Drug used to treat multiple sclerosis may improve glioblastoma outcomes

Dr. Jeremy Rich, UC San Diego

Glioblastoma is an aggressive form of cancer that invades brain tissue, making it extremely difficult to treat. Current therapies involving radiation and chemotherapy are effective in destroying the bulk of brain cancer cells, but they are not able to reach the brain cancer stem cells, which have the ability to grow and multiply indefinitely. These cancer stem cells enable the glioblastoma to continuously grow even after treatment, which leads to recurring tumor formation.

Dr. Jeremy Rich and his team at UC San Diego examined glioblastomas further by obtaining glioblastoma tumor samples donated by patients that underwent surgery and implanting these into mice. Dr. Rich and his team tested a combinational treatment that included a targeted cancer therapy alongside a drug named teriflunomide, which is used to treatment patients with multiple sclerosis. The research team found that this approach successfully halted the growth of glioblastoma stem cells, shrank the tumor size, and improved survival in the mice.

In order to continue replicating, glioblastoma stem cells make pyrimidine, one of the compounds that make up DNA. Dr. Rich and his team noticed that higher rates of pyrimidine were associated with poor survival rates in glioblastoma patients. Teriflunomide works by blocking an enzyme that is necessary to make pyrmidine, therefore inhibiting glioblastoma stem cell replication.

In a press release, Dr. Rich talks about the potential these findings hold by stating that,

“We’re excited about these results, especially because we’re talking about a drug that’s already known to be safe in humans.”

However, he comments on the need to evaluate this approach further by saying that,

“This laboratory model isn’t perfect — yes it uses human patient samples, yet it still lacks the context a glioblastoma would have in the human body, such as interaction with the immune system, which we know plays an important role in determining tumor growth and survival. Before this drug could become available to patients with glioblastoma, human clinical trials would be necessary to support its safety and efficacy.”

The full results to this study were published in Science Translational Medicine.

A new stem cell derived tool for studying brain diseases

Sergiu Pasca’s three-dimensional culture makes it possible to watch how three different brain-cell types – oligodendrocytes (green), neurons (magenta) and astrocytes (blue) – interact in a dish as they do in a developing human  brain.
Courtesy of the Pasca lab

Neurological diseases are among the most daunting diagnoses for a patient to receive, because they impact how the individual interacts with their surroundings. Central to our ability to provide better treatment options for these patients, is scientists’ capability to understand the biological factors that influence disease development and progression. Researchers at the Stanford University School of Medicine have made an important step in providing neuroscientists a better tool to understand the brain.

While animal models are excellent systems to study the intricacies of different diseases, the ability to translate any findings to humans is relatively limited. The next best option is to study human stem cell derived tissues in the laboratory. The problem with the currently available laboratory-derived systems for studying the brain, however, is the limited longevity and diversity of neuronal cell types. Dr. Sergiu Pasca’s team was able to overcome these hurdles, as detailed in their study, published in the journal Nature Neuroscience.

A new approach

Specifically, Dr. Pasca’s group developed a method to differentiate or transform skin derived human induced pluripotent stem cells (iPSCs – which are capable of becoming any cell type) into brain-like structures that mimic how oligodendrocytes mature during brain development. Oligodendrocytes are most well known for their role in myelinating neurons, in effect creating a protective sheath around the cell to protect its ability to communicate with other brain cells. Studying oligodendrocytes in culture systems is challenging because they arise later in brain development, and it is difficult to generate and maintain them with other cell types found in the brain.

These scientists circumvented this problem by using a unique combination of growth factors and nutrients to culture the oligodendrocytes, and found that they behaved very similarly to oligodendrocytes isolated from humans. Most excitingly, they observed that the stem cell-derived oligodendrocytes were able to myelinate other neurons in the culture system. Therefore they were both physically and functionally similar to human oligodendrocytes.

Importantly, the scientists were also able to generate astrocytes alongside the oligodendrocytes. Astrocytes perform many important functions such as providing essential nutrients and directing the electrical signals that help cells in the brain communicate with each other. In a press release, Dr. Pasca explains the importance of generating multiple cell types in this in vitro system:

“We now have multiple cell types interacting in one single culture. This permits us to look close-up at how the main cellular players in the human brain are talking to each other.”

This in vitro or laboratory-developed system has the potential to help scientists better understand oligodendrocytes in the context of diseases such as multiple sclerosis and cerebral palsy, both of which stem from improper myelination of brain nerve cells.

This work was partially supported by a CIRM grant.

