There is still a lot that we don’t understand about SARS-CoV-2 (COVID-19), the new coronavirus that has caused a worldwide pandemic. Some patients that contract the virus experiences heart problems, but the reasons are not entirely clear. Pre-existing heart conditions or inflammation and oxygen deprivation that result from COVID-19 have all been implicated but more evidence needs to be collected.
To evaluate this, a joint study between Cedars-Sinai Board of Governors Regenerative Medicine Institute and the UCLA Broad Stem Cell Research Center used human induced pluripotent stem cells (iPSCs), a kind of stem cell that can become any kind of cell in the body and is usually made from skin cells. The iPSCS were converted into heart cells and infected with COVID-19 in order to study the effects of the virus.
The results of this study showed that the iPSC-derived heart cells are susceptible to COVID-19 infection and that the virus can quickly divide inside the heart cells. Furthermore, the infected heart cells showed changes in their ability to beat 72 hours after infection.
In a press release, Dr. Clive Svendsen, senior and co-corresponding author of the study and director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute, elaborated on the results.
“This viral pandemic is predominately defined by respiratory symptoms, but there are also cardiac complications, including arrhythmias, heart failure and viral myocarditis. While this could be the result of massive inflammation in response to the virus, our data suggest that the heart could also be directly affected by the virus in COVID-19.”
Although this study does not perfectly replicate the conditions inside the human body, the iPSC heart cells may also help identify and screen new potential drugs that could alleviate viral infection of the heart.
The research team has already found that treatment with an antibody called ACE2 was able to decrease viral replication on the iPSC heart cells.
In the same press release Dr. Arun Sharma, first author and another co-corresponding author of the study and a research fellow at the Cedars-Sinai Board of Governors Regenerative Medicine Institute, had this to say about the ACE2 antibody.
“By blocking the ACE2 protein with an antibody, the virus is not as easily able to bind to the ACE2 protein, and thus cannot easily enter the cell. This not only helps us understand the mechanisms of how this virus functions, but also suggests therapeutic approaches that could be used as a potential treatment for SARS-CoV-2 infection.”
The study’s third co-corresponding author was Dr. Vaithilingaraja Arumugaswami, an associate professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA and member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research.
The full results of this study were published in Cell Reports Medicine.
In late March the CIRM Board approved $5 million in emergency funding for COVID-19 research. The idea was to support great ideas from California’s researchers, some of which had already been tested for different conditions, and see if they could help in finding treatments or a vaccine for the coronavirus.
Less than a month later we were funding a clinical trial and two other projects, one that targeted a special kind of immune system cell that has the potential to fight the virus.
Researchers use stem cells to model the immune response to COVID-19
By Tiare Dunlap
Cities across the United States are opening back up, but we’re still a long way from making the COVID-19 pandemic history. To truly accomplish that, we need to have a vaccine that can stop the spread of infection.
But to develop an effective vaccine, we need to understand how the immune system responds to SARS-CoV-2, the virus that causes COVID-19.
Vaccines work by imitating infection. They expose a person’s immune system to a weakened version or component of the virus they are intended to protect against. This essentially prepares the immune system to fight the virus ahead of time, so that if a person is exposed to the real virus, their immune system can quickly recognize the enemy and fight the infection. Vaccines need to contain the right parts of the virus to provoke a strong immune response and create long-term protection.
Most of the vaccines in development for SARS CoV-2 are using part of the virus to provoke the immune system to produce proteins called antibodies that neutralize the virus. Another way a vaccine could create protection against the virus is by activating the T cells of the immune system.
T cells specifically “recognize” virus-infected cells, and these kinds of responses may be especially important for providing long-term protection against the virus. One challenge for researchers is that they have only had a few months to study how the immune system protects against SARS CoV-2, and in particular, which parts of the virus provoke the best T-cell responses.
For years, they have been perfecting an innovative technology that uses blood-forming stem cells — which can give rise to all types of blood and immune cells — to produce a rare and powerful subset of immune cells called type 1 dendritic cells. Type 1 dendritic cells play an essential role in the immune response by devouring foreign proteins, termed antigens, from virus-infected cells and then chopping them into fragments. Dendritic cells then use these protein fragments to trigger T cells to mount an immune response.
