Stem Cell Agency celebrates 50 clinical trials with patient #1

Yesterday the CIRM Board approved funding for our 50th clinical trial (you can read about that here) It was an historic moment for us and to celebrate we decided to go back in history and hear from the very first person to be treated in a CIRM-funded clinical trial. Rich Lajara was treated in the Geron clinical trial after experiencing a spinal cord injury, thus he became CIRM’s patient #1. It’s a badge he says he is honored to wear. This is the speech Rich made to our Board.

Rich Lajara

Hello and good afternoon everyone. It’s an honor to be here today as the 50th clinical trial has been officially funded by CIRM. It was feels like it was just yesterday that I was enrolled into the first funded clinical trial by CIRM and in turn became California’s’ 1st embryonic stem cell patient.

I became paralyzed from the waist down in September 2011. It was Labor Day and I was at a river with some close friends. There was this natural granite rock slide feature next to a waterfall, it was about 60 feet long; all you had to do was get a bucket of water to get the rocks wet and slide down into a natural pool. I ended up slipping and went down head first backwards but was too far over and I slid off a 15’ ledge where the waterfall was. I was pulled from the water and banged up pretty bad. Someone said “look at that deformity on his back” and tapped my leg and asked if I could feel that. I knew immediately I was paralyzed. I thought this was the end, little did I know this was just the beginning. I call it being in the wrong place at the right time.

So, after a few days in the hospital of course everyone, as well as myself, wanted a cure. We quickly learned one didn’t exist. A close family friend had been making phone calls and was able to connect with the Christopher & Dana Reeve Foundation and learned about a clinical trial with “stem cells”. One of my biggest question was how any people have done this? “Close to none”, I was told.

I was also told I most likely would have no direct benefit as this was a safety trial? So why do it at all? Obviously at that time I was willing to overlook the “most likely” part because I was willing to do anything to try and get my normal life back.

Looking back the big picture was laying the ground work for others like Kris or Jake (two people enrolled in a later version of this trial). At the time I had no clue that what I was doing would be such a big deal. The data collected from me would end up being priceless. It’s stories like Jake’s and Kris’ that make me proud and reinforce my decision to have participated in California’s first stem cell clinical trial funded by prop 71.

Like I said earlier it was just the beginning for me. A couple of years later I became a patient advocate working with Americans for Cures. I have been able to meet many people in the stem cell industry and love to see the glow in their face when they learn I was California’s first embryonic stem cell patient.

I can’t even fathom all the year’s of hard work and countless hours of research that had lead up to my long anticipated surgery, but when I see their glowing smile I know they knew what it took.

I also enjoy sharing my story and bridging the gap between myths and facts about stem cells, or talking to students and helping inspire the next generation that will be in the stem cell industry.  As a matter of fact, I have 13 year old sister, Maddie, dead set on being a neurosurgeon.

Fast forward to today. Life in a wheelchair is not exactly a roll in the park (no pun intended) but I have grown accustomed to the new normal. Aside from some neuropathic pain, life is back on track.

Not once did I feel sorry for myself, I was excited to be alive. Sure I have bad days but don’t we all.

In the last 14 years CIRM has funded 50 human clinical trials, published around 2750 new peer-reviewed scientific discoveries, and they’ve transformed California into the world leader in stem cell research. As I look around the posters on the wall, of the people whose lives have been transformed by the agency, I can’t help but be struck by just how much has been achieved in such a short period of time.

While my journey might not yet be over, Evie and 40 other children like her, (children born with SCID) will never remember what it was like to live with the horrible condition they were born with because they have been cured thanks to CIRM. There are hundreds of others whose lives have been transformed because of work the agency has funded.

CIRM has proven how much can be achieved if we invest in cutting-edge medical research.

As most of you here probably know CIRM’s funding from Proposition 71 is about to run out. If I had just one message I wanted people to leave with today it would be this. Everyone in this room knows how much CIRM has done in a little over a decade and how many lives have been changed because of its existence. We have the responsibility to make sure this work continues. We have a responsibility to make sure that the stories we’ve heard today are just the beginning.

I will do everything I can to make sure the agency gets refunded and I hope that all of you will join me in that fight. I’m excited for the world of stem cells, particularly in California, and can’t wait to see what’s on the horizon.

 

How Blockchain Can Increase Accessibility to Stem Cell Therapy

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Photo courtesy of BTCManager

The revolution has arrived. Believe it or not, we are living in a world where artificial intelligence, virtual reality, and stem cell therapies are no longer concepts of science fiction, but are realities of our everyday life. While the development of these things may appear to be in their infancy, it’s undoubtedly true that they each hold a unique opportunity for science to unlock cures to diseases like ALS, Sickle Cell disease, Alzheimer’s and Duchenne’s Muscular Dystrophy.

What is equally true however, is despite the fact that these opportunities are on the horizon, on a global scale there are still significant barriers to accessing clinical trials and quality medical care.

So how do we address this?

Well, according to a company called Stem Cell Project – we need to get creative.