The story behind the book about the Stem Cell Agency

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Don Reed at his book launch: Photo by Todd Dubnicoff

WHY I WROTE “CALIFORNIA CURES”  By Don C. Reed

It was Wednesday, June 13th, 2018, the launch day for my new book, “CALIFORNIA CURES: How the California Stem Cell Research Program is Fighting Your Incurable Disease!”

As I stood in front of the audience of scientists, CIRM staff members, patient advocates, I thought to myself, “these are the kind of people who built the California stem cell program.” Wheelchair warriors Karen Miner and Susan Rotchy, sitting in the front row, typified the determination and resolve typical of those who fought to get the program off the ground. Now I was about to ask them to do it one more time.

My first book about CIRM was “STEM CELL BATTLES: Proposition 71 and Beyond. It told the story of  how we got started: the initial struggles—and a hopeful look into the future.

Imagine being in a boat on the open sea and there was a patch of green on the horizon. You could be reasonably certain those were the tops of coconut trees, and that there was an island attached—but all you could see was a patch of green.

Today we can see the island. We are not on shore yet, but it is real.

“CALIFORNIA CURES” shows what is real and achieved: the progress the scientists have made– and why we absolutely must continue.

For instance, in the third row were three little girls, their parents and grandparents.

One of them was Evangelina “Evie” Vaccaro, age 5. She was alive today because of CIRM, who had funded the research and the doctor who saved her.

Don Reed and Evie and Alysia

Don Reed, Alysia Vaccaro and daughter Evie: Photo by Yimy Villa

Evie was born with Severe Combined Immunodeficiency (SCID) commonly called the “bubble baby” disease. It meant she could never go outside because her immune system could not protect her.  Her mom and dad had to wear hospital masks to get near her, even just to give her a hug.

But Dr. Donald Kohn of UCLA operated on the tiny girl, taking out some of her bone marrow, repairing the genetic defect that caused SCID, then putting the bone marrow back.

Today, “Evie” glowed with health, and was cheerfully oblivious to the fuss she raised.

I was actually a little intimidated by her, this tiny girl who so embodied the hopes and dreams of millions. What a delight to hear her mother Alysia speak, explaining  how she helped Evie understand her situation:  she had “unicorn blood” which could help other little children feel better too.

This was CIRM in action, fighting to save lives and ease suffering.

If people really knew what is happening at CIRM, they would absolutely have to support it. That’s why I write, to get the message out in bite-size chunks.

You might know the federal statistics—133 million children, women and men with one or more chronic diseases—at a cost of $2.9 trillion dollars last year.

But not enough people know California’s battle to defeat those diseases.

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Adrienne Shapiro at the book launch: Photo by Todd Dubnicoff

Champion patient advocate Adrienne Shapiro was with us, sharing a little of the stress a parent feels if her child has sickle cell anemia, and the science which gives us hope:  the CIRM-funded doctor who cured Evie is working on sickle cell now.

Because of CIRM, newly paralyzed people now have a realistic chance to recover function: a stem cell therapy begun long ago (pride compels me to mention it was started by the Roman Reed Spinal Cord Injury Research Act, named after my son), is using stem cells to re-insulate damaged nerves in the spine.  Six people were recently given the stem cell treatment pioneered by Hans Keirstead, (currently running for Congress!)  and all six experienced some level of recovery, in a few cases regaining some use of their arms hands.

Are you old enough to remember the late Annette Funicello and Richard Pryor?  These great entertainers were stricken by multiple sclerosis, a slow paralysis.  A cure did not come in time for them. But the international cooperation between California’s Craig Wallace and Australia’s Claude Bernard may help others: by  re-insulating MS-damaged nerves like what was done with spinal cord injury.

My brother David shattered his leg in a motorcycle accident. He endured multiple operations, had steel rods and plates inserted into his leg. Tomorrow’s accident recovery may be easier.  At Cedars-Sinai, Drs. Dan Gazit and Hyun Bae are working to use stem cells to regrow the needed bone.

My wife suffers arthritis in her knees. Her pain is so great she tries to make only one trip a day down and up the stairs of our home.  The cushion of cartilage in her knees is worn out, so it is bone on bone—but what if that living cushion could be restored? Dr. Denis Evseenko of UCLA is attempting just that.

As I spoke, on the wall behind me was a picture of a beautiful woman, Rosie Barrero, who had been left blind by retinitis pigmentosa. Rosie lost her sight when her twin children were born—and regained it when they were teenagers—seeing them for the first time, thanks to Dr. Henry Klassen, another scientist funded by CIRM.

What about cancer? That miserable condition has killed several of my family, and I was recently diagnosed with prostate cancer myself. I had everything available– surgery, radiation, hormone shots which felt like harpoons—hopefully I am fine, but who knows for sure?

