myelin

CIRM funded stem cell therapy could one day help stroke and dementia patients

/ Yimy Villa / 3 Comments
Image Description: Microscope images showing brain tissue that has been damaged by white matter stroke (left) and then repaired by the new glial cell therapy (right). Myelin (seen in red), is a substance that protects the connections between neurons and is lost due to white matter stroke. As seen at right, the glial cell therapy (green) restores lost myelin and improves connections in the brain. | Credit: UCLA Broad Stem Cell Research Center/Science Translational Medicine

Dementia is a general term that describes problems with memory, attention, communication, and physical coordination. One of the major causes of dementia is white matter strokes, which occurs when multiple strokes (i.e. a lack of blood supply to the brain) gradually damages the connecting areas of the brain (i.e. white matter).

Currently, there are no therapies capable of stopping the progression of white matter strokes or enhancing the brain’s limited ability to repair itself after they occur.

However, a CIRM-funded study ($2.09 million) conducted by S. Thomas Carmichael, M.D., Ph.D. and his team at UCLA showed that a one-time injection of an experimental stem cell therapy can repair brain damage and improve memory function in mice with conditions that mimic human strokes and dementia.

The therapy consists of glial cells, which are a special type of cell present in the central nervous system that surround and protect neurons. The glial cells are derived from induced pluripotent stem cells (iPSCS), stem cells that are derived from skin or blood cells through the process of reprogramming and have the ability to become virtually any type of cell.

Dr. Carmichael and his team injected the newly developed glial cells into the brains of mice that had damage similar to humans in the early to middle stages of dementia. The team found that the cell therapy traveled to the damaged areas of the brain and secreted chemicals that stimulated the brain’s own stem cells to start repairing the damage. This not only limited the progression of damage, but also enhanced the formation of new neural connections and increased the production of myelin, a fatty substance that covers and protects neurons.

In a press release from UCLA, Francesca Bosetti, Ph.D., Pharm.D., Program Director at the National Institute of Neurological Disorders and Strokes, was optimistic about what these findings could mean for patients with strokes or dementia.

“These preliminary results suggest that glial cell-based therapies may one day help combat the white matter damage that many stroke and vascular dementia patients suffer every year.”

Another interesting finding from this study is that even if the injected cells were eliminated a few months after they had been transplanted, the mice’s recovery was unaffected. The researchers believe that this indicates that the therapy primarily serves as a way to stimulate the brain’s own repair process.

In the same press release, Dr. Carmichael elaborates on this concept.

“Because the cell therapy is not directly repairing the brain, you don’t need to rely on the transplanted cells to persist in order for the treatment to be successful.”

The team is now conducting the additional studies necessary to apply to the Food and Drug Administration (FDA) for permission to test the therapy in a clinical trial in humans. If the therapy is shown to be safe and effective through clinical trials in humans, the team envisions that it could be used at hospitals as a one-time treatment for people with early signs of white matter stroke.

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

Rare Disease, Type 1 Diabetes, and Heart Function: Breakthroughs for Three CIRM-Funded Studies

/ Yimy Villa / Leave a comment

This past week, there has been a lot of mention of CIRM funded studies that really highlight the importance of the work we support and the different disease areas we make an impact on. This includes important research related to rare disease, Type 1 Diabetes (T1D), and heart function. Below is a summary of the promising CIRM-funded studies released this past week for each one of these areas.

Rare Disease

Comparison of normal (left) and Pelizaeus-Merzbacher disease (PMD) brains (right) at age 2. 

Pelizaeus-Merzbacher disease (PMD) is a rare genetic condition affecting boys. It can be fatal before 10 years of age and symptoms of the disease include weakness and breathing difficulties. PMD is caused by a disruption in the formation of myelin, a type of insulation around nerve fibers that allows electrical signals in the brain to travel quickly. Without proper signaling, the brain has difficulty communicating with the rest of the body. Despite knowing what causes PMD, it has been difficult to understand why there is a disruption of myelin formation in the first place.