This new Japan-based company set out to create the blockchain-enabled Virtual Clinic, fully equipped with AI technology, diagnostic tools, and its own native currency, the Stem Cell Coin.

 Issues with Modern Healthcare

Modern healthcare has developed rapidly in the past few decades, but is not without its drawbacks. For many people there’s a degree of difficulty in gaining access to qualified specialists. When you consider basic factors like distance and skill shortage, or larger issues like the lack of universal healthcare, it means the average person is unable to afford the high cost of preventative medical treatments, leading to more than 45,000 deaths per year in the United States alone.

In many first-world countries, birth rates have declined over the decades whilst the general population has continued to age. Not only has this has increased the need for specialists in fields treating diseases of aging, like Cancer and Alzheimer’s, but it also means we need to accelerate our efforts to keep up with the growing population.

Using Blockchain to Access Health Records

While many hear the word blockchain and think of cryptocurrencies, it also allows for an ultra-secure means by which patients can interact with healthcare professionals without worrying if malicious third-parties can access their most sensitive personal data. It is for this reason that Stem Cell Project decided to use the groundbreaking technology in their Virtual Clinic.

“Patients are increasingly aware of how their data is being used and who is allowed to access it,” explained Stem Cell Project’s founder Shuji Yamaguchi in a news release. “We therefore wanted to find a solution that was highly secure. Having a patient’s trust is, in many ways, the first step to mass adoption for Stem Cell Coin.”

Beyond that, the platform also ensures patients have access to a decentralized and unchangeable health record. Something which to date has never been fully implemented by a large-scale healthcare organization such as the one backing Stem Cell Project.

Opening the Path to Healthcare Equality

As Stem Cell Coin’s vision continues to be rolled out, a number of complementary applications will also be developed to support the Virtual Clinic. Among these, digital initiatives such as pathological and diagnostic imaging systems have the potential to further build upon the notion of a decentralized, universally-accessible healthcare ecosystem.  Moreover, the ability to pay for stem cell treatment via Stem Cell Coin will allow people to pay and travel for therapy regardless of whether their country exerts strict capital controls. The best example of this is China, where even its wealthy citizens are unable to travel to places like the United States of America and Europe for treatment, as the current cost for stem cell therapy ($10,000 – $50,000) exceeds the limits imposed by their government on how much Yuan can be taken abroad.

Counterfeit drugs and treatments could become easier to spot:

Based on reports from the World Health Organization (WHO), the value of the counterfeit drug market is $200 billion annually. In fact, they estimate 80% of the counterfeit drugs that are consumed in the United States come from overseas. Furthermore – they believe that 16% of counterfeit drugs contain the wrong ingredients, and 17% contain the wrong levels of necessarily ingredients. Not only does this undermine the research and scientists, who are actively looking for treatments by following an established protocol, but the financial burden families and patients are enduring to have access to these drugs is considerably high – especially given that WHO reports that 30% of the counterfeit drugs that are available don’t contain any active ingredients whatsoever. A blockchain-based system would ensure a chain-of-custody log, tracking each step of the supply chain at the individual drug/product level.

Results from clinical trials could become more transparent:

It is estimated that 50% of clinical trials go unreported, and investigators often fail to share their study results. This has created crucial safety issues for patients and knowledge gaps for healthcare stakeholders and health policymakers. Some say, blockchain-enabled, time-stamped immutable records of clinical trials, protocols and results could address the issues of fraudulent outcome reporting, data snooping and selective reporting, thereby reducing the incidence of fraud and error in clinical trial records. Furthermore, blockchain-based systems could help drive unprecedented collaboration between participants and researchers for innovative research projects.

 As new projects such as Stem Cell Coin are able to increase access to regenerative medicine, not only will distance or income cease to determine health outcomes, but we might even be able to address other issues plaguing the healthcare industry.

 

 

 

Full Steam Ahead: First Patient is Dosed in Expanded CIRM Spinal Cord Injury Trial

Today we bring you more good news about a CIRM-funded clinical trial for spinal cord injury that’s received a lot of attention lately in the news. Asterias Biotherapeutics has treated its first patient in an expanded patient population of spinal cord injury patients who suffer from cervical, or neck, injuries.

In late August, Asterias reported that they had passed the first hurdle in their Phase 1/2a trial and showed that their stem cell therapy is safe to use in patients with a more serious form of cervical spinal cord injuries.

Earlier this month, we received more exciting updates from Asterias – this time reporting that the their embryonic stem cell-based therapy, called AST-OPC1, appeared to benefit treated patients. Five patients with severe spinal cord injuries to their neck were dosed, or transplanted, with 10 million cells. These patients are classified as AIS-A on the ASIA impairment scale – meaning they have complete injuries in which the spinal cord tissue is severed and patients lose all feeling and use of their limbs below the injury site. Amazingly, after three months, all five of the AIS-A patients have seen improvements in their movement.