Irv Weissman, the friendly bear genius of Stanford, may have the answer to cancer.  He recognized there were cancer stem cells involved. Nobody believed him for a while, but it is now increasingly accepted that these cancer stem cells have a coating of protein which makes them invisible to the body’s defenses. The Weissman procedure may peel off that “cloak of invisibility” so the immune system can find and kill them all—and thereby cure their owner.

What will happen when CIRM’s funding runs out next year?

If we do nothing, the greatest source of stem cell research funding will be gone. We need to renew CIRM. Patients all around the world are depending on us.

The California stem cell program was begun and led by Robert N. “Bob” Klein. He not only led the campaign, was its chief writer and number one donor, but he was also the first Chair of the Board, serving without pay for the first six years. It was an incredible burden; he worked beyond exhaustion routinely.

Would he be willing to try it again, this time to renew the funding of a successful program? When I asked him, he said:

“If California polls support the continuing efforts of CIRM—then I am fully committed to a 2020 initiative to renew the California Institute for Regenerative Medicine (CIRM).”

Shakespeare said it best in his famous “to be or not to be” speech, asking if it is “nobler …to endure the slings and arrows of outrageous fortune, or to take arms against a sea of troubles—and by opposing, end them”.

Should we passively endure chronic disease and disability—or fight for cures?

California’s answer was the stem cell program CIRM—and continuing CIRM is the reason I wrote this book.

Don C. Reed is the author of “CALIFORNIA CURES: How the California Stem Cell Program is Fighting Your Incurable Disease!”, from World Scientific Publishing, Inc., publisher of the late Professor Stephen Hawking.

For more information, visit the author’s website: www.stemcellbattles.com

 

Video illustrates potential path to stem cell repair for multiple sclerosis

“Can you imagine slowly losing the ability to live life as you know it? To slowly lose the ability to see, to walk, to grab an object, all the while experiencing pain, fatigue and depression?”

These sobering questions are posed at the beginning of a recent video produced by Youreka Science and Americans for Cures about multiple sclerosis (MS), a debilitating neurodegenerative disorder in which a person’s own immune system attacks cells that are critical for sending nerve signals from the brain and spinal cord to our limbs and the rest of our body.

In recognition of Multiple Sclerosis Awareness Week, today’s blog features this video. Using an easy to understand narrative and engaging hand-drawn illustrations, this whiteboard “explainer” video does a terrific job of describing the biological basis of multiple sclerosis. It also highlights promising research out of UC Irvine showing that stem cell-based therapies may one day help repair the damage caused by multiple sclerosis.

But don’t take my word for it, check out the five-minute video below:

Related Links:

Could Stem Cells Help Beat Multiple Sclerosis?

March is Multiple Sclerosis month. In honor of MS patients and research, we are featuring a guest blog from scientist and communicator Hamideh Emrani. Thoughts expressed here are not necessarily those of CIRM.

If you are reading this post, other than out of curiosity, chances are that you know someone who has been affected by Multiple Sclerosis (MS). This unpredictable and at times confusing disease has affected too many people in my circle of friends and family. I personally have spent hours reading about it and reading about possible treatments.

For instance, M, a really close friend of mine woke up one day and everything was blurry. She could see but it seemed as if there was a thick fog covering everything. After seeing her optometrist and being evaluated via multiple tests and an MRI scan, she was diagnosed with MS. The reason behind her blurred vision was inflammation of her optic nerves.

Why do MS symptoms happen?

The nerve cells in the brain and spinal cord are connected through cellular extensions. Each cell has one long cellular extension at one end, called an axon, that looks similar to an electrical wire. Axons relay information using neural signals from one cell to another. Just as an electrical wire has a protective plastic cover to avoid leakage of electricity, these axons, are covered with a protective layer of a special fat called myelin.

The myelin on the outside of nerve cells is destroyed in patients with MS. (Source Wikimedia & Bruce Blaus)

In MS, a patient’s immune cells start to attack this protective layer in the central nervous system: the optic nerves, brain, and the spinal cord. They also attack the cells that produce myelin (called oligodendrocytes) and the injured nerve axon fibers. This results in de-myelination or the loss of myelin; and eventual deterioration and damage of the nerve axons. In turn, multiple scar tissues form on the damaged areas on nerves that can be seen through MRI, hence the name “multiple sclerosis” with sclerosis meaning scar tissue.

Generally, the demyelination and scar tissue will cause communication problems among nerves and the symptoms vary in each patient making it a complicated disease to treat. Some common resulting symptoms include excessive fatigue, pain, blurred vision, walking difficulties, muscle  stiffness and changes in brain-based skills such as memory and problem solving.