Using this technology, Crooks and Seet are working to pinpoint which specific parts of the SARS-CoV-2 virus provoke the strongest T-cell responses.
Building long-lasting immunity
“We know from a lot of research into other viral infections and also in cancer immunotherapy, that T-cell responses are really important for long-lasting immunity,” said Seet, an assistant professor of hematology-oncology at the David Geffen School of Medicine at UCLA. “And so this approach will allow us to better characterize the T-cell response to SARS-CoV-2 and focus vaccine and therapeutic development on those parts of the virus that induce strong T-cell immunity.”
Crooks’ and Seet’s project uses blood-forming stem cells taken from healthy donors and infected with a virus containing antigens from SARS-CoV-2. They then direct these stem cells to produce large numbers of type 1 dendritic cells using a new method developed by Seet and Suwen Li, a graduate student in Crooks’ lab. Both Seet and Li are graduates of the UCLA Broad Stem Cell Research Center’s training program.
“The dendritic cells we are able to make using this process are really good at chopping up viral antigens and eliciting strong immune responses from T cells,” said Crooks, a professor of pathology and laboratory medicine and of pediatrics at the medical school and co-director of the UCLA Broad Stem Cell Research Center.
When type 1 dendritic cells chop up viral antigens into fragments, they present these fragments on their cell surfaces to T cells. Our bodies produce millions and millions of T cells each day, each with its own unique antigen receptor, however only a few will have a receptor capable of recognizing a specific antigen from a virus.
When a T cell with the right receptor recognizes a viral antigen on a dendritic cell as foreign and dangerous, it sets off a chain of events that activates multiple parts of the immune system to attack cells infected with the virus. This includes clonal expansion, the process by which each responding T cell produces a large number of identical cells, called clones, which are all capable of recognizing the antigen.
“Most of those T cells will go off and fight the infection by killing cells infected with the virus,” said Seet, who, like Crooks, is also a member of the UCLA Jonsson Comprehensive Cancer Center. “However, a small subset of those cells become memory T cells — long-lived T cells that remain in the body for years and protect from future infection by rapidly generating a robust T-cell response if the virus returns. It’s immune memory.”
Producing extremely rare immune cells
This process has historically been particularly challenging to model in the lab, because type 1 dendritic cells are extremely rare — they make up less than 0.1% of cells found in the blood. Now, with this new stem cell technology, Crooks and Seet can produce large numbers of these dendritic cells from blood stem cells donated by healthy people, introduce them to parts of the virus, then see how T cells taken from the blood can respond in the lab. This process can be repeated over and over using cells taken from a wide range of healthy people.
“The benefit is we can do this very quickly without the need for an actual vaccine trial, so we can very rapidly figure out in the lab which parts of the virus induce the best T-cell responses across many individuals,” Seet said.
The resulting data could be used to inform the development of new vaccines for COVID-19 that improve T-cell responses. And the data about which viral antigens are most important to the T cells could also be used to monitor the effectiveness of existing vaccine candidates, and an individual’s immune status to the virus.
“There are dozens of vaccine candidates in development right now, with three or four of them already in clinical trials,” Seet said. “We all hope one or more will be effective at producing immediate and long-lasting immunity. But as there is so much we don’t know about this new virus, we’re still going to need to really dig in to understand how our immune systems can best protect us from infection.”
Supporting basic research into our body’s own processes that can inform new strategies to fight disease is central to the mission of the Broad Stem Cell Research Center.
“When we started developing this project some years ago, we had no idea it would be so useful for studying a viral infection, any viral infection,” Crooks said. “And it was only because we already had these tools in place that we could spring into action so fast.”
If that headline seems familiar it should. It came from an article in MIT Technology Review back in 2009. There have been many other headlines since then, all on the same subject, and yet here we are, in 2020, and still no cure for HIV/AIDS. So what’s the problem, what’s holding us back?
First, the virus is incredibly tough and wily. It is constantly mutating so trying to target it is like playing a game of ‘whack a mole’. Secondly not only can the virus evade our immune system, it actually hijacks it and uses it to help spread itself throughout the body. Even new generations of anti-HIV medications, which are effective at controlling the virus, can’t eradicate it. But now researchers are using new tools to try and overcome those obstacles and tame the virus once and for all.
