embryonic stem cells

So far, some encouraging news for stem cell clinical trial treating epilepsy

/ Kevin McCormack / 1 Comment

Neurona Therapeutics is testing a new therapy for a drug-resistant form of epilepsy and has just released some encouraging early findings. The first patient treated went from having more than 30 seizures a month to just four seizures over a three-month period.

This clinical trial, funded by the California Institute for Regenerative Medicine (CIRM), is targeting  mesial temporal lobe epilepsy (MTLE), one of the most common forms of epilepsy. Because the seizures caused by MTLE are frequent, they can be particularly debilitating and increase the risk of a decreased quality of life, depression, anxiety and memory impairment.

Neurona’s therapy, called NRTX-1001, consists of a specialized type of neuronal cell derived from embryonic stem cells.  Neuronal cells are messenger cells that transmit information between different areas of the brain, and between the brain and the rest of the nervous system.

NRTX-1001 is injected into the brain in the area affected by the seizures where it releases neurotransmitters or chemical messengers that will block the signals in the brain causing the epileptic seizures.

The first patient treated had a nine-year history of epilepsy and, despite being on anti-epileptic medications, was experiencing dozens of seizures a month. Since the therapy he has had only four seizures in three months. The therapy hasn’t produced any serious side effects.

In a news release Dr. Cory Nicholas, Neurona’s President and CEO, said while this is only one patient, it’s good news.

“The reduced number of seizures reported by the first person to receive NRTX-1001 is very encouraging, and we remain cautiously optimistic that this reduction in seizure frequency will continue and extend to others entering this cell therapy trial. NRTX-1001 administration has been well tolerated thus far in the clinic, which is in line with the extensive preclinical safety data collected by the Neurona team. With recent clearance from the Data Safety Monitoring Board we are excited to continue patient enrollment. We are very grateful to these first participants, and thank the clinical teams for the careful execution of this pioneering study.”

CIRM has been a big supporter of this work from the early Discovery stage work to this clinical trial. That’s because when we find something promising, we want to do everything we can to help it live up to its promise.

Building embryo-like cells in the lab

/ Kevin McCormack / 1 Comment
Dr. Magdalena Zernicka-Goetz: Photo courtesy Caltech

Human embryonic stem cells (hESCs) have many remarkable properties, not the least of which is their ability to turn into every other kind of cell in our body. But there are limits to what researchers can do with embryonic stem cells. One issue is that there aren’t always hESCs available – they come from eggs donated by couples who have undergone in vitro fertilization. Another is that researchers can only develop these cells in the laboratory for 14 days (though that rule may be changing).

Now researchers at Caltech have developed a kind of hESC-in-a-dish that could help make it easier to answer questions about human development without the need to wait for a new line of hESCs.

The team, led by Magdalena Zernicka-Goetz, used a line of expanded pluripotent cells (EPSCs), originally derived from a human embryo, to create a kind of 3D model that mimics some of the activities of an embryo.

The cool thing about these cells is that, because they were originally derived from an embryo, they retain some “memory” of how they are supposed to work. In a news release Zernicka-Goetz says this enables them to display elements of both polarization and cavitation, early crucial phases in the development of a human embryo.

“The ability to assemble the basic structure of the embryo seems to be a built-in property of these earliest embryonic cells that they are simply unable to ‘forget.’ Nevertheless, either their memory is not absolutely precise or we don’t yet have the best method of helping the cells recover their memories. We still have further work to do before we can get human stem cells to achieve the developmental accuracy that is possible with their equivalent mouse stem cell counterparts.”

Being able to create these embryo-like elements means researchers can generate cells in large numbers and won’t be so dependent on donated embryos.

In the study, published in the journal Nature Communications, the researchers say this could help them develop a deeper understanding of embryonic development.

“Understanding human development is of fundamental biological and clinical importance. Despite its significance, mechanisms behind human embryogenesis remain largely unknown…. this stem cell platform provides insights into the design of stem cell models of embryogenesis.

CIRM funds clinical trials targeting heart disease, stroke and childhood brain tumors

/ Kevin McCormack / Leave a comment
Gary Steinberg (Jonathan Sprague)

Heart disease and stroke are two of the leading causes of death and disability and for people who have experienced either their treatment options are very limited. Current therapies focus on dealing with the immediate impact of the attack, but there is nothing to deal with the longer-term impact. The CIRM Board hopes to change that by funding promising work for both conditions.