Depending on the stage of the disease and the extent of the damage, the disease has been categorized to four different courses.

MS Type Description
Clinically Isolated Syndrome (CIS) The person has had one episode of neurological symptoms that may or may not be accompanied by damages seen in an MRI scan.

 

Relapsing remitting MS (RRMS) The most common type of MS, which is characterized by clearly defined periods of neurologic inflammation called “MS attacks” that can be followed by periods of partial or complete recovery. The person might be completely symptom free during these remission times.
Secondary progressive MS (SPMS) Many patients with RRMS over time transition to SPMS where there is no recovery from the symptoms and disability accumulates.

 

Primary progressive MS (PPMS) There are no remissions from the onset of the disease and disability caused by disease activity worsens over time.

What is the cause of MS?

MS is affecting a growing number of human populations. While the jury is still out to define the main cause, many scientists believe that various factors play a role such as genetic predisposition, viral and bacterial infections, and environmental cues. MS is mostly prominent in countries in the Northern hemisphere and colder climates. It affects more women than men, and is mostly diagnosed between the age of 35-50.

Treatments for MS

Unfortunately, there is no cure for MS at the moment. The drugs that are available, called MS modifying treatments, try to prevent the progression of the disease but they don’t reverse it. Instead, the drugs mostly modulate the immune system to avoid further attacks or treat symptoms such as fatigue, pain, and bladder issues that are caused by the damage.

How do stem cells come into picture?

Stem cells are unique cells with the ability to both self-renew and specialize into different cell types. This amazing regeneration ability has turned them into great sources for designing treatment strategies to replace the damaged cells in MS. Two stem cell treatment approaches for MS are currently in development. In one, the researchers try to reboot or modulate the patient’s immune system to prevent it from attacking the nerve cells. In the other, scientists focus on using stem cells to make oligodendrocytes to try and regenerate and repair lost and injured nervous tissue.

Overview of Recent Clinical Trials

The most common stem cells used in clinical trials are the blood, or haematopoietic stem cells (HSCs) which are isolated from the bone marrow. Haematopoietic stem cell transplants (HSCT) have been used for decades to treat blood cancers such as leukemias, but the first time they were studied for treating MS was in the 1990s.

In this method, the patient’s HSCs are collected from the bone marrow and stored. Then, the patient’s immune system, including the bone marrow, is completely depleted through chemotherapy. Finally, the stem cells are transplanted back into the body and after a few months eventually build up a new immune system.

Just last month, Dr. Paolo Muraro et al. published a report that reviews such clinical trials and the long-term outcomes for the patients. They evaluated data for 281 patients from 25 centers in 13 countries that were followed an average of 6.5 years after the transplant. At the end they conclude that almost half of the patients receiving HSCT did not have any progression of the disease. And, younger patients with the most common form of MS, RRMS, who had less disability going into the trial, and had gone through less disease modifying treatments had a better outcome. (73% were progression free at the  5 year mark).

Additionally, over the past two years three separate phase two clinical trials in Northern America have reported results:

  • In the HALT-MS trial, a small number (24) of patients with, RRMS, whose disease was not controlled by any medications, underwent HSCT. After 5 years, 91.3% of the patients did not show any sign of disease progression.
  • In June 2016, a Canadian team of researchers reported the results of a long term follow up of an aHSCT trial (the “a” stands for autologous, meaning it used the patient’s own cells) on 24 patients whose MS had progressed even after receiving conventional treatments. After up to 13 years after the transplantation, no relapses were evident, and 35% of the patients experienced reversals in their level of disability.
  • Back in 2015, Burt et al. reported their HSCT treatment regimen for 123 RRMS patients and their follow up of up to 4 years. In their study, instead of completely depleting the patient’s immune system, they just suppressed it and performed the transplants. Their data suggest that there was no disease progression in 87% of individuals who had MS for less than 10 years.

Will Stem Cells be used for treatment of MS in the near future?

Even though the initial results of the HSCT clinical trials sound promising, the risks that are involved are not easy to ignore.  In all the mentioned trials, there were side effects related to the transplant. There were also a total of nine deaths reported in all the studies combined (since 1990s). However, most of these deaths occurred before the year of 2000 and they were attributed to transplantation techniques and patient selection methods. Over the years, researchers have been working hard to fine tune the techniques and made the procedure safer. But even now it is important for the patients to weigh the benefits and the risks before undergoing the procedure.

