mixture into both eyes.

Irreparable harm

Within days the women, who ranged in age from 72 to 88, began to experience severe side effects including bleeding in the eye, detached retinas, and vision loss. The women got expert treatment at specialist eye centers to try and undo the damage done by the clinic, but it was too late. They are now blind with little hope for regaining their eyesight.

In a news release Thomas Alibini, one of the lead authors of the study, says clinics like this prey on vulnerable people:

“There’s a lot of hope for stem cells, and these types of clinics appeal to patients desperate for care who hope that stem cells are going to be the answer, but in this case these women participated in a clinical enterprise that was off-the-charts dangerous.”

Warning signs

So what went wrong? The researchers say this clinic’s approach raised a number of “red flags”:

  • First there is almost no evidence that the fat/blood stem cell combination the clinic used could help repair the photoreceptor cells in the eye that are attacked in macular degeneration.
  • The clinic charged the women $5,000 for the procedure. Usually in FDA-approved trials the clinical trial sponsor will cover the cost of the therapy being tested.
  • Both eyes were injected at the same time. Most clinical trials would only treat one eye at a time and allow up to 30 days between patients to ensure the approach was safe.
  • Even though the treatment was listed on the clinicaltrials.gov website there is no evidence that this was part of a clinical trial, and certainly not one approved by the Food and Drug Administration (FDA) which regulates stem cell therapies.

As CIRM’s Abla Creasey told the San Francisco Chronicle’s Erin Allday, there is little evidence these fat stem cells are effective, or even safe, for eye conditions.

“There’s no doubt there are some stem cells in fat. As to whether they are the right cells to be put into the eye, that’s a different question. The misuse of stem cells in the wrong locations, using the wrong stem cells, is going to lead to bad outcomes.”

The study points out that not all projects listed on the Clinicaltrials.gov site are checked to make sure they are scientifically sound and have done the preclinical testing needed to reduce the likelihood they may endanger patients.

goldberg-jeffrey

Jeffrey Goldberg

Jeffrey Goldberg, a professor of Ophthalmology at Stanford and the co-author of the study, says this is a warning to all patients considering unproven stem cell therapies:

“There is a lot of very well-founded evidence for the positive potential of stem therapy for many human diseases, but there’s no excuse for not designing a trial properly and basing it on preclinical research.”

There are a number of resources available to people considering being part of a clinical trial including CIRM’s “So You Want to Participate in a Clinical Trial”  and the  website A Closer Look at Stem Cells , which is sponsored by the International Society for Stem Cell Research (ISSCR).

CIRM is currently funding two clinical trials aimed at helping people with vision loss. One is Dr. Mark Humayun’s research on macular degeneration – the same disease these women had – and the other is Dr. Henry Klassen’s research into retinitis pigmentosa. Both these projects have been approved by the FDA showing they have done all the testing required to try and ensure they are safe in people.

In the past this blog has been a vocal critic of the FDA and the lengthy and cumbersome approval process for stem cell clinical trials. We have, and still do, advocate for a more efficient process. But this study is a powerful reminder that we need safeguards to protect patients, that any therapy being tested in people needs to have undergone rigorous testing to reduce the likelihood it may endanger them.

These three women paid $5,000 for their treatment. But the final cost was far greater. We never want to see that happen to anyone ever again.

Three stories give us a glimpse of the real possibilities for stem cell therapies

Today we’re featuring a guest blog by Lisa Willemse about the Till and McCulloch Stem Cell Meeting in Canada. Enjoy!

Stem cell treatments should be incredibly easy. Or rather, that’s what some clinics or products would have you believe. Because, on the surface, a one-stop-shop for injectable cells to cure just about any condition or topical creams to peel away the scourge of time are very easy.

Attend one stem cell research conference and you’ll be convinced that it’s much more complicated. It’s a sea of reagents and transcription factors and unknown cause-and-effect. Many researchers will spend their entire career working on just one unknown and their caution and concern when it comes to the notion of a cure is justifiable.