Dr. Gary Steinberg and his team at Stanford were awarded almost $12 million to conduct a clinical trial to test a therapy for motor disabilities caused by chronic ischemic stroke.  While “clot busting” therapies can treat strokes in their acute phase, immediately after they occur, these treatments can only be given within a few hours of the initial injury.  There are no approved therapies to treat chronic stroke, the disabilities that remain in the months and years after the initial brain attack.

Dr. Steinberg will use embryonic stem cells that have been turned into neural stem cells (NSCs), a kind of stem cell that can form different cell types found in the brain.  In a surgical procedure, the team will inject the NSCs directly into the brains of chronic stroke patients.  While the ultimate goal of the therapy is to restore loss of movement in patients, this is just the first step in clinical trials for the therapy.  This first-in-human trial will evaluate the therapy for safety and feasibility and look for signs that it is helping patients.

Another Stanford researcher, Dr. Crystal Mackall, was also awarded almost $12 million to conduct a clinical trial to test a treatment for children and young adults with glioma, a devastating, aggressive brain tumor that occurs primarily in children and young adults and originates in the brain.  Such tumors are uniformly fatal and are the leading cause of childhood brain tumor-related death. Radiation therapy is a current treatment option, but it only extends survival by a few months.

Dr. Crystal Mackall and her team will modify a patient’s own T cells, an immune system cell that can destroy foreign or abnormal cells.  The T cells will be modified with a protein called chimeric antigen receptor (CAR), which will give the newly created CAR-T cells the ability to identify and destroy the brain tumor cells.  The CAR-T cells will be re-introduced back into patients and the therapy will be evaluated for safety and efficacy.

Joseph Wu Stanford

Stanford made it three in a row with the award of almost $7 million to Dr. Joe Wu to test a therapy for left-sided heart failure resulting from a heart attack.  The major issue with this disease is that after a large number of heart muscle cells are killed or damaged by a heart attack, the adult heart has little ability to repair or replace these cells.  Thus, rather than being able to replenish its supply of muscle cells, the heart forms a scar that can ultimately cause it to fail.  

Dr. Wu will use human embryonic stem cells (hESCs) to generate cardiomyocytes (CM), a type of cell that makes up the heart muscle.  The newly created hESC-CMs will then be administered to patients at the site of the heart muscle damage in a first-in-human trial.  This initial trial will evaluate the safety and feasibility of the therapy, and the effect upon heart function will also be examined.  The ultimate aim of this approach is to improve heart function for patients suffering from heart failure.

“We are pleased to add these clinical trials to CIRM’s portfolio,” says Maria T. Millan, M.D., President and CEO of CIRM.  “Because of the reauthorization of CIRM under Proposition 14, we have now directly funded 75 clinical trials.  The three grants approved bring forward regenerative medicine clinical trials for brain tumors, stroke, and heart failure, debilitating and fatal conditions where there are currently no definitive therapies or cures.”

Building a new mouse, one stem cell at a time

/ Kevin McCormack / Leave a comment

Science is full of acronyms. There are days where it feels like you need a decoder ring just to understand a simple sentence. A recent study found that between 1950 and 2019 researchers used more than 1.1 million unique acronyms in scientific papers. There’s even an acronym for three letter acronyms. It’s TLAs. Which of course has one more letter than the thing it stands for.

I only mention this because I just learned a new acronym, but this one could help change the way we are able to study causes of infertility. The acronym is IVG or in vitro gametogenesis and it could enable scientists to create both sperm and egg, from stem cells, and grow them in the lab. And now scientists in Japan have done just that and allowed these fertilized eggs to then develop into mice.

The study, published in the journal Science, was led by Dr. Katsuhiko Hayashi of Kyushu University in Japan. Dr. Hayashi is something of a pioneer in the field of IVG. In the past his team were the first to produce both mouse sperm, and mouse eggs from stem cells. But they ran into a big obstacle when they tried to get the eggs to develop to a point where they were ready to be fertilized.

Over the last five years they have worked to find a way around this obstacle and, using mouse embryonic stem cells, they developed a process to help these stem cell-generated eggs mature to the point where they were viable.