UCLA researchers Scott Kitchen and Irvin Chen have been awarded $13.65 million by the National Institutes of Health (NIH) to see if they can use the patient’s own immune system to fight back against HIV.
Dr. Kitchen and Dr. Chen take the patient’s own blood-forming stem cells and then, in the lab, they genetically engineer them to carry proteins called chimeric antigen receptors or CARs. Once these blood cells are transplanted back into the body, they combine with the patient’s own immune system T cells (CAR T). These T cells now have a newly enhanced ability to target and destroy HIV.
That’s the theory anyway. Lots of research in the lab shows it can work. For example, the UCLA team recently showed that these engineered CAR T cells not only destroyed HIV-infected cells but also lived for more than two years. Now the team at UCLA want to take the lessons learned in the lab and apply them to people.
In a news release Dr. Kitchen says the NIH grant will give them a terrific opportunity to do that: “The overarching goal of our proposed studies is to identify a new gene therapy strategy to safely and effectively modify a patient’s own stem cells to resist HIV infection and simultaneously enhance their ability to recognize and destroy infected cells in the body in hopes of curing HIV infection. It is a huge boost to our efforts at UCLA and elsewhere to find a creative strategy to defeat HIV.”
By the way, CIRM helped get this work off the ground with an early-stage grant. That enabled Dr. Kitchen and his team to get the data they needed to be able to apply to the NIH for this funding. It’s a great example of how we can kick-start projects that no one else is funding. You can read a blog about that early stage research here.
Severe Leukocyte Adhesion Deficiency-1 (LAD-1) is a rare condition that causes the immune system to malfunction and reduces its ability to fight off viruses and bacteria. Over time the repeated infections can take a heavy toll on the body and dramatically shorten a person’s life. But now a therapy, developed by Rocket Pharmaceuticals, is showing promise in helping people with this disorder.
The therapy, called RP-L201, targets white blood cells called neutrophils which ordinarily attack and destroy invading particles. In people with LAD-1 their neutrophils are dangerously low. That’s why the new data about this treatment is so encouraging.
“Patients with severe LAD-I have neutrophil CD18 expression of less than 2% of normal, with extremely high mortality in early childhood. In this first patient, an increase to 47% CD18 expression sustained over six months demonstrates that RP-L201 has the potential to correct the neutrophil deficiency that is the hallmark of LAD-I. We are also pleased with the continued visible improvement of multiple disease-related skin lesions. The second patient has recently been treated, and we look forward to completing the Phase 1 portion of the registrational trial for this program.”
The results were released at the 23rd Annual Meeting of the American Society of Gene and Cell Therapy.
The team took muscle progenitor cells – which show what’s happening in development before a baby is born – and compared them to muscle stem cells – which control muscle development after a baby is born. That enabled them to identify which genes are active at what stage of development.
In a news release, April Pyle, senior author of the paper, says this could open the door to new therapies for a variety of conditions:
“Muscle loss due to aging or disease is often the result of dysfunctional muscle stem cells. This map identifies the precise gene networks present in muscle progenitor and stem cells across development, which is essential to developing methods to generate these cells in a dish to treat muscle disorders.”
Stroke is the third leading cause of death and disability in the US. Every 45 seconds someone in the US has a stroke. Every year around 275,000 people die from a stroke many more survive but are often impaired by the brain attack. The impact is not just physical, but psychological and emotional. It takes an enormous toll on individuals and their families. So, it’s not surprising that there is a lot of research underway to try and find treatments to help people, including using stem cells.
That’s why CIRM is hosting a special Facebook Live ‘Ask the Stem Cell Team About Stroke event on Wednesday, March 25th at noon PDT. Just head over to our Facebook Page on the 25th at noon to hear from two great guests.
We will be joined by Dr. Tom Carmichael, a Professor of Neurology and the Co-Director of the UCLA Broad Stem Cell Center. He has a number of CIRM grants focused on helping repair the damage caused by strokes.
CIRM Senior Science Officer, Dr. Lila Collins, will also join us to talk about other stem cell research targeting stroke, its promise and some of the problems that still need to be overcome.
You will have a chance to ask questions of both our experts, either live on the day or by sending us questions in advance at email@example.com.