Whistler (Courtesy of Lisa Willemse)

Whistler (Courtesy of Lisa Willemse)

Which makes it all the more impactful when you attend a research conference and hear three talks, back-to-back, that demonstrate that we’re ticking off some of those unknowns and getting much closer to real – not sham – therapies. Therapies with a sound scientific basis that are well planned and done with patient safety (not sales) in mind. Last week’s Till and McCulloch Meetings, held in Whistler, British Columbia gave us a sense of what is possible for three conditions: macular degeneration (vision), septic shock and a rare neurologic disease (Stiff Person Syndrome). Other blogs have covered  different aspects of this meeting here and here.

Vision Repair – Age-related Macular Degeneration (AMD)

As the world’s first clinical trial to use induced pluripotent stem cells launched amid sweeping regulatory changes in Japan, Dr. Masayo Takahashi’s treatment protocol for AMD has received no small amount of scrutiny. After a brief hiatus, the trial was back on track earlier this year and Takahashi’s presentation at this meeting was highly anticipated.

Dr. Masayo Takahashi

Dr. Masayo Takahashi

It did not disappoint. Takahashi spent the better part of her time outlining the steps taken to reach the point where the clinical trial was possible, including multiple studies in mice and further refinement of the treatment to ensure it would be stable in humans even with genetic changes over time. Given that one of the reasons the trial was put on hold was due to genetic mutations found in the cells prepared for the second potential human transplant, Takahashi’s careful work in ensuring the product was safe bodes well for the future of this trial.

The first patient was treated in 2014, a 78-year-old woman with wet AMD in the right eye, and although only minimal visual improvement was documented, the patient anonymously told the Japan Times, “I’m glad I received the treatment. I feel my eyesight has brightened and widened.”

Takahashi also alluded to some of the other challenges she’d had to overcome to make this trial a reality, including would-be critics who told her that the nervous system and the retina were too complicated to regenerate. Takahashi’s response? “You don’t know stem cells [and] you don’t understand the needs of the patient.”

While it was unclear when the next patient will receive treatment, Takahashi did say that three new applications for clinical trials using her refined protocols have been submitted for approval.

Septic shock  

Septic shock is not a condition that gets a lot of attention, most likely because it’s not a primary illness, but a secondary one; a drastic and often fatal immune response that severely reduces blood pressure and cell metabolism. It accounts for 20% of all intensive care unit (ICU) admissions and is the most common cause of non-coronary mortality in the ICU. For those who survive septic shock, there are significant and long-term health consequences.

Over 100 clinical trials have attempted to improve outcomes for patients with septic shock, but not one has been successfully translated into the clinical setting. Supportive care remains the mainstay of therapy.

Dr. Lauralyn McIntyre

Dr. Lauralyn McIntyre

This was the sober backdrop painted by critical care physician, Dr. Lauralyn McIntyre as she began her talk on the world’s first stem cell clinical trial for septic shock she is co-leading in Ottawa with Dr. Duncan Stewart.

Like Takahashi, McIntyre spent a good deal of time explaining the rationale and research that underpin the trial, which takes advantage of the immune-modulating properties of mesenchymal stromal cells (also called mesenchymal stem cells or MSCs) to suppress and reverse the effects of septic shock. This work includes reviews of more than 50 studies that looked at the effects of MSCs in both human trials and animal studies.

McIntyre also discussed research she did with mice in 2010 as a proof-of-concept, where the MSC therapy was delayed for six days. This delay is important as it better simulates the time frame in which most patients arrive in the hospital. As McIntryre pointed out, if the therapy only worked when given within hours of disease development, what good would it be for patients who come in on day six?

Fortunately, the therapy worked in the mice, even after a delayed timeframe, providing a green light for safety testing in humans. The small first human trial is currently underway for nine patients (with a control arm of 21) with results not yet published – although one of the patients shared his experience earlier this year. McIntyre relayed that the early data is very encouraging – enough that the team is moving ahead with a Phase 2 randomized trial in 10 centres across Canada in 2017.