In an article in STAT News Richard Anderson, Chair of Clinical Reproductive Science at the University of Edinburgh, said this was a huge achievement: “It’s a very serious piece of work. This group has done a lot of impressive things leading up to this, but this latest paper really completes the in vitro gametogenesis story by doing it in a completely stem-cell-derived way.”

The technique could prove invaluable in helping study infertility in people and, theoretically, could one day lead to women struggling with infertility to be able to use their own stem cells to create eggs or men their own sperm. However, the researchers say that even if that does become possible it’s likely a decade or more away.

While the study is encouraging on a scientific level, it’s raising some concerns on an ethical level. Should there be limits on how many of these manufactured embryos that a couple can create? Can someone create dozens or hundreds of these embryos and then sift through them, using genetic screening tools, to find the ones that have the most desirable traits?

One thing is clear, while the science is evolving, bioethicists, scholars and the public need to be discussing the implications for this work, and what kinds of restraints, if any, need to be applied before it’s RFPT (ready for prime time – OK, I made that one up.)

CIRM funded trial for AMD shows promising results

/ Yimy Villa / 13 Comments

This upcoming July is healthy vision month, a time to remember the importance of making vision and eye health a priority. It’s also a time to think about the approximately 12 million people, 40 and over in the United States, that have a vision impairment. Vision can be something that many of us take for granted, but losing even a portion of it can have a profound impact on our everyday life. It can impact your ability to do everyday things, from basic hygiene routines and driving to hobbies such as reading, writing, or watching a film.

It is because of this that CIRM has made vision related problems a priority, providing over $69 million in funding for six clinical trials related to vision loss. There is reason to be hopeful as these trials have demonstrated promising results. One of these trials, conducted by Regenerative Patch Technologies LLC (RPT), announced today results from its CIRM funded clinical trial ($16.3 million) for advanced, dry age-related macular degeneration (AMD).

AMD is a progressive disease resulting in death of the retinal pigment epithelium (RPE), an area of the eye that plays a key role in maintaining vision. Damage to the RPE causes distortion to central vision and eventually leads to legal blindness. Thanks to CIRM funding, RPT and scientists at the University of Southern California (USC) and UC Santa Barbara (UCSB) are growing specialized RPE cells from human embryonic stem cells (hESCs), placing them on a single layer scaffold, and implanting the combination device in the back of the eye to try to reverse the blindness caused by AMD.

One of the trial participants is Anna Kuehl, a USC alumna and avid nature lover. She was diagnosed with AMD in her mid 30s and gradually began losing the central vision in her left eye. Although her peripheral vision remained intact, she could no longer make out people’s faces clearly, drive a car, or read the time on her watch. This also meant she would have much more difficulty going on the nature hikes she enjoys so much. After receiving treatment, she noticed improvements in her vision.

Anna was not alone in these improvements post treatment. The implant, known as CPCB-RPE1, was delivered to the worst eye of 15 patients with AMD. All treated eyes were legally-blind having a best corrected visual acuity (BCVA) of 20/200 or worse (20/20 indicates perfect vision).

Patients in the clinical trial were assessed for visual function and the results were as follows:

  • At an average of 34 months post-implantation (range 12-48 months), 27% (4/15) showed a greater than 5 letter improvement in BCVA and 33% (5/15) remained stable with a BCVA within 5 letters of baseline value. The improvements ranged from 7-15 letters or 1-3 lines on an eye chart.
  • In contrast, BCVA in the fellow, untreated eye declined by more than 5 letters (range 8-21 letters or 1-4 lines on an eye chart) in 80% (12/15) of subjects. There was no improvement in BCVA in the untreated eye of any subject. 
  • The implant was delivered safely and remained stably in place throughout the trial.
  • Refinements to the implantation procedure during the trial further improved its efficiency and safety profile.

In a news release from RPT, Mark Humayun, M.D., Ph.D., founder and co-owner of RPT, Director of the USC Ginsburg Institute for Biomedical Therapeutics and Co-Director of the USC Roski Eye Institute, Keck Medicine of USC, had this to say about the trial results.

“The improvements in best corrected visual acuity observed in some eyes receiving the implant are very promising, especially considering the very late stage of their disease. Improvements in visual acuity are exceedingly rare in geographic atrophy as demonstrated by the large decline in vision in many of the untreated eyes which also had disease. There are currently no approved therapies for this level of advanced dry age-related macular degeneration”. 