Today, Asterias announced that it has treated its first patient with an AIS-B grade cervical spinal cord injury with a dose of 10 million cells at the Sheperd Center in Atlanta. AIS-B patients have incomplete neck injuries, meaning that they still have some spinal cord tissue at the injury site, some feeling in their arms and legs, but no movement. This type of spinal cord injury is still severe, but these patients have a better chance at gaining back some of their function and movement after treatment.

In a press release by Asterias, Chief Medical Officer Dr. Edward Wirth said:

“We have been very encouraged by the first look at the early efficacy data, as well as the safety profile, for AST-OPC1 in AIS-A patients, and now look forward to also evaluating efficacy and safety in AIS-B patients. AIS-B patients also have severe spinal cord injuries, but compared to AIS-A patients they have more spared tissue in their spinal cords.  This may allow these patients to have a greater chance of meaningful functional improvement after being treated with AST-OPC1 cells.”

Dr. Donald Peck Leslie, who directs the Sheperd Center and is the lead investigator at the Atlanta clinical trial site, expressed his excitement about the trials’ progress.

“As someone who regularly treats patients who have sustained paralyzing spinal cord injuries, I am encouraged by the progress we’ve seen in evaluations of AST-OPC1 in people with AIS-A injuries, particularly the improvements in hand, finger and arm function. Now, I am looking forward to continuing the evaluation of this promising new treatment in AIS-B patients, as well.”

Asterias has plans to enroll a total of five to eight AIS-B patients who will receive a dose of 10 million cells. They will continue to monitor all patients in this trial (both AIS-A and B) and will conduct long-term follow up studies to make sure that the AST-OPC1 treatment remains safe.

We hope that the brave patients who have participated in the Asterias trial continue to show improvements following treatment. Inspiring stories like that of Kris Boesen, who was the first AIS-A patient to get 10 million cells in the Asterias trial and now has regained the use of his arms and hands (and regaining some sensation in his legs), are the reason why CIRM exists and why we are working so hard to fund promising clinical trials. If we can develop even one stem cell therapy that gives patients back their life, then our efforts here at CIRM will be worthwhile.

Kris Boesen, CIRM spinal cord injury clinical trial patient.

Kris Boesen, CIRM spinal cord injury clinical trial patient.


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CIRM-funded study suggests methods to make pluripotent stem cells are safe

We live in an era where stem cell treatments are already being tested in human clinical trials for eye disease, spinal cord injury, and type 1 diabetes. The hope is that transplanting stem cells or their cell derivatives will replace diseased tissue, restore function, and cure patients – all while being safe and without causing negative side effects.

Safety will be the key to the future success of stem cell replacement therapies. We’ve learned our lesson from early failed gene therapy experiments where genetically altered stem cells that were supposed to help patients actually caused them to get cancer. Science has since developed methods of gene therapy that appear safe, but new concerns have cropped up around the safety of the methods used to generate pluripotent stem cells, which are considered a potential starting material for cell replacement therapies.

Stem cell reprogramming can cause problems

Induced pluripotent stem cells (iPS cells) cultured in a dish.

Induced pluripotent stem cells (iPS cells) cultured in a dish.

Induced pluripotent stem cells, or iPS cells, are a potential source of pluripotent stem cells for cell therapy. These cells are equivalent to embryonic stem cells but can be generated from adult tissue (such as skin or even blood) by reprogramming cells back to a pluripotent state. During cellular reprogramming, one set of genes is turned off and another set is turned on through a process called epigenetic remodeling. We don’t have time to explain epigenetics in this blog, but to be brief, it involves chromatin remodeling (chromatin is the complex of DNA and protein that make up chromosomes) and is essential for controlling gene expression.

To make healthy iPS cells, the intricate steps involved in cellular reprogramming and epigenetic remodeling have to be coordinated perfectly. Scientists worry that these processes aren’t always perfect and that cancer-causing mutations could be introduced that could cause tumors when transplanted into patients.

A CIRM-funded study published Friday in Nature Communications offers some relief to this potential roadblock to using reprogrammed iPS cells for cell therapy. Scientists from The Scripps Research Institute (TSRI) and the J. Craig Venter Institute (JCVI) collaborated on a study that assessed the safety of three common methods for generating iPS cells. Their findings suggest that these reprogramming methods are relatively safe and unlikely to give cancer-causing mutations to patients.

Comparing three reprogramming methods

In case you didn’t know, iPS cells are typically made by turning on expression of four genes – OCT4, SOX2, KLF4, and c-MYC – that maintain stem cells in a pluripotent state. Scientists can force an adult cell to express these genes by delivering extra copies into the cell. In this study, the scientists conducted a comparative genomic analysis of three commonly used iPS cell reprogramming methods (integrating retroviral vectors, non-integrating Sendai virus, and synthetic mRNAs) to search for potential cancer-causing mutations in the DNA of the iPS cells.

Unlike previous studies that focused on finding a single type of genetic mutation in reprogrammed iPS cells, the group looked at multiple types of genetic mutations – from single nucleotide changes in DNA to large structural variations – by comparing whole-genome sequencing data of the starting parental cells (skin cells) to iPS cells.