Stiff Person Syndrome

Tina Ceroni’s story is much more personal. She is only the second person in the world to have received an experimental stem cell treatment for Stiff Person Syndrome, a rare neurologic condition that causes uncontrolled and sustained contractions of the arm, leg or other muscles. Often misdiagnosed initially as Multiple Sclerosis or anxiety/depression, SPS is also an autoimmune disease for which the cause is unknown.

Tina Ceroni

Tina Ceroni (The Ottawa Hospital)

I’ve written about Tina’s story before – about how she was hospitalized 47 times in one year and how a chance meeting with another SPS patient propelled Ceroni on a journey that included an intensive stem cell therapy under the guidance of Dr. Harry Atkins at the Ottawa Hospital, in which her blood stem cells were harvested from her bone marrow and used to repopulate her system after her immune system was wiped clean with chemotherapy.

Now a stem cell advocate, Ceroni’s story keeps getting better – not merely in how powerfully and passionately she tells it, but in the continued good health she enjoys after her treatment and in her efforts to share it more broadly.

Most importantly, she drives home a key message:

“My story underscores the importance of clinical trials…. My experience will help to change the future for others. I am living proof that a clinical trial for stem cell therapy can have a life-changing outcome.”

“Often hope is the only medicine we have.”

It’s important that patients like Ceroni continue share their story, not just with the research community to give a human face to the work they do, but to show that solid research is making an impact, one that can be measured in lives saved.


Lisa Willemse

Lisa Willemse

This article is published simultaneously, with permission by the author, Lisa Willemse, on the Ontario Institute for Regenerative Medicine (OIRM) Expression blog.

Seeing is believing: how some scientists – including two funded by CIRM – are working to help the blind see

retinitis pigmentosas_1

How retinitis pigmentosa destroys vision – new stem cell research may help reverse that

“A pale hue”. For most of us that is a simple description, an observation about color. For Kristin Macdonald it’s a glimpse of the future. In some ways it’s a miracle. Kristin lost her sight to retinitis pigmentosa (RP). For many years she was virtually blind. But now, thanks to a clinical trial funded by CIRM she is starting to see again.

Kristin’s story is one of several examples of restoring sight in an article entitled “Why There’s New Hope About Ending Blindness” in the latest issue of National Geographic.  The article explores different approaches to treating people who were either born without vision or lost their vision due to disease or injury.

Two of those stories feature research that CIRM has funded. One is the work that is helping Kristin. Retinitis pigmentosa is a relatively rare condition that destroys the photoreceptors at the back of the eye, the cells that actually allow us to sense light. The National Geographic piece highlights how a research team at the University of California, Irvine, led by Dr. Henry Klassen, has been working on a way to use stem cells to replace and repair the cells damaged by RP.

“Klassen has spent 30 years studying how to coax progenitor cells—former stem cells that have begun to move toward being specific cell types—into replacing or rehabilitating failed retinal cells. Having successfully used retinal progenitor cells to improve vision in mice, rats, cats, dogs, and pigs, he’s testing a similar treatment in people with advanced retinitis pigmentosa.”

We recently blogged about this work and the fact that this team just passed it’s first major milestone – – showing that in the first nine patients treated none experienced any serious side effects. A Phase 1 clinical trial like this is designed to test for safety, so it usually involves the use of relatively small numbers of cells. The fact that some of those treated, like Kristin, are showing signs of improvement in their vision is quite encouraging. We will be following this work very closely and reporting new results as soon as they are available.

The other CIRM-supported research featured in the article is led by what the writer calls “an eyeball dream team” featuring University of Southern California’s Dr. Mark Humayun, described as “a courteous, efficient, impeccably besuited man.” And it’s true, he is.

The team is developing a stem cell device to help treat age-related macular degeneration, the leading cause of vision loss in the US.

“He and his fellow principal investigator, University of California, Santa Barbara stem cell biologist Dennis Clegg, call it simply a patch. That patch’s chassis, made of the same stuff used to coat wiring for pacemakers and neural implants, is wafer thin, bottle shaped, and the size of a fat grain of rice. Onto this speck Clegg distributes 120,000 cells derived from embryonic stem cells.”