In a previous blog post, we discussed new findings in a CIRM supported study at the Salk Institute for Autism Spectrum Disorder (ASD), a developmental disorder that comes in broad ranges and primarily affects communication and behavior.
This week, a new study, also supported by CIRM, finds that a gene associated with ASD, intellectual disability, and language impairment can affect brain stem cells, which in turn, influence early brain development. Dr. Bennett Novitch and his team at UCLA evaluated a gene, called Foxp1, which has been previously studied for its function in the neurons in the developing brain.
In this study, Dr. Novitch and his team looked at Foxp1 levels in the brains of developing mouse embryos. What they discovered is that, in normal developing mice the gene was active much earlier than previous studies had indicated. It turns out that the gene was active during the period when neural stem cells are just beginning to expand in numbers and generate a subset of brain cells found deep within the developing brain.
When mice lacked the gene entirely, there were fewer neural stem cells at early stages of brain development, as well as fewer brain cells deep within the developing brain. Alternatively, when the levels of the gene were above normal, the researchers found significantly more neural stem cells and brain cells deep within the developing brain. Additionally, higher levels of the neural stem cells were observed in mice with high levels of the gene even after they were born.
In a press release from UCLA, Dr. Novitch explains how the different levels of the gene can be tied to the variation of Foxp1 levels seen in ASD patients.
“What we saw was that both too much and too little Foxp1 affects the ability of neural stem cells to replicate and form certain neurons in a specific sequence in mice. And this fits with the structural and behavioral abnormalities that have been seen in human patients.”
A few years ago, Brenden Whittaker was running out of time. Brenden was born with a rare condition called x-linked chronic granulomatous disease or XCGD. It meant he lacked a critical part of his immune system that protects against bacterial or fungal infections.
Over 22 years Brenden was in and out of the hospital hundreds of times. Twice he almost died. When antibiotics failed to clear up persistent infections surgeons had to remove parts of his lungs and liver.
Brenden felt he was running out of options. Then he signed up for a clinical trial (funded by CIRM) that would use his own stem cells to correct the problem. More than four years later Brenden is doing just fine.
And he’s not the only one. A new study, published in the journal Nature Medicine, shows that six other patients in the clinical trial are now in remission and have stopped taking any other medications.
Don Kohn, the lead researcher on the team from UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, says that in the past the only “cure” for people with CGD was a bone marrow transplant, but that was rarely an option for most patients. In a news release he said finding a perfect match for a transplant was difficult, and even then, patients had to take powerful anti-rejection medications to stop their body rejecting the transplant. So, they developed another approach, using genetically re-engineered stem cells from the patient themselves.
“With this gene therapy, you can use a patient’s own stem cells instead of donor cells for a transplant. This means the cells are perfectly matched to the patient and it should be a much safer transplant, without the risks of rejection.”
The team removed blood stem cells from the patients and, in the lab, corrected the genetic mutation that caused CGD. They then returned those cells to the patients which, because they are stem cells, multiplied and created a new blood supply – one free of CGD – and repaired the immune system.
Brenden was the first of five patients treated in the US. Another four were treated in Europe. All were between the ages of 2 and 27 (CGD patients often die in their 20’s because of the impact of repeated infections).
Two patients died because of previously incurred infections
Six of the seven surviving patients have discontinued previous treatments
Four new patients have since been treated and are currently free of infections
Dr. Kohn said the results are really encouraging: “None of the patients had complications that you might normally see from donor cells and the results were as good as you’d get from a donor transplant — or better.”
The next step is for the researchers to work with the US Food and Drug Administration to get permission to carry out a larger trial, with the eventual goal of getting approval to make it available to all patients who need it.
Regular readers of our blog will remember that Don Kohn also pioneered a similar approach in treating, and curing, children battling another rare immune disorder, severe combined immunodeficiency or SCID. You can read about that here.
As for Brenden, he is now in college and has his sights set on medical school. In 2016 we profiled him in our Annual Report and ran a long interview with him on the blog where he talked about the joys of mowing the lawn and learning to live without a deadly disease stalking him.
Chemotherapy and radiation are two of the front-line weapons in treating cancer. They can be effective, even life-saving, but they can also be brutal, taking a toll on the body that lasts for months. Now a team at UCLA has developed a therapy that might enable the body to bounce back faster after chemo and radiation, and even make treatments like bone marrow transplants easier on patients.
First a little
background. Some cancer treatments use chemotherapy and radiation to kill the
cancer, but they can also damage other cells, including those in the bone
marrow responsible for making blood stem cells. Those cells eventually recover
but it can take weeks or months, and during that time the patient may feel
fatigue and be more susceptible to infections and other problems.
In a CIRM-supported study, UCLA’s Dr. John Chute and his team developed a drug that speeds up the process of regenerating a new blood supply. The research is published in the journal Nature Communications.
They focused their
attention on a protein called PTP-sigma that is found in blood stem cells and
acts as a kind of brake on the regeneration of those cells. Previous studies by
Dr. Chute showed that, after undergoing radiation, mice that have less
PTP-sigma were able to regenerate their blood stem cells faster than mice that
had normal levels of the protein.
So they set out to
identify something that could help reduce levels of PTP-sigma without affecting
other cells. They first identified an organic compound with the charming name
of 6545075 (Chembridge) that was reported to be effective against PTP-sigma.
Then they searched a library of 80,000 different small molecules to find
something similar to 6545075 (and this is why science takes so long).
From that group they
developed more than 100 different drug candidates to see which, if any, were
effective against PTP-sigma. Finally, they found a promising candidate, called DJ009.
In laboratory tests DJ009 proved itself effective in blocking PTP-sigma in
human blood stem cells.
They then tested
DJ009 in mice that were given high doses of radiation. In a news
release Dr. Chute said the results were very encouraging:
“The potency of this compound in animal models was very
high. It accelerated the recovery of blood stem cells, white blood cells and
other components of the blood system necessary for survival. If found to be
safe in humans, it could lessen infections and allow people to be discharged
from the hospital earlier.”
Of the radiated mice, most that were given DJ009
survived. In comparison, those that didn’t get DJ009 died within three weeks.
They saw similar benefits in mice given chemotherapy.
Mice with DJ009 saw their white blood cells – key components of the immune
system – return to normal within two weeks. The untreated mice had dangerously
low levels of those cells at the same point.
It’s encouraging work and the team are already getting
ready for more research so they can validate their findings and hopefully take
the next step towards testing this in people in clinical trials.
governing Board of the California Institute for Regenerative Medicine (CIRM) awarded
two grants totaling $11.15 million to carry out two new clinical trials. These latest additions bring the total number
of CIRM funded clinical trials to 53.
$6.56 Million was awarded to Rocket Pharmaceuticals, Inc. to conduct a clinical trial for
treatment of infants with Leukocyte Adhesion Deficiency-I (LAD-I)
LAD-I is a rare pediatric disease caused a mutation in a specific gene that
affects the body’s ability to combat infections. As a result, infants with
severe LAD-I are often affected immediately after birth. During infancy, they
suffer from recurrent life-threatening bacterial and fungal infections that
respond poorly to antibiotics and require frequent hospitalizations. Those that survive infancy experience
recurrent severe infections, with mortality rates for severe LAD-I at 60-75%
prior to the age of two and survival very rare beyond the age of five.
Rocket Pharmaceuticals, Inc. will test a treatment that uses a patient’s own blood stem cells and inserts a functional version of the gene. These modified stem cells are then reintroduced back into the patient that would give rise to functional immune cells, thereby enabling the body to combat infections.
The award is in
the form of a CLIN2 grant, with the goal of conducting a clinical trial to
assess the safety and effectiveness of this treatment in patients with LAD-I.
utilizes a gene therapy approach, similar to that of three other clinical
trials funded by CIRM and conducted at UCLA by Dr. Don Kohn, for X-linked
Chronic Granulomatous Disease, an inherited immune deficiency “bubble baby”
disease known as ADA-SCID, and Sickle Cell Disease.
An additional $4.59 million was awarded to Dr.
Theodore Nowicki at UCLA to conduct a clinical trial for treatment of patients
with sarcomas and other advanced solid tumors. In 2018 alone, an
estimated 13,040 people were diagnosed with soft tissue sarcoma (STS) in the
United States, with approximately 5,150 deaths.
Standard of care treatment for sarcomas typically consists of surgery,
radiation, and chemotherapy, but patients with late stage or recurring tumor
growth have few options.
Dr. Nowicki and his team will genetically modify peripheral blood stem cells (PBSCs) and peripheral blood monocular cells (PBMCs) to target these solid tumors. The gene modified stem cells, which have the ability to self-renew, provide the potential for a durable effect.
This award is
also in the form of a CLIN2 grant, with the goal of conducting a clinical trial
to assess the safety of this rare solid tumor treatment.
“CIRM has funded 23 clinical stage programs utilizing cell and gene medicine approaches” says Maria T. Millan, M.D., the President and CEO of CIRM. “The addition of these two programs, one in immunodeficiency and the other for the treatment of malignancy, broaden the scope of unmet medical need we can impact with cell and gene therapeutic approaches.”
Here are the stem cell stories that caught our eye this week.
Photos of the week
TGIF! We’re so excited that the weekend is here that we are sharing not one but TWO amazing stem cell photos of the week.
Image caption: Cells of a human intestinal lining, after being placed in an Intestine-Chip, form intestinal folds as they do in the human body. (Photo credit: Cedars-Sinai Board of Governors Regenerative Medicine Institute)
Photo #1 is borrowed from a blog we wrote earlier this week about a new stem cell-based path to personalized medicine. Scientists at Cedars-Sinai are collaborating with a company called Emulate to create intestines-on-a-chip using human stem cells. Their goal is to create 3D-organoids that represent the human gut, grow them on chips, and use these gut-chips to screen for precision medicines that could help patients with intestinal diseases. You can read more about this gut-tastic research here.
Image caption: UCLA scientists used four different fluorescent-colored proteins to determine the origin of cardiomyocytes in mice. (Image credit: UCLA Broad Stem Cell Research Center/Nature Communications)
Photo #2 is another beautiful fluorescent image, this time of a cross-section of a mouse heart. CIRM-funded scientists from UCLA Broad Stem Cell Research Center are tracking the fate of stem cells in the developing mouse heart in hopes of finding new insights that could lead to stem cell-based therapies for heart attack victims. Their research was published this week in the journal Nature Communications and you can read more about it in a UCLA news release.
Stem cell injection improves muscle function in muscular dystrophy mice
Another study by CIRM-funded Cedars-Sinai scientists came out this week in Stem Cell Reports. They discovered that they could improve muscle function in mice with muscular dystrophy by injecting cardiac progenitor cells into their hearts. The injected cells not only improved heart function in these mice, but also improved muscle function throughout their bodies. The effects were due to the release of microscopic vesicles called exosomes by the injected cells. These cells are currently being used in a CIRM-funded clinical trial by Capricor therapeutics for patients with Duchenne muscular dystrophy.
How to build a better brain (blob)
For years stem cell researchers have been looking for ways to create “mini brains”, to better understand how our own brains work and develop new ways to repair damage. So far, the best they have done is to create blobs, clusters of cells that resemble some parts of the brain. But now researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have come up with a new method they think can advance the field.
Their approach is explained in a fascinating article in the journal Science News, where lead researcher Bennet Novitch says finding the right method is like being a chef:
“It’s like making a cake: You have many different ways in which you can do it. There are all sorts of little tricks that people have come up with to overcome some of the common challenges.”
Brain cake. Yum.
A more efficient way to make iPS cells
Shinya Yamanaka. (Image source: Ko Sasaki, New York Times)
In 2006 Shinya Yamanaka discovered a way to take ordinary adult cells and reprogram them into embryonic-like stem cells that have the ability to turn into any other cell in the body. He called these cells induced pluripotent stem cells or iPSC’s. Since then researchers have been using these iPSC’s to try and develop new treatments for deadly diseases.
There’s been a big problem, however. Making these cells is really tricky and current methods are really inefficient. Out of a batch of, say, 1,000 cells sometimes only one or two are turned into iPSCs. Obviously, this slows down the pace of research.
Now researchers in Colorado have found a way they say dramatically improves on that. The team says it has to do with controlling the precise levels of reprogramming factors and microRNA and…. Well, you can read how they did it in a news release on Eurekalert.