They concluded that the three reprogramming methods generally do not cause serious problems and hypothesized that cancer-causing mutations likely happen at a later step after the iPS cells are already made, an issue the team is addressing in ongoing work.

They explained in their publication:

“We detected subtle differences in the numbers of [genetic] variants depending on the method, but rarely found mutations in genes that have any known association with increased cancer risk. We conclude that mutations that have been reported in iPS cell cultures are unlikely to be caused by their reprogramming, but instead are probably due to the well-known selective pressures that occur when hPSCs [human pluripotent stem cells] are expanded in culture.”

The safety of patients comes first

Senior authors on the study, Dr. Jeanne Loring from TSRI and Dr. Nicholas Schork from JCVI, explained in a TSRI News Release that the goal of this study was to make sure that the reprogramming methods used to make iPS cells were safe for patients.

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Jeanne Loring

“We wanted to know whether reprogramming cells would make the cells prone to mutations,” said Jeanne Loring, “The answer is ‘no.’ The methods we’re using to make pluripotent stem cells are safe.”

 

Nicholas Schork added:

Nicholas Schork

Nicholas Schork

“The safety of patients comes first, and our study is one of the first to address the safety concerns about iPSC-based cell replacement strategies and hopefully will spark further interest.”

 

 

Moving from bench to clinic

It’s good news that reprogramming methods are relatively safe, but the fact that maintaining and expanding iPS cells in culture causes cancerous mutations is still a major issue that scientists need to address.

Jeanne Loring recognizes this important issue and says that the next steps are to use similar genomic analyses to assess the safety of reprogrammed iPS cells before they are used in patients.

“We need to move on to developing these cells for clinical applications,” said Loring. “The quality control we’re recommending is to use genomic methods to thoroughly characterize the cells before you put them into people.”

From Science Fiction to Science Fact: Gene Editing May Make Personalized Therapies for Blindness

Have you seen the movie Elysium? It’s a 2013 futuristic science fiction film starring one of my favorite actors Matt Damon. The plot centers on the economic, social and political disparities between two very different worlds: one, an overpopulated earth where people are poor, starving, and have little access to technology or medical care, the other, a terraformed paradise in earth’s orbit that harbors the rich, the beautiful, and advanced technologies.

Med-Bays.

Med-Bays.

The movie is entertaining (I give it 4 stars, Rotten Tomatoes says 67%), but as a scientist, one of the details that stuck out most was the Med-Bays. They’re magical, medical machines that can diagnose and cure any disease, regrow body parts, and even make people young again.

Wouldn’t it be wonderful if Med-Bays actually existed? Unfortunately, we currently lack the capabilities to bring this technology out of the realm of science fiction. However, recent efforts in the areas of personalized stem cell therapies and precision medicine are putting paths for creating potential cures for a wide range of diseases on the map.

One such study, published in Scientific Reports, is using precision medicine to help cure patients with a rare eye disease. Scientists from the University of Iowa and Columbia University Medical Center used CRISPR gene editing technology to fix induced pluripotent stem cells (iPS cells) derived from patients with an inherited form of blindness called X-linked retinitis pigmentosa (XLRP). The disease is caused by a single genetic mutation in the RPGR gene, which causes the retina of the eye to break down, leaving the patient blind or with very little vision. (For more on RP and other diseases of blindness, check out our Stem Cells in your Face video.)

CRISPR is a hot new tool that allows scientists to target and change specific sequences of DNA in the genome with higher accuracy and efficiency than other gene editing tools. In this study, researchers were concerned that it would be hard for CRISPR to correct the RPGR gene mutation because it’s located in a repetitive section of DNA that can be hard to accurately edit. After treating patient stem cells with the CRISPR modifying cocktail, the scientists found that the RPGR mutation had a 13% correction rate, which is comparable to other iPS cell based CRISPR editing studies.

Skin cells from a patient with X-linked Retinitis Pigmentosa were transformed into induced pluripotent stem cells and the blindness-causing point mutation in the RPGR gene was corrected using CRISPR/Cas9. Image by Vinit Mahajan.

Stem cells derived from a patient with X-linked Retinitis Pigmentosa. (Image by Vinit Mahajan)

The authors claim that this is the first study to successfully correct a genetic mutation in human stem cells derived from patients with degenerative retinal disease. The study is important because it indicates that XLRP patients can benefit from personalized stem cell therapy where scientists make individual patient iPS cell lines, use precision medicine to genetically correct the RPGR mutation, and then transplant healthy retinal cells derived from the corrected stem cells back into the same patients to hopefully give them back their sight.

Senior author on the study, Vinit Mahajan explained in a University of Iowa news release:

Vinit Mahajan

Vinit Mahajan

“With CRISPR gene editing of human stem cells, we can theoretically transplant healthy new cells that come from the patient after having fixed their specific gene mutation. And retinal diseases are a perfect model for stem cell therapy, because we have the advanced surgical techniques to implant cells exactly where they are needed.”