Humayun and Clegg have just started their clinical trial with this work so it is likely going to be some time before we have any results.

These are just two of the many different approaches, using several different methods, to address vision loss. The article is a fascinating read, giving you a sense of how science is transforming people’s lives. It’s also wonderfully written by David Dobbs, including observations like this:

“Neuroscientists love the eye because “it’s the only place you see the brain without drilling a hole,” as one put it to me.”

For a vision of the future, a future that could mean restoring vision to those who have lost it, it’s a terrific read.

 

From flies to mice: Improving stem cell therapy for degenerative eye diseases

Stem cell therapies for degenerative eye diseases sound promising – inject retinal progenitor cells derived from human pluripotent stem cells into the eye where they will integrate and replace damaged retinal tissue to hopefully restore sight. However, a significant road block is preventing these stem cell transplants from doing their job: the transplanted cells are unable to survive and generate healthy retinal tissue due to the unhealthy, degenerative environment they find themselves in.

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)

In patients with age-related macular degeneration or retinitis pigmentosa, retinal tissue in the eye is in a state of inflammation initiated by innate immune cells such as macrophage-derived microglia. When activated, microglia can either promote an inflammatory response or resolve inflammation and promote tissue repair and regeneration.

This balance between a pro-inflammation and tissue regeneration is something that scientists are looking to manipulate in order to develop new potential therapeutic strategies for degenerative eye diseases.

Chapter 1: Identifying MANF in flies

In a paper published today in the journal Science, Buck researchers report that they have identified a natural immune system modulator called MANF that improved the success of retinal repair in both fly and mouse models of eye diseases, and enhanced retinal cell transplantation in mouse models of photoreceptor degeneration.

The story of MANF starts with Drosophila fruit flies grown in the lab of Buck Professor Dr. Heinrich Jasper. His lab studies hemocytes, the fly equivalent of blood cells, and the repair factors that they secrete in response to injury. To model retinal damage, Jasper and his lab exposed photoreceptors in the retina of flies to UV light and then screened for secreted proteins that were released by hemocytes in response to UV damage.

They identified a protein called a secreted protein called MANF and hypothesized that this factor could promote tissue regeneration and act as a neuroprotective, “retinal repair factor”.

In a Buck Institute news release, Jasper explained how further experiments showed that MANF was secreted by hemocytes in response to UV induced damage in the retina, and that it shifted these immune cells from promoting inflammation to reducing inflammation and promoting retinal regeneration.

Chapter 2: MANF is neuroprotective in mice

Deepak Lamba and his lab

Deepak Lamba and his lab

Part two of the story involved determining whether MANF had similar neuroprotective and anti-inflammatory properties in mammalian models. Dr. Deepak Lamba, Buck Professor and co-senior author on the study, took the lead and first tested whether MANF could reduce light-induced damage of photoreceptors in mouse models of retinal degeneration.

Injecting MANF protein into the eyes of these mice significantly reduced cell death caused by light exposure. Similarly, injection of fibroblast cells that secreted MANF also had a neuroprotective effect in the damaged retina by recruiting innate immune cells to promote the body’s natural repair mechanisms.

Chapter 3: MANF improves cell transplantation in mice

The final chapter involved testing whether MANF could improve the outcome of transplanted photoreceptor cells in blind mice genetically engineered to have retinal damage. The addition of MANF improved the survival and integration of the transplanted cells in the retinas of the mice and also improved the animals’ visual function.

Lamba concluded in a Buck news release that, “MANF promotes healing and helps create a microenvironment conducive to successful transplantation.”

These preliminary results in flies and mice are encouraging and Jasper believes that the neuroprotective effects of MANF could potentially be applied to other diseases of aging at an early stage that could prevent disease progression.