However, in a CIRM-funded study, Dr. David Rowitch, alongside a team of researchers at UCSF, Stanford, and the University of Cambridge, has been developing potential stem cell therapies to reverse or prevent myelin loss in PMD patients.

Two new studies, of which Dr. Rowitch is the primary author, published in Cell Stem Cell, and Stem Cell Reports, respectively report promising progress in using stem cells derived from patients to identify novel PMD drugs and in efforts to treat the disease by directly transplanting neural stem cells into patients’ brains. 

In a UCSF press release, Dr. Rowitch talks about the implications of his findings, stating that,

“Together these studies advance the field of stem cell medicine by showing how a drug therapy could benefit myelination and also that neural stem cell transplantation directly into the brains of boys with PMD is safe.”

Type 1 Diabetes

Viacyte, a company that is developing a treatment for Type 1 Diabetes (T1D), announced in a press release that the company presented preliminary data from a CIRM-funded clinical trial that shows promising results. T1D is an autoimmune disease in which the body’s own immune system destroys the cells in the pancreas that make insulin, a hormone that enables our bodies to break down sugar in the blood. CIRM has been funding ViaCyte from it’s very earliest days, investing more than $72 million into the company.

The study uses pancreatic precursor cells, which are derived from stem cells, and implants them into patients in an encapsulation device. The preliminary data showed that the implanted cells, when effectively engrafted, are capable of producing circulating C-peptide, a biomarker for insulin, in patients with T1D. Optimization of the procedure needs to be explored further.

“This is encouraging news,” said Dr. Maria Millan, President and CEO of CIRM. “We are very aware of the major biologic and technical challenges of an implantable cell therapy for Type 1 Diabetes, so this early biologic signal in patients is an important step for the Viacyte program.”

Heart Function

Although various genome studies have uncovered over 500 genetic variants linked to heart function, such as irregular heart rhythms and heart rate, it has been unclear exactly how they influence heart function.

In a CIRM-funded study, Dr. Kelly Frazer and her team at UCSD studied this link further by deriving heart cells from induced pluripotent stem cells. These stem cells were in turn derived from skin samples of seven family members. After conducting extensive genome-wide analysis, the team discovered that many of these genetic variations influence heart function because they affect the binding of a protein called NKX2-5.

In a press release by UCSD, Dr. Frazer elaborated on the important role this protein plays by stating that,

“NKX2-5 binds to many different places in the genome near heart genes, so it makes sense that variation in the factor itself or the DNA to which it binds would affect that function. As a result, we are finding that multiple heart-related traits can share a common mechanism — in this case, differential binding of NKX2-5 due to DNA variants.”

The full results of this study were published in Nature Genetics.

Old cells need not apply: how a stem cell’s age can impact potential treatments

/ Yimy Villa / 2 Comments

Getting older is a normal, at times existential, part of life. The outward changes are abundant and noticeable: thinning of the hair, greying of the hair, and added lines to the face. There are also changes that happen that are not so abundantly clear in terms of outward appearance: slowing of healing time for bone fractures and a gradual loss of bodily function. The process of aging poses one very fundamental question — Could understanding how stem cells age lead to a greater understanding of how diseases develop? More importantly, could it guide the approach towards developing potential treatments? Two different studies highlight the importance of evaluating and understanding the process of aging in stem cells.

The first study, led by Dr. Michael Fehlings, looked at the impact of donor age in relation to stem cell therapies for spinal cord injuries (SCI). Dr. Fehlings, with a team of investigators from the University of Toronto and Krembil Research Institute, University Health Network, used an adult rat model to look at how cells derived from young vs. old stem cells affected tissue regeneration and recovery after a spinal cord injury.

Some rats with a SCI received cells derived from stem cells in the umbilical cord blood, which are considered “young” stem cells. The other rats with a SCI received cells derived from stem cells in the bone marrow, which are considered “old” stem cells. The results showed, ten weeks after treatment, that rats given the “young” stem cells exhibited a better recovery in comparison to those given the “old” stem cells.

In a press release, Dr. Fehlings stated that,

“Together, this minimally invasive and effective approach to cell therapy has significant implications on the treatment of traumatic cervical SCI and other central nervous system injuries. These results can help to optimize cell treatment strategies for eventual use in humans.”

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

The second, separate study, conducted by Dr. Stephen Crocker at UConn Health, looks at brain stem cells in people with multiple sclerosis (MS), a neurodegenerative disease caused by the inflammation and destruction of the insulation around the nerves, also known as myelin. Problems with insulation around the nerves can prevent or complicate the electrical signals sent from the brain to the body, which can lead to problems with walking or other bodily movements.

Drawing of a healthy nerve cell with insulation (left) and one damaged by multiple sclerosis (right). Image courtesy of Shutterstock

Dr. Crocker and his team found that brain stem cells in patients with MS look much older when compared to the brain stem cells of a healthy person around the same age. Not only did these brain stem cells look older, but they also acted much older in comparison to their healthy counterparts. It was also discovered that the brain stem cells of MS patients were producing a protein that prevented the development of insulation around the nerves. What is more remarkable is that Dr. Crocker and his team demonstrated that when this protein is blocked, the insulation around the nerves develops normally again.

In a press release, Dr. Valentina Fossati, a neurologist at the New York Stem Cell Foundation who evaluated these brain stem cells, stated that,

“We are excited that the study of human stem cells in a dish led to the discovery of a new disease mechanism that could be targeted in much-needed therapeutics for progressive MS patients.”

The complete study was published in the Proceedings of the National Academy of Sciences (PNAS).

Adding the missing piece: “mini-brain” method now includes important cell type

/ Todd Dubnicoff / Leave a comment

Although studying brain cells as a single layer in petri dishes has led to countless ground-breaking discoveries in neurobiology, it’s pretty intuitive that a two-dimensional “lawn” of cells doesn’t fully represent what’s happening in our complex, three-dimensional brain.

In the past few years, researchers have really upped their game with the development of brain organoids, self-organizing balls of cells that more accurately mimic the function of particular parts of the brain’s anatomy. Generating brain organoids from induced pluripotent stem cells (iPSCs) derived from patient skin samples is revolutionizing the study of brain diseases (see our previous blog stories here, here and here.)

Copy of oligocortical_spheroids_in_wells

Tiny brain organoid spheres in petri dishes. Image: Case Western

This week, Case Western researchers reported in Nature Methods about an important improvement to the organoid technique that includes all the major cell types found in the cerebral cortex, the outer layer of the brain responsible for critical functions like our memory, language, and consciousness. The new method incorporates oliogodendrocytes, a cell type previously missing from the “mini-cortexes”. Oliogodendrocytes make myelin, a mix of proteins and fats that form a protective wrapping around nerve connections. Not unlike the plastic coating around an electrical wire, myelin is crucial for a neuron’s ability to send and receive signals from other neurons. Without the myelin, those signals short-circuit. It’s this breakdown in function that causes paralysis in multiple sclerosis patients and spinal cord injury victims.

With these new and improved organoids in hand, the researchers can now look for novel therapeutic strategies that could boost myelin production. In fact, the researchers generated brain organoids using iPSCs derived from patients with Pelizaeus-Merzbacher disease, a rare but fatal inherited myelin disorder. Each patient had a different mutation and an analysis of each organoid pointed to potential targets for drug treatments.

Dr. Mayur Madhavan, a co-first author on the study, explained the big picture implications of their new method in a press release:

Mayur Madhavan, PhD

“These organoids provide a way to predict the safety and efficacy of new myelin therapeutics on human brain-like tissue in the laboratory prior to clinical testing in humans.”

 

 

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

/ Todd Dubnicoff / 6 Comments

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

Picture1

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

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

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

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

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

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

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

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

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

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

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

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

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

Slide13 cropped

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

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

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

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