It’s important to note that this study is still in its early stages. Stephen Tsang, a co-author on the study, commented:

“There is still work to do. Before we go into patients, we want to make sure we are only changing that particular, single mutation and we are not making other alterations to the genome.”


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New Stem Cell Treatment for ALS May Slow Disease Progression

Exciting news was published this week that will give patients suffering from ALS, also known as Lou Gehrig’s disease, something to cheer about. The journal JAMA Neurology reported that a new stem cell treatment was successful in slowing disease progression in a small group of ALS patients in a Phase 2 clinical trial.

This is big news for a fatal, incurable disease that is well known for its progressive, degenerating effects on nerve cells in the brain and spinal cord. We’ve written about ALS a lot in the Stem Cellar, so if you want more background on the disease, read our “Progress to a Cure for ALS” blog.

A patient’s own stem cells can help

The stem cell therapy involves extracting mesenchymal stem cells from the bone marrow of ALS patients. These stem cells are then manipulated in culture into cells that secrete a growth factor called NeuroTrophic Factor (NTF), which helps keep nerve cells in the brain and spinal cord healthy and alive. The NTF-secreting stem cells (called NurOwn cells) are then transplanted back into the same ALS patient (making this an autologous stem cell therapy) by injection into either the spinal fluid or the muscles.

logoThe NurOwn method was developed by BrainStorm Cell Therapeutics, a biotech company based in the US and Israel. Clinical trials to test the safety and efficacy of NurOwn stem cells began in 2011 at the Hadassah Medical Organization (HMO). So far, 26 patients have participated in the trials both in the US and in Israel.

According to the JAMA publication, patients were monitored 3 months before and 6 months after they received stem cell transplants and 6 months after. Twelve of the 26 patients participated in an early stage of the trial (phase 1/2) to test the safety and tolerability of the stem cell therapy. The other 14 patients participated in a later stage (phase 2a), dose-escalating study where their modified stem cells were injected into both their spinal fluid and muscles. Following the treatment, the scientists looked at the safety profile of the transplanted stem cells and for signs of clinical improvement in patients such as their ease of breathing or ability to control their muscle movement.

Stem cell treatment is effective in most ALS patients

Results from the clinical trial showed that a majority of the patients benefitted from the NurOwn stem cell therapy. HMO Principle scientist and senior author on the study, Dr. Dimitrios Karussis, explained:

Dr. Dimitrios Karussis (Image credit: Israel21c)

Dimitrios Karussis (Israel21c)

“The results are very encouraging.  Close to 90% of patients who were injected intrathecally through the spinal cord fluid were regarded as responders to the treatment either in terms of their respiratory function or their motor disability.  Almost all of the patients injected in this way showed less progression and some even improved in their respiratory functions or their motor functions.”

A PRNewswire press release covering this study called the stem cell therapy the “first-of-its-kind treatment for treating neurodegenerative diseases.”

Not a cure just yet

This stem cell therapy will need to be tested in more patients before the it can be determined truly effective in slowing progression of ALS. And Dr. Karussis was quick to note that the NurOwn stem cell therapy isn’t a cure for ALS, but rather an early-stage therapy that will provide significant benefit to patients by slowing disease progression.

“I am optimistic that within the foreseeable future, we may provide a treatment to ALS patients that can slow down or stop the progression. I believe we are in the early stages of something new and revolutionary with this harvested stem cell infusion therapy.  While this is absolutely by no means a cure, it is the first step in a long process in that direction.  I see this treatment as being potentially one of the major future tools to treat degenerative diseases of the brain and spinal cord, in general.”

Other stem cell treatments for ALS in the works

A single stem cell therapy that could treat multiple neurodegenerative diseases would be extremely valuable to patients and doctors. However, it’s not clear that the “one ring to rule them all” scenario (couldn’t help making a Lord of the Rings reference) will play out well for all diseases that affect the brain and spinal cord. Luckily, Dr. Karussis and Brainstem Cell Therapeutics are not the only ones pursuing stem cell therapies for ALS.

Clive Svendsen has been on a 15-year quest to develop an ALS therapy

Clive Svendsen

CIRM is currently funding 21 studies (a total of $56.6 million) that use stem cells to either study ALS or to develop therapies to treat the disease. We wrote about one recent study by Clive Svendsen at Cedars Sinai which is using a combination of gene therapy and brain stem cells to deliver growth factors to protect nerve cells in the brain and spinal cord of ALS patients. Currently, Svendsen and his team are in the latter stages of research and hope to apply for FDA approval to test their therapy in patients in the near future. Svendsen told CIRM, “we will begin recruiting patients the first week we have approval.”


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Have Scientists Found a Stem Cell-lution to Thyroid Disorders?

The thyroid gland is located in the neck. (WebMD)

The thyroid gland is located in the neck. (WebMD)

Have you thanked your thyroid today? If not, you should because your thyroid is essential for many of life’s daily activities and processes that you probably take for granted.

You can thank your thyroid for things like regulating your body temperature and appetite, and keeping you energetic, slim, and focused. That’s because these small glands in your neck are hormone-producing factories, and thyroid secreted hormones (TSH) control the growth and development of our organs and tissues and regulate important processes like your metabolism.

When your thyroid doesn’t work…

People who have thyroid disorders suffer from a number of uncomfortable or even nasty symptoms. Those with overactive thyroid glands (hyperthyroidism) produce too much thyroid hormone and have an overactive metabolism, which causes symptoms such as excessive sweating, weight loss, heart problems, and sensitivity to heat. Those with underactive thyroids (hypothyroidism) don’t produce enough hormone and have an impaired metabolism, which causes symptoms of tiredness, reduced heart rate, hair loss, feeling cold, and weight gain.

There are other types of thyroid problems (cancer and inflammation to name a few), but the bottom line is that, if your thyroid isn’t functioning properly, your quality of life will be negatively affected.

A stem cell-lution to hypothyroidism

However, there maybe a new “stem cell-lution” therapy for some forms of thyroid dysfunction. Scientists from the Boston University School of Medicine and the Beth Israel Deaconess Medical Center reported in Cell Stem Cell on Thursday that they can generate functional thyroid tissue from stem cells derived from different mammalian models. This is a huge deal because previously, scientists were unable to manipulate pluripotent stem cells into mature thyroid cells that had the correct thyroid identity (meaning they turned on the correct combination of thyroid-specific genes). This previous inability has made it very difficult for scientists to model thyroid diseases in a dish.

In this study, the authors used two factors, BMP and FGF, to directly differentiate mouse pluripotent stem cells into thyroid progenitor cells. These progenitors could be coaxed further into mature and properly functioning thyroid organoids (3D thyroid-like structures) that secreted thyroid hormone both in a dish and when transplanted back into mice.

Scientists generated thyroid tissue from pluripotent stem cells of frogs, mice and humans. (Cell Stem Cell)

Scientists generated thyroid tissue from pluripotent stem cells of frogs, mice and humans. (Cell Stem Cell)

What was truly exciting about their discovery, was that the same two factors could make functional thyroid tissue from mouse, frog, and human pluripotent stem cells, showing that the role of BMP4 and FGF2 in thyroid development is conserved across multiple species.

With the bases loaded, the authors hit a grand slam by using BMP4 and FGF2 to generate thyroid progenitor cells from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) derived from the skin cells of both healthy individuals and patients with hypothyroidism.

Thyroid organoids generated from mouse embryonic stem cells. (Cell Stem Cell)

Thyroid organoids generated from mouse embryonic stem cells. (Cell Stem Cell)

Big Picture

This study not only offers a new understanding of the early stages of thyroid development, but provides a potential source of transplantable stem-cell derived thyroid progenitor cells for cell-based therapies that could treat some forms of hypothyroidism.

In a press release from the Beth Israel Deaconess Medical Center, co-senior author of the study Anthony Hollenberg explained the significance of their findings:

This research represents an important step toward the goal of being able to better treat thyroid diseases and being able to permanently rescue thyroid function through the transplantation of a patient’s own engineered pluripotent stem cells.

 

Co-senior author Darrell Kotton went further to describe the novelty of their discovery:

Until now, we haven’t fully understood the natural process that underlies early thyroid development. With this paper, we’ve identified the signaling pathways in thyroid cells that regulate their differentiation, the process by which unspecialized stem cells give rise to specialized cells during early fetal development.”

 

Remembering Anita Kurmann

Anita Kurmann

Anita Kurmann

While this discovery is a major step forward in the field of thyroid disease and regenerative medicine, the victory is bittersweet in light of the recent passing of the study’s first author, Anita Kurmann. Anita was a Swiss surgeon and a talented scientist who was tragically killed while riding her bike in Boston’s Back Bay on August 7th, 2015. She had just heard that her publication would be accepted to Cell Stem Cell days before the accident and was planning to start her own lab at the end of the year in Switzerland.

Her colleagues, friends, and the science world will miss her dearly. As a tribute to Anita, her co-authors dedicated the Cell Stem Cell publication to her memory.

We dedicate this work to the memory of our co-first author, Dr. Anita Kurmann, who died in a tragic bicycle accident when this manuscript was in the final stages of formatting. She was intelligent, well read, kind, humble, and tirelessly committed to her patients, her thyroid research, her family, and her colleagues, who miss her dearly.


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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.

CAP1

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.

CAP2

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.

Cell mate: the man who makes stem cells for clinical trials

When we announced that one of the researchers we fund – Dr. Henry Klassen at the University of California, Irvine – has begun his clinical trial to treat the vision-destroying disease retinitis pigmentosa, we celebrated the excitement felt by the researchers and the hope from people with the disease.

But we missed out one group. The people who make the cells that are being used in the treatment. That’s like praising a champion racecar driver for their skill and expertise, and forgetting to mention the people who built the car they drive.

Prof. Gerhard Bauer

Prof. Gerhard Bauer

In this case the “car” was built by the Good Manufacturing Practice (GMP) team, led by Prof. Gerhard Bauer, at the University of California Davis (UC Davis).

Turns out that Gerhard and his team have been involved in more than just one clinical trial and that the work they do is helping shape stem cell research around the U.S. So we decided to get the story behind this work straight from the horse’s mouth (and if you want to know why that’s a particularly appropriate phrase to use here read this previous blog about the origins of GMP)

When did the GMP facility start, what made you decide this was needed at UC Davis?

Gerhard: In 2006 the leadership of the UC Davis School of Medicine decided that it would be important for UC Davis to have a large enough manufacturing facility for cellular and gene therapy products, as this would be the only larger academic GMP facility in Northern CA, creating an important resource for academia and also industry. So, we started planning the UC Davis Institute for Regenerative Cures and large GMP facility with a team of facility planners, architects and scientists, and by 2007 we had our designs ready and applied for the CIRM major facilities grant, one of the first big grants CIRM offered. We were awarded the grant and started construction in 2008. We opened the Institute and GMP facility in April of 2010.

How does it work? Do you have a number of different cell lines you can manufacture or do people come to you with cell lines they want in large numbers?

Gerhard: We perform client driven manufacturing, which means the clients tell us what they need manufactured. We will, in conjunction with the client, obtain the starting product, for instance cells that need to undergo a manufacturing process to become the final product. These cells can be primary cells or also cell lines. Cell lines may perhaps be available commercially, but often it is necessary to derive the primary cell product here in the GMP facility; this can, for instance, be done from whole donor bone marrow, from apheresis peripheral blood cells, from skin cells, etc.

How many cells would a typical – if there is such a thing – order request?

Gerhard: This depends on the application and can range from 1 million cells to several billions of cells. For instance, for an eye clinical trial using autologous (from the patient themselves) hematopoietic stem and progenitor cells, a small number, such as a million cells may be sufficient. For allogeneic (from an unrelated donor) cell banks that are required to treat many patients in a clinical trial, several billion cells would be needed. We therefore need to be able to immediately and adequately adjust to the required manufacturing scale.

Why can’t researchers just make their own cells in their own lab or company?

Gerhard: For clinical trial products, there are different, higher, standards than apply for just research laboratory products. There are federal regulations that guide the manufacturing of products used in clinical trials, in this special case, cellular products. In order to produce such products, Good Manufacturing Practice (GMP) rules and regulations, and guidelines laid down by both the Food and Drug Administration (FDA) and the United States Pharmacopeia need to be followed.

The goal is to manufacture a safe, potent and non-contaminated product that can be safely used in people. If researchers would like to use the cells or cell lines they developed in a clinical trial they have to go to a GMP manufacturer so these products can actually be used clinically. If, however, they have their own GMP facility they can make those products in house, provided of course they adhere to the rules and regulations for product manufacturing under GMP conditions.

Besides the UC Irvine retinitis pigmentosa trial now underway what other kinds of clinical trials have you supplied cells for?

Gerhard: A UC Davis sponsored clinical trial in collaboration with our Eye Center for the treatment of blindness (NCT01736059), which showed remarkable vision recovery in two out of the six patients who have been treated to date (Park et al., PMID:25491299, ), and also an industry sponsored clinical gene therapy trial for severe kidney disease. Besides cellular therapy products, we also manufacture clinical grade gene therapy vectors and specialty drug formulations.

For several years we have been supplying clinicians with a UC Davis GMP facility developed formulation of the neuroactive steroid “allopregnanolone” that was shown to act on resident neuronal stem cells. We saved several lives of patients with intractable seizures, and the formulation is also applied in clinical trials for the treatment of traumatic brain injury, Fragile X syndrome and Alzheimer’s disease.

What kinds of differences are you seeing in the industry, in the kinds of requests you get now compared to when you started?

Gerhard: In addition, gene therapy vector manufacturing and formulation work is really needed by several clients. One of the UC Davis specialties is “next generation” gene-modified mesenchymal stem cells, and we are contacted often to develop those products.

Where will we be in five years?

Gerhard: Most likely, some of the Phase I/II clinical trials (these are early stage clinical trials with, usually, relatively small numbers of patients involved) will have produced encouraging results, and product manufacturing will need to be scaled up to provide enough cellular products for Phase III clinical trials (much larger trials with many more people) and later for a product that can be licensed and marketed.

We are already working with companies that anticipate such scale up work and transitioning into manufacturing for marketing; we are planning this upcoming process with them. We also believe that certain cellular products will replace currently available standard medical treatments as they may turn out to produce superior results.

What does the public not know about the work you do that you think they should know?

Gerhard: The public should know that UC Davis has the largest academic Good Manufacturing Practice Facility in Northern California, that its design was well received by the FDA, that we are manufacturing a wide variety of products – currently about 16 – that we are capable of manufacturing several products at one time without interfering with each other, and that we are happy to work with clients from both academia and private industry through both collaborative and Fee-for-Service arrangements.

We are also very proud to have, during the last 5 years, contributed to saving several lives with some of the novel products we manufactured. And, of course, we are extremely grateful to CIRM for building this state-of-the-art facility.

You can see a video about the building of the GMP facility at UC Davis here.

Study Identifies Safer Stem Cell Therapies

To reject or not reject, that is the question facing the human immune system when new tissue or cells are transplanted into the body.

Stem cell-therapy promises hope for many debilitating diseases that currently have no cures. However, the issue of immune rejection has prompted scientists to carefully consider how to develop safe stem cell therapies that will be tolerated by the human immune system.

Before the dawn of induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs) were suggested as a potential source for transplantable cells and tissue. However, ESCs run into a couple of issues, including their origin, and the fact that ESC-derived cells likely would be rejected when transplanted into most areas of a human due to differences in genetic backgrounds.

The discovery of iPSCs in the early 2000’s gave new hope to the field of stem cell therapy. By generating donor cells and tissue from a patient’s own iPSCs, transplanting those cells/tissue back into the same individual shouldn’t – at least theoretically – cause an immune reaction. This type of transplantation is called “autologous” meaning that the stem cell-derived cells have the same genetic background as the person.

Unfortunately, scientists have run up against a roadblock in iPSC-derived stem cell therapy. They discovered that even cells derived from a patient’s own iPSCs can cause an immune reaction when transplanted into that patient. The answers as to why this occurs remained largely unanswered until recently.

In a paper published last week in Cell Stem Cell, scientists from the University of California, San Diego (UCSD) reported that different mature cell types derived from human iPSCs have varying immunogenic effects (the ability to cause an immune reaction) when transplanted into “humanized” mice that have a human immune system. This study along with the research conducted to generate the humanized mice was funded by CIRM grants (here, here).

In this study, retinal pigment epithelial cells (RPE) and skeletal muscle cells (SMC) derived from human iPSCs were transplanted into humanized mice. RPEs were tolerated by the immune system while SMCs were rejected. (Adapted from Zhao et al. 2015)

Scientists took normal mice and replaced their immune system with a human one. They then took human iPSCs generated from the same human tissue used to generate the humanized mice and transplanted different cell types derived from the iPSCs cells into these mice.

Because they were introducing cells derived from the same source of human tissue that the mouse’s immune system was derived from, in theory, the mice should not reject the transplant. However, they found that many of the transplants did indeed cause an immune reaction.

Interestingly, they found that certain mature cell types derived from human iPSCs created a substantial immune reaction while other cell types did not. The authors focused on two specific cell types, smooth muscle cells (SMC) and retinal pigment epithelial cells (RPE), to get a closer look at what was going on.

iPSC-derived smooth muscle cells created a large immune response when transplanted into humanized mice. However, when they transplanted iPSC-derived retinal epithelial cells (found in the retina of the eye), they didn’t see the same immune reaction. As a control, they transplanted RPE cells made from human ESCs, and as expected, they saw an immune response to the foreign ESC-derived RPE cells.

RPE_1

iPSC derived RPE cells (green) do not cause an immune reaction (red) after transplantation into humanized mice while H9 embryonic stem cell derived RPE cells do. (Zhao et al. 2015)

When they looked further to determine why the humanized mice rejected the muscle cells but accepted the retinal cells, they found that SMCs had a different gene expression profile and higher expression of immunogenic molecules. The iPSC-derived RPE cells had low expression of these same immunogenic molecules, which is why they were well tolerated in the humanized mice.

Results from this study suggest that some cell types generated from human iPSCs are safer for transplantation than others, an issue which can be addressed by improving the differentiation techniques used to produce mature cells from iPSCs. This study also suggests that iPSC-derived RPE cells could be a safe and promising stem cell therapy for the treatment of eye disorders such as age-related macular degeneration (AMD). AMD is a degenerative eye disease that can cause vision impairment or blindness and usually affects older people over the age of 50. Currently there is no treatment for AMD, a disease that affects approximately 50 million people around the world. (However there is a human iPSC clinical trial for AMD out of the RIKEN Center for Developmental Biology in Japan that has treated one patient but is currently on hold due to safety issues.)

The senior author on this study, Dr. Yang Xu, commented on the importance of this study in relation to AMD in a UCSD press release:

Dr. Yang Xu

Dr. Yang Xu

Immune rejection is a major challenge for stem cell therapy. Our finding of the lack of immune rejection of human iPSC-derived retinal pigment epithelium cells supports the feasibility of using these cells for treating macular degeneration. However, the inflammatory environment associated with macular degeneration could be an additional hurdle to be overcome for the stem cell therapy to be successful.

Xu makes an important point by acknowledging that iPSC-derived RPE cells aren’t a sure bet for curing AMD just yet. More research needs to be done to address other issues that occur during AMD in order for this type of stem cell therapy to be successful.

 


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