Heinrich Jasper

Heinrich Jasper

“Our hope is that MANF will be useful for treatment of inflammatory conditions in many disease contexts,” Jasper explained. “Focusing on immune modulation to promote a healthy repair response to tissue damage rather than a deleterious inflammatory response is a new frontier in aging research.”

In the Race to Cure Blindness, Who Will Cross the Finish Line First Optogenetics or Stem Cells?

San Francisco Sunset. (Karen Ring)

San Francisco Sunset. (Karen Ring)

Before you read this blog, I wanted to share a photo that I took (yes with my iPhone 6…) last week of a beautiful sunset at Ocean Beach in San Francisco. I’m showing you this picture not to gloat that I live by the ocean, but to make a point. You’re able to enjoy this picture because you have the ability to see. But more than 20 million Americans in the US who suffer from some form of visual impairment can’t, and they are the inspiration for my blog today.

Age-related macular degeneration (AMD), the leading cause of blindness in the US, destroys the macula, the part of the eye responsible for central vision. Others patients suffer from retinitis pigmentosa (RP), which ravages the photoreceptors in the retina located in the back inside layer of the eye causing night blindness, tunnel vision, and eventually blindness. (For more on RP and AMD, check out our Stem Cells In Your Face video on “Eyeing Stem Cell Therapies for Vision Loss). Other diseases such as cataracts, glaucoma, and diabetic retinopathy can also cause people to lose some or all of their vision.

Unfortunately, there is no cure for many forms of blindness, but science has advanced to the point where multiple technologies are being tested in human clinical trials with the hopes of improving sight in blind patients. The two technologies I’m going to talk about today are optogenetics and stem cells – both innovative techniques that have made rapid progress in recent years.

What is optogenetics and how will it help restore sight?

First published about in the early 2000’s, optogenetics is a relatively new and really cool technology that can control how cells function by genetically manipulating them to be responsive to light. Scientists can use optogenetics to turn the activity of nerve cells in the brain on or off, to make muscle cells contract, and now to make eye cells activate in response to light.

The technique relies on light-sensitive proteins called opsins. Through genetic engineering, opsin proteins are delivered to the surface of the desired cell, and when they are exposed to the right wave-length of light, they send signals that turn the cells’ activity on or off.

Encouraged by the success of using optogenetics to restore sight in animal models of blindness, scientists are now hoping to test it in human clinical trials. A company called RetroSense Therapeutics in Ann Arbor, Michigan has developed a gene therapy technology that uses optogenetics, and it has partially restored sight in animal models. They’re targeting retinal ganglion cells, which are nerve cells located at the inner surface of the retina, and turning them into light-sensing cells to replace the ones that have died off.

A clinical trial using RetroSense’s optogenetics therapy is already underway in patients with RP and the trial’s first patient was treated at a clinic in Texas in February. The goal of the trial is baby steps – doctors hope that patients won’t experience negative side effects and that they will go from zero vision to some vision. You can read more about this clinical trial in a piece by Katherine Bourzac in the MIT Technology Review.

Stem Cell Treatments for Blindness in the Works

I’m switching gears now to talk about stem cell therapies for blindness. This area of research has received a lot more attention from scientists compared to optogenetics probably because it’s been around longer and offers more options for therapeutic development.

To be brief, scientists are testing the potential of stem cells to treat patients with diseases like RP and AMD using different types of stem cells including pluripotent stem cells (both embryonic and induced pluripotent or iPS) and retinal progenitor cells derived from fetal tissue. A common approach with AMD is to generate retinal pigment epithelial (RPE) cells – support cells that keep the retina healthy – from pluripotent stem cells and transplant them into the eye. Clinical trials around the world are testing the safety and efficacy of stem-cell derived RPE cells in patients with both the dry and wet forms of AMD.

Researchers seek to restore health to the retina in the back of the eye using cells such as these precursors of an area called the RPE.

An image of RPE cells made from human  stem cells.