That’s why neurologists and stem cell scientists do not currently recommend  blood stem cell transplants as the top-of-the-line treatment option for most MS patients. Other types of stem cells are being investigated for their potential in deriving oligodendrocytes and nerve cells to re-myelinate and repair the damaged ones. However, they are still in development and have not reached a clinical trial in people.

At the moment, many stem cell treatment approaches are all at the experimental level and more research is needed to completely prove them to be safe and effective. There are many trusted sources to get information from and the international society for stem cell research (ISSCR) has produced a great nine step guideline for patients and family members considering stem cell treatments. Also the national MS society website is a great resource for learning more about Multiple Sclerosis, including participating in clinical trial studies.


Hamideh Emrani

Hamideh Emrani is a science and technology communicator in Toronto, Canada. She is a graduate of UC Berkeley and has a Masters degree from the University of Toronto. You can follow Hamideh on Twitter.

Stories that caught our eye: stem cell transplants help put MS in remission; unlocking the cause of autism; and a day to discover what stem cells are all about

multiple-sclerosis

Motor neurons

Stem cell transplants help put MS in remission: A combination of high dose immunosuppressive therapy and transplant of a person’s own blood stem cells seems to be a powerful tool in helping people with relapsing-remitting multiple sclerosis (RRMS) go into sustained remission.

Multiple sclerosis (MS) is an autoimmune disorder where the body’s own immune system attacks the brain and spinal cord, causing a wide variety of symptoms including overwhelming fatigue, blurred vision and mobility problems. RRMS is the most common form of MS, affecting up to 85 percent of people, and is characterized by attacks followed by periods of remission.

The HALT-MS trial, which was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), took the patient’s own blood stem cells, gave the individual chemotherapy to deplete their immune system, then returned the blood stem cells to the patient. The stem cells created a new blood supply and seemed to help repair the immune system.

Five years after the treatment, most of the patients were still in remission, despite not taking any medications for MS. Some people even recovered some mobility or other capabilities that they had lost due to the disease.

In a news release, Dr. Anthony Fauci, Director of NIAID, said anything that holds the disease at bay and helps people avoid taking medications is important:

“These extended findings suggest that one-time treatment with HDIT/HCT may be substantially more effective than long-term treatment with the best available medications for people with a certain type of MS. These encouraging results support the development of a large, randomized trial to directly compare HDIT/HCT to standard of care for this often-debilitating disease.”

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Scripps Research Institute

Using stem cells to model brain development disorders. (Karen Ring) CIRM-funded scientists from the Scripps Research Institute are interested in understanding how the brain develops and what goes wrong to cause intellectual disabilities like Fragile X syndrome, a genetic disease that is a common cause of autism spectrum disorder.

Because studying developmental disorders in humans is very difficult, the Scripps team turned to stem cell models for answers. This week, in the journal Brain, they published a breakthrough in our understanding of the early stages of brain development. They took induced pluripotent stem cells (iPSCs), made from cells from Fragile X syndrome patients, and turned these cells into brain cells called neurons in a cell culture dish.

They noticed an obvious difference between Fragile X patient iPSCs and healthy iPSCs: the patient stem cells took longer to develop into neurons, a result that suggests a similar delay in fetal brain development. The neurons from Fragile X patients also had difficulty forming synaptic connections, which are bridges that allow for information to pass from one neuron to another.

Scripps Research professor Jeanne Loring said that their findings could help to identify new drug therapies to treat Fragile X syndrome. She explained in a press release;

“We’re the first to see that these changes happen very early in brain development. This may be the only way we’ll be able to identify possible drug treatments to minimize the effects of the disorder.”

Looking ahead, Loring and her team will apply their stem cell model to other developmental diseases. She said, “Now we have the tools to ask the questions to advance people’s health.”

A Day to Discover What Stem Cells Are All about.  (Karen Ring) Everyone is familiar with the word stem cells, but do they really know what these cells are and what they are capable of? Scientists are finding creative ways to educate the public and students about the power of stem cells and stem cell research. A great example is the University of Southern California (USC), which is hosting a Stem Cell Day of Discovery to educate middle and high school students and their families about stem cell research.

The event is this Saturday at the USC Health Sciences Campus and will feature science talks, lab tours, hands-on experiments, stem cell lab video games, and a resource fair. It’s a wonderful opportunity for families to engage in science and also to expose young students to science in a fun and engaging way.

Interest in Stem Cell Day has been so high that the event has already sold out. But don’t worry, there will be another stem cell day next year. And for those of you who don’t live in Southern California, mark your calendars for the 2017 Stem Cell Awareness Day on Wednesday, October 11th. There will be stem cell education events all over California and in other parts of the country during that week in honor of this important day.