The full presentation can be found on RPT’s website linked here.

Watch the video below to learn more about Anna’s story.

Battling COVID and turning back the clock on stem cell funding

/ Kevin McCormack / 5 Comments
Coronavirus

Battling the virus that causes COVID-19 is something that is top of everyone’s mind right now. That’s why CIRM is funding 17 different projects targeting the virus. But one of the most valuable tools in helping develop vaccines against a wide variety of diseases in the past is now coming under threat. We’ll talk about both issues in a live broadcast we’re holding on Wednesday, October 14th at noon (PDT).

That date is significant because it’s Stem Cell Awareness Day and we thought it appropriate to host a meeting looking at two of the most important issues facing the field.

The first part of the event will focus on the 17 projects that CIRM is funding that target COVID-19. This includes three clinical trials aiming to treat people who have been infected with the virus and are experiencing some of the more severe effects, such as damaged lungs.

We’ll also look at some of the earlier stage research that includes:

  • Work to help develop a vaccine
  • Using muscle stem cells to help repair damage to the diaphragm in patients who have spent an extended period on a ventilator
  • Boosting immune system cells to help fight the virus

The second part of the event will look at ways that funding for stem cell research at the federal level is once again coming into question. The federal government has already imposed new restrictions on funding for fetal tissue research, and now there are efforts in Congress to restrict funding for embryonic stem cell research.

The impacts could be significant. Fetal tissue has been used for decades to help develop some of the most important vaccines used today including rubella, chickenpox, hepatitis A, and shingles. They have also been used to make approved drugs against diseases including hemophilia, rheumatoid arthritis, and cystic fibrosis.

We’ll look at some of the reasons why we are seeing these potential restrictions on the medical research and what impact they could have on the ability to develop new treatments for the coronavirus and other deadly diseases.

You can watch the CIRM Stem Cell Awareness Day live event by going here: https://www.youtube.com/c/CIRMTV/videos at noon on Wednesday, October 14th.

Feel free to share news about this event with anyone you think might be interested.

We look forward to seeing you there.

Creating an on-off switch to test stem cell therapy for Parkinson’s Disease

/ Kevin McCormack / 1 Comment

Sometimes you read about a new study where the researchers did something that just leaves you gob smacked. That’s how I felt when I read a study in the journal Cell Stem Cell about a possible new approach to helping people with Parkinson’s Disease (PD).

More on the gob smacking later. But first the reason for the study.

We know that one of the causes of Parkinson’s disease is the death of dopamine-producing neurons, brain cells that help plan and control body movement. Over the years, researchers have tried different ways to try and replace those cells but getting the cells where they need to be and getting them to integrate into the brain has proved challenging.

A team at the University of Wisconsin-Madison think they may have found a way to fix that. In an article in Drug Target Review  lead researcher Dr. Su-Chun Zhang, explained their approach:

“Our brain is wired in such an accurate way by very specialized nerve cells in particular locations so we can engage in all our complex behaviors. This all depends on circuits that are wired by specific cell types. Neurological injuries usually affect specific brain regions or specific cell types, disrupting circuits. In order to treat those diseases, we have to restore these circuits.”

The researchers took human embryonic stem cells and transformed them into dopamine-producing neurons, then they transplanted those cells into mice specially bred to display PD symptoms. After several months the team were able to show that not only had the mice improved motor skills but that the transplanted neurons were able to connect to the motor-control regions of the brain and also establish connections with regulatory regions of the brain, which prevented over stimulation. In other words, the transplanted cells looked and behaved the way they would in a healthy human brain.

Now here comes the gob smack part. The team wanted to make sure the cells they transplanted were the reason for the improved motor control in the mice. So, they had inserted a genetic on-and-off switch into the stem cells. By using specially designed drugs the researchers were able to switch the cells on or off.

When the cells were switched off the mice’s motor improvements stopped. When they were switched back on, they were restored.

Brilliant right! Well, I thought it was.

Next step is to test this approach in larger animals and, if all continues to look promising, to move into human clinical trials.

CIRM is already funding one clinical trial in Parkinson’s disease. You can read about it here.