In the US and Korea, Ocata Therapeutics (recently acquired by Astellas Therapeutics) generated RPE cells from human embryonic stem cells and transplanted them into patients with AMD in a Phase 1 clinical trial. They reported some improvement in vision and no adverse side effects and launched a Phase 2 trial in 2015. In Japan, scientists at RIKEN transplanted a living sheet of RPE cells from an AMD patient’s own iPS cells and transplanted them patients with AMD. While the first patient did not suffer any negative side effects, the trial was put on hold due to safety issues associated with findings from the iPS cells in laboratory tests. Other stem cell clinical trials are ongoing and you can read about them in this article in Drug Discovery & Development.

CIRM is also funding stem cell trials to treat blindness. One team led by Henry Klassen at UC Irvine, is using fetal retinal progenitor cells to treat patients with RP. They inject these cells into the fluid of the eye, and the cells release proteins and growth factors that boost the health of the remaining photoreceptors in the retina of RP patients. Another team at USC and UC Santa Barbara led by Mark Humayun, David Hinton and Dennis Clegg generated monolayer sheets of RPE cells derived from embryonic stem cells and growing them on synthetic scaffolds that will be transplanted into patients with AMD. Both teams are testing the safety and usefulness of their stem cell treatments in Phase 1 clinical trials. If you want to learn more about them, check out our recent blog.

So what will it be, optogenetics or stem cells?

Artistic representation of the human eye. (Dr. Kang Zhang, Dr. Yizhi Liu)

Artistic representation of the human eye. (Dr. Kang Zhang, Dr. Yizhi Liu)

It’s hard to tell which technology will be first to succeed in restoring sight to patients suffering from blindness and which technology will be more beneficial in the long run because both have their obstacles and vices.

Current optogenetics techniques require the use of viruses to transfer genes that contain the code for making the light-sensitive opsin proteins. These viruses are injected into the eye and have to target the right cells (and not the wrong ones) and the infected cell needs to produce that opsin forever for the technology to work effectively. Then there is the issue of making sure light can reach the genetically modified cells. Luckily nerves in the eye are easier to access than nerve cells in the brain, which require invasive surgery to implant optical fibers that deliver light. However, activating the ganglion nerve cells in the eye will still be a challenge according to MIT Technology review:

“Vision that works through light-sensitive ganglion cells will likely be different than vision that relies on a healthy retina. When you go outside, for instance, it can be about 10,000 times brighter than inside. Healthy retinas rapidly adapt their sensitivity to adjust to this, but the light-sensing cells created by the gene therapy will not likely be able to adapt. For that reason, it may be necessary for the RetroSense therapy, if it works, to be coupled with some kind of video-projection glasses that can perform these adjustments and tailor the incoming light to the treated eye, sending a brighter signal indoors than it does outdoors, for example.”

 

As for stem cells, there’s always the worry that transplanting cells derived from pluripotent stem cells could cause cancer over time. The Japan iPS cell trial for AMD is a good example. It was put on hold because scientists identified potential cancer-causing mutation in a second patient’s iPS cells. (The cause of the mutation was unknown – it could have been caused by the reprogramming method, the iPS cell culturing process, or could have existed prior to reprogramming). Another issue with stem cell treatments is achieving regulatory approval. In the US, the only widely stem cell based therapy is for bone marrow transplantation. If clinical trials using stem cells to treat diseases of blindness begin to show promising results, it would a major roadblock if they can’t push past current regulatory barriers and reach the patients who need them.

So which technology will cross the finish line first in the race to cure blindness: optogenetics or stem cells? The answer is that it doesn’t matter which technology wins. The important thing is they continue to move forward and hopefully one or even both technologies will produce a safe and effective treatment to restore sight in patients suffering from blindness in the near future.

National honor for helping “the blind see”

Those of us fortunate to have good health take so many things for granted, not the least of which is our ability to see. But, according to the World Health Organization, there are 39 million people worldwide who are blind, and another 246 million who are visually impaired. Any therapy, any device, that can help change that is truly worthy of celebration.

Dr.MarkHumayun2 copy

Dr. Mark Humayun: Photo courtesy USC

That’s why we are celebrating the news that Professor Mark Humayun has been awarded the National Medal of Technology and Innovation, the nation’s top technology honor, by President Obama.

