Despite advances in treatments in recent years heart disease remains the leading cause of death in the US. It accounts for one in three deaths in this country, and many people are not even aware they have a problem until they have a heart attack.
One of the early warning signs of danger is a heart arrhythmia; that’s when electrical signals that control the hearts beating don’t work properly and can result in the heart beating too fast, too slow, or irregularly. However, predicting who is at risk of these arrhythmias is difficult. Now new research may have found a way to change that.
A research team at the Institute of Molecular and Cell Biology in Singapore combined stem cells with machine learning, and developed a way to predict arrhythmias, with a high degree of accuracy.
The team used stem cells to create different batches of cardiomyocytes or heart muscle cells. Some of these batches were healthy heart cells, but some had arrhythmias caused by different problems such as a genetic disorder or drug induced.
They then trained a machine learning program to use videos to scan the 3,000 different groups of cells. By studying the different beating patterns of the cells, and then using the levels of calcium in the cells, the machine was able to predict, with 90 percent accuracy, which cells were most likely to experience arrhythmias.
The researchers say their approach is faster, simpler and more accurate than current methods of trying to predict who is at risk for arrhythmias and could have a big impact on our ability to intervene before the individual suffers a fatal heart attack.
While stem cell and gene therapy research has advanced dramatically in recent years, there are still many unknowns and many questions remaining about how best to use these approaches in developing therapies. That’s why the governing Board of the California Institute for Regenerative Medicine (CIRM) today approved investing almost $25 million in 19 projects in early stage or Discovery research.
The awards are from CIRM’s DISC2 Quest program, which supports the discovery of promising new stem cell-based and gene therapy technologies that could be translated to enable broad use and ultimately, improve patient care.
“Every therapy that helps save lives or change lives begins with a researcher asking a simple question, “What if?”, says Dr. Maria T. Millan, the President and CEO of CIRM. “Our Quest awards reflect the need to keep supporting early stage research, to gain a deeper understanding of stem cells work and how we can best tap into that potential to advance the field.”
Dr. Judy Shizuru at Stanford University was awarded $1.34 million to develop a safer, less-toxic form of bone marrow or hematopoietic stem cell transplant (HCT). HCT is the only proven cure for many forms of blood disorders that affect people of all ages, sexes, and races worldwide. However, current methods involve the use of chemotherapy or radiation to destroy the patient’s own unhealthy blood stem cells and make room for the new, healthy ones. This approach is toxic and complex and can only be performed by specialized teams in major medical centers, making access particularly difficult for poor and underserved communities.
Dr. Shizuru proposes developing an antibody that can direct the patient’s own immune cells to kill diseased blood stem cells. This would make stem cell transplant safer and more effective for the treatment of many life-threatening blood disorders, and more accessible for people in rural or remote parts of the country.
Dr. Lili Yang at UCLA was awarded $1.4 million to develop an off-the-shelf cell therapy for ovarian cancer, which causes more deaths than any other cancer of the female reproductive system.
Dr. Yang is using immune system cells, called invariant natural killer T cells (iNKT) to attack cancer cells. However, these iNKT cells are only found in small numbers in the blood so current approaches involve taking those cells from the patient and, in the lab, modifying them to increase their numbers and strength before transplanting them back into the patient. This is both time consuming and expensive, and the patient’s own iNKT cells may have been damaged by the cancer, reducing the likelihood of success.
In this new study Dr. Yang will use healthy donor cord blood cells and, through genetic engineering, turn them into the specific form of iNKT cell therapy targeting ovarian cancer. This DISC2 award will support the development of these cells and do the necessary testing and studies to advance it to the translational stage.
Timothy Hoey and Tenaya Therapeutics Inc. have been awarded $1.2 million to test a gene therapy approach to replace heart cells damaged by a heart attack.
Heart disease is the leading cause of death in the U.S. with the highest incidence among African Americans. It’s caused by damage or death of functional heart muscle cells, usually due to heart attack. Because these heart muscle cells are unable to regenerate the damage is permanent. Dr. Hoey’s team is developing a gene therapy that can be injected into patients and turn their cardiac fibroblasts, cells that can contribute to scar tissue, into functioning heart muscle cells, replacing those damaged by the heart attack.
Sometimes when I am giving public presentations people ask if stem cells are good for the face. I always say that if stem cells could help improve people’s faces would I look like this. It’s a line that gets a laugh but it’s also true. The ads you see touting stem cells as being beneficial for skin are all using plant stem cells. But now some new research has managed to turn back the clock for skin cells, and it might do a lot more than just help skin look younger.
Back in 2007 Japanese scientist Shinya Yamanaka discovered a way to turn ordinary skin cells back into an embryonic-like state, meaning those cells could then be turned into any other cell in the body. He called these cells induced pluripotent stem cells or iPSCs. Dr. Yamanaka was later awarded the Nobel Prize for Medicine for this work.
Using this work as their starting point, a team at Cambridge University in the UK, have developed a technique that can rewind the clock on skin cells but stop it less than a third of the way through, so they have made the cells younger but didn’t erase their identity as skin cells.
The study, published in the journal ELifeSciences, showed the researchers were able to make older skin cells 30 years younger. This wasn’t about restoring a sense of youthful beauty to the skin, instead it was about something far more important, restoring youthful function to the skin.
In a news release, Dr Diljeet Gill, a lead author on the study, said: “Our understanding of ageing on a molecular level has progressed over the last decade, giving rise to techniques that allow researchers to measure age-related biological changes in human cells. We were able to apply this to our experiment to determine the extent of reprogramming our new method achieved.”
The team proved the potential for their work using fibroblasts, the most common kind of cell found in connective tissues such as skin. Fibroblasts are important because they produce collagen which helps provide support and structure to tissues and also helps in healing wounds. When the researchers examined the rejuvenated skin cells they found they were producing more collagen than cells that had not been rejuvenated. They also saw signs that these rejuvenated cells could help heal wounds better than the old cells.
The researchers also noted that this approach had an effect on other genes linked to age-related conditions, such Alzheimer’s disease and the development of cataracts.
The researchers acknowledge that this is all very early on, but the fact that they were able to make the cells behave and act like younger cells, without losing their identity as skin cells, holds tremendous promise not just for conditions affecting the skin, but for regenerative medicine as a whole.
Dr. Diljeet concluded: “Our results represent a big step forward in our understanding of cell reprogramming. We have proved that cells can be rejuvenated without losing their function and that rejuvenation looks to restore some function to old cells. The fact that we also saw a reverse of ageing indicators in genes associated with diseases is particularly promising for the future of this work.”
In our recently launched 5-year Strategic Plan, the California Institute for Regenerative Medicine (CIRM) profiled two researchers who have leveraged CIRM funding to translate basic biological discoveries into potential real-world solutions for devastating diseases.
Dr. Joseph Wu is director of the Stanford Cardiovascular Institute and the recipient of several CIRM awards. Eleven of them to be exact! Over the past 10 years, Dr. Wu’s lab has extensively studied the application of induced pluripotent stem cells (iPSCs) for cardiovascular disease modeling, drug discovery, and regenerative medicine.
Dr. Wu’s extensive studies and findings have even led to a cancer vaccine technology that is now being developed by Khloris Biosciences, a biotechnology company spun out by his lab.
Through CIRM funding, Dr. Wu has developed a process to produce cardiomyocytes (cardiac muscle cells) derived from human embryonic stem cells for clinical use and in partnership with the agency. Dr. Wu is also the principal investigator in the first-in-US clinical trial for treating ischemic heart disease. His other CIRM-funded work has also led to the development of cardiomyocytes derived from human induced pluripotent stem cells for potential use as a patch.
Over at UCLA, Dr. Lili Yang and her lab team have generated invariant Natural Killer T cells (iNKT), a special kind of immune system cell with unique features that can more effectively attack tumor cells.
More recently, using stem cells from donor cord-blood and peripheral blood samples, Dr. Yang and her team of researchers were able to produce up to 300,000 doses of hematopoietic stem cell-engineered iNKT (HSC–iNKT) cells. The hope is that this new therapy could dramatically reduce the cost of producing immune cell products in the future.
Additionally, Dr. Yang and her team have used iNKT cells to develop both autologous (using the patient’s own cells), and off-the-shelf anti-cancer therapeutics (using donor cells), designed to target blood cell cancers.
The success of her work has led to the creation of a start-up company called Appia Bio. In collaboration with Kite Pharma, Appia Bio is planning on developing and commercializing the promising technology.
CIRM has been an avid supporter of Dr. Yang and Dr. Wu’s research because they pave the way for development of next-generation therapies. Through our new Strategic Plan, CIRM will continue to fund innovative research like theirs to accelerate world class science to deliver transformative regenerative medicine treatments in an equitable manner to a diverse California and the world.
In the world of scientific research, the people doing clinical trials tend to suck up all the oxygen in the room. They’re the stars, the ones who are bringing potential therapies to patients. However, there’s another group of researchers who toil away in the background, but who are equally deserving of praise and gratitude.
These are the scientists who do basic or discovery-level research. This is where all great therapies start. This is where a researcher gets an idea and tests it to see if it holds promise. A good idea and a scientist who asks a simple question, “I wonder if…..”
In our latest “Talking ‘Bout (re)Generation” podcast we talk to three researchers who are asking those questions and getting some truly encouraging answers. They are scientists at the Gladstone Institutes in San Francisco: one seasoned scientist and two young post-docs trying to make a name for themselves. And they might just have discovered a therapy that could help people battling Alzheimer’s disease.
Scientists at Gladstone Institutes have discovered how to grow a first-of-its-kind organoid—a three-dimensional, organ-like cluster of cells—that mimics how gut and heart tissues arise cooperatively from stem cells.
The study was supported by a grant from CIRM and the Gladstone BioFulcrum Heart Failure Research Program.
Gladstone Senior Investigator Todd McDevitt, PhD said this first-of-its-kind organoid could serve as a new tool for laboratory research and improve our understanding of how developing organs and tissues cooperate and instruct each other.
McDevitt’s team creates heart organoids from human induced pluripotent stem cells, coaxing them into becoming heart cells by growing them in various cocktails of nutrients and other naturally occurring substances. In this case, the scientists tried a different cocktail to potentially allow a greater variety of heart cells to form.
To their surprise, they found that the new cocktail led to organoids that contained not only heart, but also gut cells.
“We were intrigued because organoids normally develop into a single type of tissue—for example, heart tissue only,” says Ana Silva, PhD, a postdoctoral scholar in the McDevitt Lab and first author of the new study. “Here, we had both heart and gut tissues growing together in a controlled manner, much as they would in a normal embryo.”
The researchers also found that compared to conventional heart organoids, the new organoids resulted in much more complex and mature heart structures—including some resembling more mature-like blood vessels.
These organoids offer a promising new look into the relationship between developing tissues, which has so far relied on growing single-tissue organoids separately and then attempting to combine them. Not only that, the organoids could help clarify how the process of human development can go wrong and provide insight on congenital disorders like chronic atrial and intestinal dysrhythmias that are known to affect both heart and gut development.
“Once it became clear that the presence of the gut tissue contributed to the maturity of the heart tissue, we realized we had arrived at something new and special,” says McDevitt.
Taking even the most promising therapy and moving it out of the lab and into people is an incredibly complex process and usually requires a great team. Now, two great teams have paired up to do just that with a therapy for type 1 diabetes (T1D). ViaCyte and CRISPR Therapeutics have put their heads together and developed an approach that has just been given clearance by Health Canada to start a clinical trial.
Regular readers of this blog know that CIRM has been a big supporter of ViaCyte for many years, investing more than $72 million in nine different awards. They have developed an implantable device containing embryonic stem cells that develop into pancreatic progenitor cells, which are precursors to the islet cells destroyed by T1D. The hope is that when this device is transplanted under a patient’s skin, the progenitor cells will develop into mature insulin-secreting cells that can properly regulate the glucose levels in a patient’s blood.
One of the challenges in earlier testing was developing a cell-based therapy that could evade the immune system, so that people didn’t need to have their immune system suppressed to prevent it attacking and destroying the cells. This particular implantable version sprang out of an early stage award we made to ViaCyte (DISC2-10591). ViaCyte and CRISPR Therapeutics helped with the design of the therapeutic called VCTX210.
In a news release, Michael Yang, the President and CEO of ViaCyte, said getting approval for the trial was a major milestone: “Being first into the clinic with a gene-edited, immune-evasive cell therapy to treat patients with type 1 diabetes is breaking new ground as it sets a path to potentially broadening the treatable population by eliminating the need for immunosuppression with implanted cell therapies. This approach builds on previous accomplishments by both companies and represents a major step forward for the field as we strive to provide a functional cure for this devastating disease.”
The clinical trial, which will be carried out in Canada, is to test the safety of the therapy, whether it creates any kind of reaction after being implanted in the body, and how well it does in evading the patient’s immune system. In October our podcast – Talking ‘Bout (re)Generation – highlighted work in T1D and included an interview with Dr. Manasi Jaiman, ViaCyte’s Vice President for Clinical Development. Here’s an excerpt from that podcast.
A new therapeutic approach, supported by CIRM, that blocks the signals in the brain that can cause epilepsy has been given permission by the US Food and Drug Administration (FDA) to be tested in a clinical trial.
Nearly 3.5 million Americans suffer from some form of epilepsy. It can affect people in different ways from stiff muscles or staring spells, to violent shaking and loss of consciousness. The impact it has on people’s lives extends far beyond the condition itself. People who suffer from epilepsy experience a higher frequency of depression and other mood disorders, social isolation, challenges in school and with living independently, higher unemployment, limitations on driving, and higher risk of early death.
Medications can help control the seizures in some people, but around one-third of patients don’t respond to those drugs. The alternative is surgery, which is invasive and can cause damage to delicate brain tissue.
Now Neurona Therapeutics has developed an approach, called NRTX-1001, that turns stem cells into interneurons, a kind of nerve cell in the brain. These cells secrete chemical messengers, called GABA inhibitory neurotransmitters, that help rebalance the misfiring electrical signals in the brain and hopefully eliminate or reduce the seizures.
Cory Nicholas, PhD, Neuron’s Therapeutics co-founder and CEO, said getting the go-ahead from the FDA for a clinical trial is a key milestone for the company. “Neurona’s accomplishments are a testament to longstanding support from CIRM. CIRM has supported the NRTX-1001 program from bench to bedside, dating back to early research in the Neurona founders’ laboratories at the University of California, San Francisco to the recent IND-enabling studies conducted at Neurona. It’s an exciting time for the field of regenerative medicine and is gratifying to see the NRTX-1001 neuronal cell therapy now cleared by the FDA to enter clinical testing in people who have drug resistant temporal lobe epilepsy. We are thankful to CIRM for their support of this important work that has the potential to provide seizure-freedom for patients who currently have limited treatment options.”
In a news release Dr. Nicholas said the timing was perfect. “This milestone is especially rewarding and timely given that November is Epilepsy Awareness Month. NRTX-1001 is a new type of inhibitory cell therapy that is targeted to the focal seizure onset region in the brain and, in a single treatment, has the potential to significantly improve the lives of people living with focal epilepsy.”
In animal models NRTX-1001 produced freedom from seizures in more than two-thirds of the treated group, compared to just 5 percent of the untreated group. It also resulted in reduced tissue damage in the seizure-affected area of the brain.
The clinical trial will initially target people affected by mesial temporal lobe epilepsy (MTLE) where seizures often begin in a structure called the hippocampus. MTLE is the most common type of focal epilepsy.
CIRM has invested almost $6.67 million in funding three stages of this project, from the early Discovery work to this latest late-stage preclinical work, highlighting our commitment to doing all we can to advance the most promising science from the bench to the bedside.