Testing a drug is safe before you give it to a pregnant woman

/ Kevin McCormack / Leave a comment
Pregnant woman holding medicine.

When a doctor gives you a medication you like to think that it’s safe, that it has been tested to make sure it will do you some good or, at the very least, won’t do you any harm. That’s particularly true when the patient is a pregnant woman. You hope the medication won’t harm her or her unborn child. Now scientists in Switzerland have found a new way to do that that is faster and easier than previous methods, and it uses cell cultures instead of animals.

Right now, drugs that are intended for use in pregnant women have to undergo some pretty rigorous testing before they are approved. This involves lots of tests in the lab, and then in animals such as rats and rabbits. It’s time consuming, costly, and not always accurate because animals never quite mimic what happens in people.

In the past researchers tested new medications in the lab on so-called “embryoid bodies”. These are three-dimensional clumps of cells developed from embryonic stem cells from mice. The problem is that even when tested in this way the cells don’t always reflect what happens to a medication as it passes through the body. For example, some medications can seem fine on the surface but after they pass through the liver can take on toxic qualities. 

So, scientists at ETH Zurich in Basel, Switzerland, developed a better way to test for toxicity.

They took a cell-culture chip and created several compartments on it, in some they placed the embryoid bodies and in others they put microtissue samples from human livers.  The different compartments were connected so that fluid flowed freely from the embryoid bodies to the liver and vice versa.

In a news release, Julia Boos, a lead author of the study, says this better reflects what happens to a medication exposed to a human metabolism.

“We’re the first to directly combine liver and embryonic cells in a body-on-a-chip approach. Metabolites created by the liver cells – including metabolites that are stable for just a few minutes – can thus act directly on the embryonic cells. In contrast to tests on mice, in our test, the substances are metabolised by human liver cells – in other words, just as they would be in the human body when the medication is administered.”

To see if this worked in practice the researchers tested their approach on the chemotherapy drug cyclophosphamide, which is turned into a toxic substance after passing through the liver.

They compared results from testing cyclophosphamide with the new liver/embryoid body method to the older method. They found the new approach was far more sensitive and determined that a 400 percent lower concentration of cyclophosphamide was enough to pose a toxic threat.

The team now hope to refine the test even further so it can one day, hopefully, be applied to drug development on a large scale.

Their findings are published in the journal Advanced Science

First patient treated for colon cancer using reprogrammed adult cells

/ Yimy Villa / 3 Comments
Dr. Sandip Patel (left) and Dr. Dan Kaufman (center) of UC San Diego School of Medicine enjoy a light-hearted moment before Derek Ruff (right) receives the first treatment for cancer using human-induced pluripotent stem cells (hiPSCs). Photo courtesy of UC San Diego Health.

For patients battling cancer for the first time, it can be quite a draining and grueling process. Many treatments are successful and patients go into remission. However, there are instances where the cancer returns in a much more aggressive form. Unfortunately, this was the case for Derek Ruff.

After being in remission for ten years, Derek’s cancer returned as Stage IV colon cancer, meaning that the cancer has spread from the colon to distant organs and tissues. According to statistics from Fight Colorectal Cancer, colorectal cancer is the 2nd leading cause of cancer death among men and women combined in the United States. 1 in 20 people will be diagnosed with colorectal cancer in their lifetime and it is estimated that there will be 140,250 new cases in 2019 alone. Fortunately, Derek was able to enroll in a groundbreaking clinical trial to combat his cancer.

In February 2019, as part of a clinical trial at the Moores Cancer Center at UC San Diego Health in collaboration with Fate Therapeutics, Derek became the first patient in the world to be treated for cancer with human-induced pluripotent stem cells (hiPSCs). hiPSCs are human adult cells, such as those found on the skin, that are reprogrammed into stem cells with the ability to turn into virtually any kind of cell. In this trial, hiPSCs were reprogrammed into natural killer (NK) cells, which are specialized immune cells that are very effective at killing cancer cells, and are aimed at treating Derek’s colon cancer.

A video clip from ABC 10 News San Diego features an interview with Derek and the groundbreaking work being done.

In a public release, Dr. Dan Kaufman, one of the lead investigators of this trial at UC San Diego School of Medicine, was quoted as saying,

“This is a landmark accomplishment for the field of stem cell-based medicine and cancer immunotherapy. This clinical trial represents the first use of cells produced from human induced pluripotent stem cells to better treat and fight cancer.”

In the past, CIRM has given Dr. Kaufman funding related to the development of NK cells. One was a $1.9 million grant for developing a different type of NK cell from hiPSCs, which could also potentially treat patients with lethal cancers. The second grant was a $4.7 million grant for developing NK cells from human embryonic stem cells (hESCs) to potentially treat patients with acute myelogenous leukemia (AML).

In the public release, Dr. Kaufman is also quoted as saying,

“This is a culmination of 15 years of work. My lab was the first to produce natural killer cells from human pluripotent stem cells. Together with Fate Therapeutics, we’ve been able to show in preclinical research that this new strategy to produce pluripotent stem cell-derived natural killer cells can effectively kill cancer cells in cell culture and in mouse models.”

Stories that caught our eye: National Geographic takes a deep dive into iPS cells; Japanese researchers start iPS cell clinical trial for spinal cord injury; and do high fat diets increase your risk of colorectal cancer

/ Kevin McCormack / 1 Comment

Can cell therapy beat the most difficult diseases?

That’s the question posed in a headline in National Geographic. The answer; maybe, but it is going to take time and money.

The article focuses on the use of iPS cells, the man-made equivalent of embryonic stem cells that can be turned into any kind of cell or tissue in the body. The reporter interviews Kemal Malik, the member of the Board of Management for pharmaceutical giant Bayer who is responsible for innovation. When it comes to iPS cells, it’s clear Malik is a true believer in their potential.

“Because every cell in our bodies can be produced from a stem cell, the applicability of cell therapy is vast. iPSC technology has the potential to tackle some of the most challenging diseases on the planet.”

But he also acknowledges that the field faces some daunting challenges, including:

  • How to manufacture the cells on a large scale without sacrificing quality and purity
  • How do you create products that have a stable shelf life and can be stored until needed?
  • How do you handle immune reactions if you are giving these cells to patients?

Nonetheless, Malik remains confident we can overcome those challenges and realize the full potential of these cells.

“I believe human beings are on the cusp of the next big wave of pharmaceutical innovation. The use of living cells to make people better.”

As if to prove Malik right there was also news this week that researchers at Japan’s Keio University have been given permission to start a clinical trial using iPS cells to treat people with spinal cord injuries. This would be the first of its kind anywhere in the world.

Japan launches iPSC clinical trial for spinal cord injury

An article in Biospace says that the researchers plan to treat four patients who have suffered varying degrees of paralysis due to a spinal cord injury.  They will take cells from the patients and, using the iPS method, turn them into the kind of nerve cells found in the spinal cord, and then transplant two million of them back into the patient. The hope is that this will create new connections that restore movement and feeling in the individuals.

This trial is expected to start sometime this summer.

CIRM has already funded a first-of-its-kind clinical trial for spinal cord injury with Asterias Biotherapeutics. That clinical trial used embryonic stem cells turned into oligodendrocyte progenitor cells – which develop into cells that support and protect nerve cells in the central nervous system. We blogged about the encouraging results from that trial here.

High fat diet drives colorectal cancer

Finally today, researchers at Salk have uncovered a possible cause to the rise in colorectal cancer deaths among people under the age of 55; eating too much high fat food.

Our digestive system works hard to break down the foods we eat and one way it does that is by using bile acids. Those acids don’t just break down the food, however, they also break down the lining of our intestines. Fortunately, our gut has a steady supply of stem cells that can repair and replace that lining. Unfortunately, at least according to the team from Salk, mutations in these stem cells can lead to colorectal cancer.

The study, published in the journal Cell, shows that bile acids affect a protein called FXR that is responsible for ensuring that gut stem cells produce a steady supply of new lining for the gut wall. When someone eats a high fat diet it upsets the balance of bile acids, starting a cascade of events that help cancer develop and grow.

In a news release Annette Atkins, a co-author of the study, says there is a strong connection between bile acid and cancer growth:

“We knew that high-fat diets and bile acids were both risk factors for cancer, but we weren’t expecting to find they were both affecting FXR in intestinal stem cells.”

So next time you are thinking about having that double bacon cheese burger for lunch, you might go for the salad instead. Your gut will thank you. And it might just save your life.