Humayun, a researcher at USC’s Keck School of Medicine and a CIRM grantee, is being honored for his work in developing an artificial retina, one that enables people with a relatively rare kind of blindness to see again.

But we are also celebrating the potential of his work that we are funding that could help restore sight to millions of people suffering from the leading cause of blindness among the elderly. But we’ll get back to that in a minute.

First, let’s talk about the invention that has earned him this prestigious award. It’s called the Argus II and it can help people with retinitis pigmentosa, an inherited degenerative disease that slowly destroys a person’s vision. It affects around 100,000 Americans.

The Argus II uses a camera mounted on glasses that send signals to an electronic receiver that has been implanted inside the eye. The receiver then relays those signals through the optic nerve to the brain where they are interpreted as a visual image.

In a story posted on the USC website, USC President C. L. Max Nikias praised Humayun’s work:

“He dreamed the impossible: to help the blind see. With fearless imagination, bold leadership and biomedical expertise, he and his team made that dream come true with the world’s first artificial retina. USC is tremendously proud to be Professor Humayun’s academic home.”

At CIRM we are tremendously proud to be funding the clinical trial that Humayun and his team are running to find a stem cell therapy for age-related macular degeneration (AMD), the leading cause of vision loss in the world.  It’s estimated that by 2020 more than 6 million Americans will suffer from AMD.

Humayun’s team is using embryonic stem cells to produce the support cells, or RPE cells, needed to replace those lost in AMD. We recently produced this video that highlights this work, and other CIRM-funded work that targets vision loss.

In a statement released by the White House honoring all the winners, President Obama said:

“Science and technology are fundamental to solving some of our nation’s biggest challenges. The knowledge produced by these Americans today will carry our country’s legacy of innovation forward and continue to help countless others around the world. Their work is a testament to American ingenuity.”

Which is why we are honored to be partners with Humayun and his team in advancing this research and, hopefully, helping find a treatment for millions of people who dream of one day being able to see again.

 

 

 

 

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

The New World That iPS Cells Will Bring

A stem cell champion was crowned last month. Dr. Takahashi from the RIKEN center in Japan received the prestigious Ogawa-Yamanaka Prize for developing a human iPS cell therapy to treat a debilitating eye disease called macular degeneration. We wrote about the event held at the Gladstone Institutes in a previous blog and saved the juicy insights from Dr. Takahashi’s scientific presentation and her CIRM-exclusive interview for today.  We also put together a two minute video (see below) based on the interview with her as well as with Dr. Deepak Srivastava, Director of the Gladstone Institute of Cardiovascular Disease and Mr. Hiro Ogawa, a co-founder of the Ogawa-Yamanaka Prize.

Dawn of iPS Cells

As part of the ceremony, Dr. Takahashi gave a scientific talk on the “new world that iPS cells will bring”. She began with a historical overview of stem cell research, starting with embryonic stem cells and the immune rejection and ethical issues associated with their use. She then discussed Dr. Yamanaka’s game-changing discovery of iPS cells, which offered new strategies for disease modeling and potential treatments that avoid some of the issues can complicate embryonic stem cells.

Her excitement over this discovery was palpable as she explained how she immediately jumped into the iPS cell field and got her hands dirty. Knowing that this technology could have huge implications for regenerative medicine and the development of stem cell therapies, she made herself a seemingly unattainable promise. “I said to myself, I will apply iPS cells to humans within five years. And I became a woman of her words.”

An iPS cell world

Dr. Takahashi went on to tell her success story, and why she chose to develop an iPS cell therapy to treat a disease of blindess, age-related macular degeneration (AMD). She explained how AMD is a serious unmet medical need. The current treatment involves injections of an antibody that blocks the activity of a growth factor called VEGF. This factor causes an overgrowth of blood vessels in the eye, which does major damage to the cells in the retina and can cause blindness. This therapy however, is only useful for some forms of AMD not all.

