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.
The California Institute for Regenerative Medicine has invested more than $180 million in more than 80 different projects, including four clinical trials, targeting heart disease.
Every year millions of Americans suffer damage to their cartilage, either in their knee or other joints, that can eventually lead to osteoarthritis, pain and immobility. Today the governing Board of the California Institute for Regenerative Medicine (CIRM) approved two projects targeting repair of damaged cartilage.
The projects were among 17 approved by CIRM as part of the DISC2 Quest Discovery Program. The program promotes 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.
Dr. Darryl D’Lima and his team at Scripps Health were awarded $1,620,645 to find a way to repair a torn meniscus. Every year around 750,000 Americans experience a tear in their meniscus, the cartilage cushion that prevents the bones in the knee grinding against each other. These injuries accelerate the early development of osteoarthritis, for which there is no effective treatment other than total joint replacement, which is a major operation. There are significant socioeconomic benefits to preventing disabling osteoarthritis. The reductions in healthcare costs are also likely to be significant.
The team will use stem cells to produce meniscal cells in the lab. Those are then seeded onto a scaffold made from collagen fibers to create tissue that resembles the knee meniscus. The goal is to show that, when placed in the knee joint, this can help regenerate and repair the damaged tissue.
This research is based on an earlier project that CIRM funded. It highlights our commitment to helping good science progress, hopefully from the bench to the bedside where it can help patients.
Dr. Kevin Stone: Photo courtesy Stone Research Foundation
Dr. Kevin Stone and his team at The Stone Research Foundation for Sports Medicine and Arthritis were awarded $1,316,215 to develop an approach to treat and repair damaged cartilage using a patient’s own stem cells.
They are using a paste combining the patient’s own articular tissue as well as Mesenchymal Stem Cells (MSC) from their bone marrow. This mixture is combined with an adhesive hydrogel to form a graft that is designed to support cartilage growth and can also stick to surfaces without the need for glue. This paste will be used to augment the use of a microfracture technique, where micro-drilling of the bone underneath the cartilage tear brings MSCs and other cells to the fracture site. The hope is this two-pronged approach will produce an effective and functional stem cell-based cartilage repair procedure.
If effective this could produce a minimally invasive, low cost, one-step solution to help people with cartilage injuries and arthritis.
The full list of DISC2 grantees is:
Application
Title
Principal Investigator and Institution
Amount
DISC2-13212
Preclinical development of an exhaustion-resistant CAR-T stem cell for cancer immunotherapy
Ansuman Satpathy – Stanford University
$ 1,420,200
DISC2-13051
Generating deeper and more durable BCMA CAR T cell responses in Multiple Myeloma through non-viral knockin/knockout multiplexed genome engineering
Julia Carnevale – UC San Francisco
$ 1,463,368
DISC2-13020
Injectable, autologous iPSC-based therapy for spinal cord injury
Sarah Heilshorn – Stanford University
$789,000
DISC2-13009
New noncoding RNA chemical entity for heart failure with preserved ejection fraction.
Eduardo Marban – Cedars-Sinai Medical Center
$1,397,412
DISC2-13232
Modulation of oral epithelium stem cells by RSpo1 for the prevention and treatment of oral mucositis
Jeffrey Linhardt – Intact Therapeutics Inc.
$942,050
DISC2-13077
Transplantation of genetically corrected iPSC-microglia for the treatment of Sanfilippo Syndrome (MPSIIIA)
Dilated cardiomyopathy (DCM), a condition where the muscles of the heart are weak and can lead to heart failure, is considered rare in children. However, because the symptoms are not always easy to recognize the condition can go unnoticed for many years, and in severe cases can damage the heart irreparably. In that case the child’s only option is a heart transplant, and a lack of organ donors means that is not always available.
Now, new research out of Japan – published in the journal Science Translation Medicine – could lead the way to new treatments to help children avoid the need for a transplant.
In the study, researchers at Okayama University used heart stem cells called cardiosphere-derived cells (CDCs) to try and repair the damage caused by DCM.
In a news release, lead researcher Professor Hidemasa Oh, says previous work has shown that because CDCs have the ability to turn into heart tissue they have the potential of reversing damage, but it’s not clear if this would work in children.
“I have been working on cardiac regeneration therapy since 2001. In this study, my team and I assessed the safety and efficacy of using CDCs to treat DCM in children.”
Tests in animal models with DCM showed that the CDCs resulted in a thickening of the heart muscle leading to increased blood flow around the body. This increased blood supply helped repair damaged tissue. Based on this trial the researcher determined what might be a suitable dose of CDCs for children with DCM and were granted permission to carry out a Phase 1 clinical trial.
Five young patients were treated and the results were cautiously encouraging. After a year none of the patients had experienced any severe side effects, but all had indications of improved heart function.
The study also gave the researchers some strong clues as to how the therapy seem to work. They found that when the CDCs were transplanted into the patient they secreted exosomes, which play an important role in cells communicating with one another. These exosomes then helped create a series of actions within the body; they blocked further damage to the heart tissue and they also helped kickstart the repair process.
The Okayama team are now hoping to carry out a Phase 2 clinical trial with more patients. Ultimately, they hope to be able to see if this approach could help prevent the need for a heart transplant in children, and even adults.
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.”
Immune fluorescence of HIP cardiomyocytes in a dish; Photo courtesy of UCSF
Transplanting cells or an entire organ from one person to another can be lifesaving but it comes with a cost. To avoid the recipient’s body rejecting the cells or organ the patient has to be given powerful immunosuppressive medications. Those medications weaken the immune system and increase the risk of infections. But now a team at the University of California San Francisco (UCSF) have used a new kind of stem cell to find a way around that problem.
The cells are called HIP cells and they are a specially engineered form of induced pluripotent stem cell (iPSC). Those are cells that can be turned into any kind of cell in the body. These have been gene edited to make them a kind of “universal stem cell” meaning they are not recognized by the immune system and so won’t be rejected by the body.
The UCSF team tested these cells by transplanting them into three different kinds of mice that had a major disease; peripheral artery disease; chronic obstructive pulmonary disease; and heart failure.
The results, published in the journal Proceedings of the National Academy of Science, showed that the cells could help reduce the incidence of peripheral artery disease in the mice’s back legs, prevent the development of a specific form of lung disease, and reduce the risk of heart failure after a heart attack.
In a news release, Dr. Tobias Deuse, the first author of the study, says this has great potential for people. “We showed that immune-engineered HIP cells reliably evade immune rejection in mice with different tissue types, a situation similar to the transplantation between unrelated human individuals. This immune evasion was maintained in diseased tissue and tissue with poor blood supply without the use of any immunosuppressive drugs.”
Deuse says if this does work in people it may not only be of great medical value, it may also come with a decent price tag, which could be particularly important for diseases that affect millions worldwide.
“In order for a therapeutic to have a broad impact, it needs to be affordable. That’s why we focus so much on immune-engineering and the development of universal cells. Once the costs come down, the access for all patients in need increases.”
Every so often you hear a story and your first reaction is “oh, I have to share this with someone, anyone, everyone.” That’s what happened to me the other day.
I was talking with Kristin MacDonald, an amazing woman, a fierce patient advocate and someone who took part in a CIRM-funded clinical trial to treat retinitis pigmentosa (RP). The disease had destroyed Kristin’s vision and she was hoping the therapy, pioneered by jCyte, would help her. Kristin, being a bit of a pioneer herself, was the first person to test the therapy in the U.S.
Anyway, Kristin was doing a Zoom presentation and wanted to look her best so she asked a friend to come over and do her hair and makeup. The woman she asked, was Rosie Barrero, another patient in that RP clinical trial. Not so very long ago Rosie was legally blind. Now, here she was helping do her friend’s hair and makeup. And doing it beautifully too.
That’s when you know the treatment works. At least for Rosie.
There are many other stories to be heard – from patients and patient advocates, from researchers who develop therapies to the doctors who deliver them. – at our CIRM 2020 Grantee Meeting on next Monday September 14th Tuesday & September 15th.
It’s two full days of presentations and discussions on everything from heart disease and cancer, to COVID-19, Alzheimer’s, Parkinson’s and spina bifida. Here’s a link to the Eventbrite page where you can find out more about the event and also register to be part of it.
Like pretty much everything these days it’s a virtual event so you’ll be able to join in from the comfort of your kitchen, living room, even the backyard.
And it’s free!
You can join us for all two days or just one session on one day. The choice is yours. And feel free to tell your friends or anyone else you think might be interested.
It’s not often you get a chance to hear some of the brightest minds around talk about their stem cell research and what it could mean for you, me and everyone else. That’s why we’re delighted to be bringing some of the sharpest tools in the stem cell shed together in one – virtual – place for our CIRM 2020 Grantee Meeting.
The event is Monday September 14th and Tuesday September 15th. It’s open to anyone who wants to attend and, of course, it’s all being held online so you can watch from the comfort of your own living room, or garden, or wherever you like. And, of course, it’s free.
Dr. Daniela Bota, UC Irvine
The list of speakers is a Who’s Who of researchers that CIRM has funded and who also happen to be among the leaders in the field. Not surprising as California is a global center for regenerative medicine. And you will of course be able to post questions for them to answer.
Dr. Deepak Srivastava, Gladstone Institutes
The key speakers include:
Larry Goldstein: the founder and director of the UCSD Stem Cell Program talking about Alzheimer’s research
Irv Weissman: Stanford University talking about anti-cancer therapies
Daniela Bota: UC Irvine talking about COVID-19 research
Deepak Srivastava: Gladsone Institutes, talking about heart stem cells
Other topics include the latest stem cell approaches to COVID-19, spinal cord injury, blindness, Parkinson’s disease, immune disorders, spina bifida and other pediatric disorders.
You can choose one topic or come both days for all the sessions. To see the agenda for each day click here. Just one side note, this is still a work in progress so some of the sessions have not been finalized yet.
And when you are ready to register go to our Eventbrite page. It’s simple, it’s fast and it will guarantee you’ll be able to be part of this event.
In these uncertain times, we often look to our top scientists for answers as well as potential solutions. But where does one begin to try and solve a problem of this magnitude? The first logical step is building on the supplies currently available, the work already accomplished, and the knowledge acquired.
This is the approach that the Gladstone Institutes in San Francisco is taking. Various scientists at this institution have shifted their current operations towards helping with the current coronavirus pandemic. These efforts have focused on helping with diagnostics, treatment, and prevention of COVID-19.
Diagnostics
Dr. Jennifer Doudna and Dr. Melanie Ott are collaborating in order to develop an effective method to rapidly diagnose those with COVID-19. Dr. Doudna’s work has focused on CRISPR technology, which we have talked about in detail in a previous blog post, while Dr. Ott has focused on studying viruses. By combining their expertises, these two scientists hope to develop a diagnostic tool capable of delivering rapid results and usable in areas such as airports, ports of entry, and remote communities.
Treatment
Dr. Nevan Krogan has discovered all of the human host cell proteins that COVID-19 interacts with to hijack the cell’s machinery. These proteins serve as new targets for potential drug therapies.
Since the high fatality rate of the virus is driven by lung and heart failure, Dr. Ott, Dr. Bruce Conklin, and Dr. Todd McDevitt will test effects of the virus and potential drug therapies in human lung organoids and human heart cells, both developed from human stem cells.
Dr. Warner Greene, who also focuses on the study of viruses, is screening a variety of FDA-approved drugs to identify those that could be rapidly repurposed as a treatment for COVID-19 patients or even as a preventive for high risk-groups.
Prevention
Dr. Leor Weinberger has developed a new approach to fight the spread of viruses. It is called therapeutic interfering particles (TIPs) and could be an alternative to a vaccine. TIPs are defective virus fragments that mimic the virus but are not able to replicate. They combat the virus by hijacking the cell machinery to transform virus-infected cells into factories that produce TIPS, amplifying the effect of TIPs in stopping the spread of virus. TIPs targeting COVID-19 would transmit along the same paths as the virus itself, and thus provide protection to even the most vulnerable populations.
You can read more about these groundbreaking projects in the news release linked here.
Last week’s news headlines were dominated by one big story, the use of a stem cell transplant to effectively cure a person of HIV. But there were other stories that, while not quite as striking, did also highlight how the field is advancing.
A new way to boost brain cells
(in mice!)
It’s hard to fix
something if you don’t really know what’s wrong in the first place. It would be
like trying to determine why a car is not working just by looking at the hood
and not looking inside at the engine. The human brain is far more complex than
a car so trying to determine what’s going wrong is infinitely more challenging.
But a new study could help give us a new option.
Researchers in
Luxembourg and Germany have developed a new computer model for what’s happening
inside the brain, identifying what cells are not operating properly, and fixing
them.
Antonio del Sol, one
of the lead authors of the study – published in the journal Cell
– says their new model allows them to identify which stem cells are active and
ready to divide, or dormant.
“Our results constitute an important
step towards the implementation of stem cell-based therapies, for instance for
neurodegenerative diseases. We were able to show that, with computational
models, it is possible to identify the essential features that are
characteristic of a specific state of stem cells.”
The work, done in
mice, identified a protein that helped keep brain stem cells inactive in older
animals. By blocking this protein they were able to help “wake up” those stem
cells so they could divide and proliferate and help regenerate the aging brain.
And if it works in
mice it must work in people right? Well, that’s what they hope to see next.
Deeper understanding of fetal development
According to the Mayo
Clinic between 10 and 20 percent of known pregnancies end in
miscarriage (though they admit the real number may be even higher) and our lack
of understanding of fetal development makes it hard to understand why. A new
study reveals a previously unknown step in this development that could help
provide some answers and, hopefully, lead to ways to prevent miscarriages.
Researchers at the
Karolinska Institute in Sweden used genetic sequencing to follow the
development stages of mice embryos. By sorting those different sequences into a
kind of blueprint for what’s happening at every stage of development they were
able to identify a previously unknown phase. It’s the time between when the
embryo attaches to the uterus and when it begins to turn these embryonic stem
cells into identifiable parts of the body.
Qiaolin Deng, Karolinska Institute
Lead researcher Qiaolin Deng says this finding provides vital new evidence.
“Being able to follow the
differentiation process of every cell is the Holy Grail of developmental
biology. Knowledge of the events and factors that govern the development of the
early embryo is indispensable for understanding miscarriages and congenital
disease. Around three in every 100 babies are born with fetal malformation
caused by faulty cellular differentiation.”
The study is
published in the journal Cell
Reports.
Could a new drug discovery
reduce damage from a heart attack?
Every 40 seconds someone in the US has a heart attack. For many it is fatal but even for those who survive it can lead to long-term damage to the heart that ultimately leads to heart failure. Now British researchers think they may have found a way to reduce that likelihood.
Using stem cells to
create human heart muscle tissue in the lab, they identified a protein that is
activated after a heart attack or when exposed to stress chemicals. They then
identified a drug that can block that protein and, when tested in mice that had
experienced a heart attack, they found it could reduce damage to the heart
muscle by around 60 percent.
Prof Michael Schneider,
the lead researcher on the study, published in Cell
Stem Cell, said this could be a game changer.
“There are no
existing therapies that directly address the problem of muscle cell death and
this would be a revolution in the treatment of heart attacks. One reason why
many heart drugs have failed in clinical trials may be that they have not been
tested in human cells before the clinic. Using both human cells and animals
allows us to be more confident about the molecules we take forward.”
Scientists from the Gladstone Institutes have done it again. They’ve made a better and faster way of generating healthy heart tissue in mice with damaged hearts. With further advancements, their findings could potentially be translated into a new way of treating heart failure in patients.
Previously, the Gladstone team discovered that they could transform scar tissue in the damaged hearts of mice into healthy, beating heart muscle cells by a process called direct reprogramming. The team found that turning on three transcription factors, Gata4, Mef2c and Tbx5 (collectively called GMT), in the damaged hearts of mice activated heart genes that turned scar tissue cells, also known as cardiac fibroblasts, into beating heart cells or cardiomyocytes.
Their GMT direct cardiac reprogramming technology was only able to turn 10 percent of cardiac fibroblasts into cardiomyocytes in mice over the period of six to eight week. In their new CIRM-funded study published in Circulation, they improved upon their original reprogramming method by identifying two chemicals that improved the efficiency of making new heart cells. Not only were they able to create eight times the number of beating cardiomyocytes from mouse cardiac fibroblasts, but they were also able to speed up the reprogramming process to a period of just one week.
To find these chemicals, they screened a library of 5,500 small molecules. The chemicals that looked most promising for cardiac reprogramming were inhibitors of the TGF-β and WNT signaling pathways. The importance of these chemicals was explained in a Gladstone news release:
“The first chemical inhibits a growth factor that helps cells grow and divide and is important for repairing tissue after injury. The second chemical inhibits an important pathway that regulates heart development. By combining the two chemicals with GMT, the researchers successfully regenerated heart muscle and greatly improved heart function in mice that had suffered a heart attack.”
Senior author on the study, Deepak Srivastava, further explained:
“While our original process for direct cardiac reprogramming with GMT has been promising, it could be more efficient. With our screen, we discovered that chemically inhibiting two biological pathways active in embryonic formation improves the speed, quantity, and quality of the heart cells produced from our original process.”
Encouraged by their studies in mice, the scientists also tested their new and improved direct reprogramming method on human cells. Previously they found that while the same GMT transcription factors could reprogram human cardiac fibroblasts into cardiomyocytes, a combination of seven factors was required to make quality cardiomyocytes comparable to those seen in mice. But with the addition of the two inhibitors, they were able to reduce the number of reprogramming factors from seven to four, which included the GMT factors and one additional factor called Myocardin. These four factors plus the two chemical inhibitors were capable of reprograming human cardiac fibroblasts into beating heart cells.
With heart failure affecting more than 20 million people globally, the need for new therapies that can regenerate the heart is pressing. The Gladstone team is hoping to advance their research to a point where it could be tested in human patients with heart failure. First author on the study, Tamer Mohamed, concluded:
“Heart failure afflicts many people worldwide, and we still do not have an effective treatment for patients suffering from this disease. With our enhanced method of direct cardiac reprogramming, we hope to combine gene therapy with drugs to create better treatments for patients suffering from this devastating disease.”
Tamer Mohamed and Deepak Srivastava. Photo courtesy of Chris Goodfellow, Gladstone Institutes
The Stem Cellar 