Ogawa_Award_Gladstone-0808

Dr. Masayo Takahashi describing her team’s iPS-based therapy for macular degeneration during the inaugural ceremony for the Ogawa-Yamanaka Prize at The Gladstone Institutes.

She believed she could fix this problem by developing an iPS cell technology that would replace lost cells in the eye in AMD patients. To a captivated crowd, she described how she was able to generate a sheet of human iPS derived cells called retinal pigment epithelial (RPE) cells from a patient with AMD. This sheet was transplanted into the eye of the patient in the first ever iPS cell clinical trial. The transplant was successful and the patient had no adverse effects to the treatment.

While the clinical trial is currently on hold, Dr. Takahashi explained that she and her team learned a lot from this experience. They are currently pursuing additional safety measures for their iPS cell technology to make sure that the stem cell transplants will not cause cancer or other bad outcomes in humans.

Autologous vs. Allogeneic?

Another main topic in her speech, was the choice between using autologous (iPS cells made from a patient and transplanted back into the same patient) and allogeneic (iPS cells made from a donor and then transplanted into a patient) iPS cells for transplantation in humans. Dr. Tahakashi’s opinion was that autologous would be ideal, but not scaleable due to high costs and the amount of time it would take to make iPS cell lines for individual patients.

Plath_iPS2

iPS cells reprogrammed from a woman’s skin. Blue shows nuclei. Green and red indicate proteins found in reprogrammed cells but not in skin cells (credit: Kathrin Plath / UCLA).

Her solution is to use an arsenal of allogeneic iPS cells that can be transplanted into patients without rejection by the immune system. This may be possible if both the donor and the patient share the same combination (called a “haplotype”) of cell surface proteins on their immune cells called human leukocyte antigens (HLA). She highlighted the work ongoing in Japan to generate a stock of HLA haplotype matched iPS cell lines that could be used for most of the Japanese population.

 Changing the regulatory landscape in Japan

It was clear from her talk that her prize winning accomplishments didn’t happen without a lot of blood, sweat, and tears both at the bench and in the regulatory arena. In a CIRM exclusive interview, Dr. Takahashi further explained how her pioneering efforts to bring iPS cells to patients helped revolutionize the regulatory landscape in Japan to make it faster and easier to test iPS cells in the clinic.

The power of iPS cells changed the Japanese [regulatory] law dramatically. We made a new chapter for regenerative medicine in pharmaceutical law. With that law, the steps are very quick for cell therapy. In the new chapter [of the law] … conditional approval will be given if you prove the safety of the cell [therapy]. It’s very difficult to show the efficacy completely in a statistical manner for regenerative medicine. So the law says we don’t have to prove the efficacy [of the therapy] thoroughly with thousands of patients. Only a small number of patients are needed for the conditional approval. That’s the big difference.”

We were curious about Dr. Takahashi’s involvement in getting these regulatory changes to pass, and learned that she played a significant role on the academic side to convince the Japanese ministry to change the laws.

This law was made in the cooperation with the ministry and academia. That was one thing that had never happened before. Academia means mainly the Japanese society for the regenerative medicine, and I’m a committee member of that. So we talked about the ideal law for regenerative medicine, and our society suggested various points to the ministry. And to our surprise, the ministry accepted almost all of the points and included them into the law. That was wonderful. Usually we are very conservative and slow in changing, but this time, I was amazed how quickly the law has been changed. It’s the power of iPS cells.”

The iPS cell future is now

As a champion stem cell scientist and a leader in regenerative medicine, Dr. Takahashi took the opportunity at the end of the event to emphasize that all scientists and clinicians in the iPS cell therapy field need to consider three things: develop safe protocols for generating iPS cells that become standard practice, understand the patient’s needs by focusing on how to benefit patients the most, and think of iPS cells as a treatment and consider the risk when developing these therapies.

The new world of iPS cells is opening doors onto uncharted territory, but Dr. Takahashi’s wise words provide a solid roadmap for the future success of iPS cell therapies.

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: