This scanning electron microscope image shows SARS-CoV-2 (yellow)—also known as 2019-nCoV, the virus that causes COVID-19—isolated from a patient in the U.S., emerging from the surface of cells (blue/pink) cultured in the lab. Image Credit:National Institute of Allergy and Infectious Diseases–Rocky Mountain Laboratories
During this global pandemic, many scientists are pursuing various avenues for potential treatments of COVID-19. The Infectious Disease Research Institute (IDRI), in collaboration with Celularity Inc., will conduct a clinical trial with 100 patients using an immunotherapy for treatment of COVID-19.
The treatment will involve administering specialized immune cells called Natural Killer (NK) cells, which are a type of white blood cell that are a vital part of the immune system. Previously, these cells have been administered in early safety studies to treat patients with blood cancers. NK cells play an important role in fighting off viral infections. In initial patients with severe cases of COVID-19, low NK cell counts were observed.
The NK cells used in this study are derived from blood stem cells obtained from the placenta. They will be administered to patients diagnosed with a COVID-19 infection causing pneumonia.
In a press release, IDRI’s CEO Corey Casper talks in more detail about how the NK cells could help treat patients with COVID-19.
“The hypothesis is that administering NK cells to patients with moderate to severe COVID-19 will allow the immune cells find the sites of active viral infection, kill the virus, and induce a robust immune response that will help heal the damage and control the infection.”
In the same press release, Corey Casper also mentions the other applications this treatment could have.
“Beyond its promise as a critically needed treatment for COVID-19, the biology of NK cells indicates a possibility that this immunotherapy could be used as an off-the-shelf treatment for future pandemic infections.”
Image of a blood stem cell in its natural environment: Photo courtesy UC Merced
When it comes to using stem cells for therapy you don’t just need to understand what kinds of cell to use, you also need to understand the environment that is best for them. Trying to get stem cells to grow in the wrong environment would be like trying to breed sheep in a pond. It won’t end well.
But for years scientists struggled to understand how to create the right environment, or niche, for these cells. The niche provides a very specific micro-environment for stem cells, protecting them and enabling them to self-renew over long periods of time, helping repair damaged tissues and organs in the body.
But different stem cells need different niches, and those involve both physical and chemical properties, and getting that mixture right has been challenging. That in turn has slowed down our ability to use those cells to develop new therapies.
UC Merced’s Joel Spencer in the lab: Photo courtesy UC Merced
Now UC Merced’s Professor Joel Spencer and his team have developed a way of capturing an image of hematopoietic or blood stem cells (HSCs), inside their niche in the bone marrow. In an article on UC Merced News, he says this could be a big step forward.
“Everyone knew black holes existed, but it took until last year to directly capture an image of one due to the complexity of their environment. It’s analogous with stem cells in the bone marrow. Until now, our understanding of HSCs has been limited by the inability to directly visualize them in their native environment.
“This work brings an advancement that will open doors to understanding how these cells work which may lead to better therapeutics for hematologic disorders including cancer.”
In the past, studying HSCs involved transplanting them into a mouse or other animal that had undergone radiation to kill off its own bone marrow cells. It enabled researchers to track the HSCs but clearly the new environment was very different than the original, natural one. So, Spencer and his team developed new microscopes and imaging techniques to study cells and tissues in their natural environment.
In the study, published in the journal Nature, Spencer says all this is only possible because of recent technological breakthroughs.
“My lab is seeking to answer biological questions that were impossible until the advancements in technology we have seen in the past couple decades. You need to be able to peer inside an organ, inside a live animal and see what’s happening as it happens.”
Being able to see how these cells behave in their natural environment may help researchers learn how to recreate that environment in the lab, and help them develop new and more effective ways of using those cells to repair damaged tissues and organs.
UCLA’s Dr. Hanna Mikkola and Vincenzo Calvanese, lead scientists on the study. Photo courtesy UCLA
Blood stem cells are a vital part of us. They create all the other kinds of blood cells in our body and are used in bone marrow transplants to help people battling leukemia or other blood cancers. The problem is growing these blood stem cells outside the body has always proved challenging. Up till now.
Researchers at UCLA, with CIRM funding, have identified a protein that seems to play a key role in helping blood stem cells renew themselves in the lab. Why is this important? Because being able to create a big supply of these cells could help researchers develop new approaches to treating a wide array of life-threatening diseases.
One of the most important elements that a stem cell has is its ability to self-renew itself over long periods of time. The problem with blood stem cells has been that when they are removed from the body they quickly lose their ability to self-renew and die off.
To discover why this is the case the team at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA analyzed blood stem cells to see which genes turn on and off as those cells turn into other kinds of blood cells – red, white and platelets. They identified one gene, called MLLT3, which seemed to play a key role in helping blood stem cells self-renew.
To test this finding, the researchers took blood stem cells and, in the lab, inserted copies of the MLLT3 gene into them. The modified cells were then able to self-renew at least 12 times; a number far greater than in the past.
Dr. Hanna Mikkola, a senior author of the study says this finding could help advance the field:
“If we think about the amount of blood stem cells needed to treat a patient, that’s a significant number. But we’re not just focusing on quantity; we also need to ensure that the lab-created blood stem cells can continue to function properly by making all blood cell types when transplanted.”
Happily, that seemed to be the case. When they subjected the MLLT3-enhanced blood stem cells to further analysis they found that they appeared to self-renew at a safe rate and didn’t multiply too much or mutate in ways that could lead to leukemia or other blood cancers.
The next steps are to find more efficient and effective ways of keeping the MLLT3 gene active in blood stem cells, so they can develop ways of using this finding in a clinical setting with patients.
Their findings are published in the journal Nature.
Following radiation, the bone marrow shows nearly complete loss of blood cells in mice (left). Mice treated with the PTP-sigma inhibitor displayed rapid recovery of blood cells (purple, right): Photo Courtesy UCLA
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.
John Chute: Photo courtesy UCLA
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.
Today the governing Board of the California Institute for
Regenerative Medicine (CIRM) approved a grant of almost $12 million to Dr.
Stephanie Cherqui at the University of California, San Diego (UCSD) to conduct
a clinical trial for treatment of cystinosis.
This
award brings the total number of CIRM funded clinical trials to 55.
Cystinosis is
a rare disease that primarily affects children and young adults, and leads to
premature death, usually in early adulthood. Patients inherit
defective copies of a gene called CTNS, which results in abnormal accumulation
of an amino acid called cystine in all cells of the body. This buildup of cystine can lead to
multi-organ failure, with some of earliest and most pronounced effects on the
kidneys, eyes, thyroid, muscle, and pancreas.
Many patients suffer end-stage kidney failure and severe vision defects
in childhood, and as they get older, they are at increased risk for heart
disease, diabetes, bone defects, and neuromuscular defects. There is currently a drug treatment for
cystinosis, but it only delays the progression of the disease, has severe side
effects and is expensive.
Dr. Cherqui’s clinical trial will use a gene therapy
approach to modify a patient’s own blood stem cells with a functional version
of the defective CTNS gene. Based on pre-clinical
data, the approach is to reintroduce the corrected stem cells into the patient
to give rise to blood cells that will reduce cystine buildup in affected
tissues.
Because this is the first time this approach has been tested in patients, the primary goal of the clinical trial is to see if the treatment is safe. In addition, patients will be monitored for improvements in the symptoms of their disease. This award is in collaboration with the University of California, Los Angeles which will handle the manufacturing of the therapy.
CIRM has also funded the preclinical work
for this study, which involved completing the testing needed to apply to the
Food and Drug Administration (FDA) for permission to start a clinical trial in
people.
“CIRM has funded 24 clinical stage programs utilizing
cell and gene medicine approaches to date,” says Maria T. Millan, M.D., the
President and CEO of CIRM. “This project
continues to broaden the scope of unmet medical need we can impact with these
types of approaches.”
A transplant can be a lifesaving procedure for many people across the United States. In fact, according to the Health Resources & Services Administration, 36,528 transplants were performed in 2018. However, as of January 2019, the number of men, women, and children on the national transplant waiting list is over 113,000, with 20 people dying each day waiting for a transplant and a new person being added to the list every 10 minutes.
Before considering a transplant, there needs to be an immunological match between the donated tissue and/or blood stem cells and the recipient. To put it simply, a “match” indicates that the donor’s cells will not be marked by the recipient’s immune cells as foreign and begin to attack it, a process known as graft-versus-host disease. Unfortunately, these matches can be challenging to find, particularly for some ethnic minorities. Often times, immunosuppression drugs are also needed in order to prevent the foreign cells from being attacked by the body’s immune system. Additionally, chemotherapy and radiation are often needed as well.
Fortunately, a CIRM-funded study at Stanford has shown some promising results towards addressing the issue of matching donor cells and recipient. Dr. Irv Weissman and his colleagues at Stanford have found a way to prepare mice for a transplant of blood stem cells, even when donor and recipient are an immunological mismatch. Their method involved using a combination of six specific antibodies and does not require ongoing immunosuppression.
The combination of antibodies did this by eliminating several types of immune cells in the animals’ bone marrow, which allowed blood stem cells to engraft and begin producing blood and immune cells without the need for continued immunosuppression. The blood stem cells used were haploidentical, which, to put it simply, is what naturally occurs between parent and child, or between about half of all siblings.
Additional experiments also showed that the mice treated with the six antibodies could also accept completely mismatched purified blood stem cells, such as those that might be obtained from an embryonic stem cell line.
The results established in this mouse model could one day lay the foundation necessary to utilize this approach in humans after conducting clinical trials. The idea would be that a patient that needs a transplanted organ could first undergo a safe, gentle transplant with blood stem cells derived in the laboratory from embryonic stem cells. The same embryonic stem cells could also then be used to generate an organ that would be fully accepted by the recipient without requiring the need for long-term treatment with drugs to suppress the immune system.
In a news release, Dr. Weissman is quoted as saying,
“With support by the California Institute for Regenerative Medicine, we’ve been able to make important advances in human embryonic stem cell research. In the past, these stem cell transplants have required a complete match to avoid rejection and reduce the chance of graft-versus-host disease. But in a family with four siblings the odds of having a sibling who matches the patient this closely are only one in four. Now we’ve shown in mice that a ‘half match,’ which occurs between parents and children or in two of every four siblings, works without the need for radiation, chemotherapy or ongoing immunosuppression. This may open up the possibility of transplant for nearly everyone who needs it. Additionally, the immune tolerance we’re able to induce should in the future allow the co-transplantation of [blood] stem cells and tissues, such as insulin-producing cells or even organs generated from the same embryonic stem cell line.”
The full results to this study were published in Cell Stem Cell.
Blood stem cells offer promise for a variety of immune and blood related disorders such as sickle cell disease and leukemia. Like other stem cells, blood stem cells have the ability to generate additional blood stem cells in a process called self-renewal. Additionally, they are able to generate blood cells in a process called differentiation. These newly generated blood cells have the potential to be utilized for transplantations and gene therapies.
However, two limitations have hindered the progress made in this field. One problem relates to the amount of blood stem cells needed to make a potential transplantation or gene therapy viable. Unfortunately, it has been challenging to isolate and grow blood stem cells in large quantity needed for these approaches. A part of this reason relates to getting the blood stem cells to self-renew rather than differentiate.
The second problem involves the existing blood stem cells in the patient’s body prior to transplantation. In order for the procedure to work, the patient’s own blood stem cells must be eliminated to make space for the transplanted blood stem cells. This is done through a process known as conditioning, which typically involves chemotherapy and/or radiation. Unfortunately, chemotherapy and radiation can cause life-threatening side effects due to its toxicity, particularly in pediatric patients, such as growth retardation, infertility and secondary cancer in later life. Very sick or elderly patients are unable to tolerate this conditioning process, making them ineligible for transplants.
A CIRM funded study by a team at Stanford and the University of Tokyo has unlocked the code related to the generation of blood stem cells.
The collaborative team was able to modify the components used to grow blood stem cells. By making these modifications, which effects the growth and physical conditions of blood stem cells, the researchers have shown for the first time that it’s possible to get blood stem cells from mice to renew themselves hundreds or even thousands of times within a period of just 28 days.
Furthermore, the team showed that when they transplanted the newly grown cells into mice that had not undergone conditioning, the donor cells had engrafted and remained functional.
The team also found that gene editing technology such as CRISPR could be used while growing an adequate supply of blood stem cells for transplantation. This opens the possibility of obtaining a patient’s own blood stem cells, correcting the problematic gene, and reintroducing these back to the patient.
In a news release, Dr. Hiromitsu Nakauchi, a senior author of the study, is quoted as saying,
“For 50 years, researchers from laboratories around the world have been seeking ways to grow these cells to large numbers. Now we’ve identified a set of conditions that allows these cells to expand in number as much as 900-fold in just one month. We believe this approach could transform how [blood] stem cell transplants and gene therapy are performed in humans.”
For years researchers have struggled to create human blood stem cells in the lab. They have done it several times with animal models, but the human kind? Well, that’s proved a bit trickier. Now a CIRM-funded team at UC San Diego (UCSD) think they have cracked the code. And that would be great news for anyone who may ever need a bone marrow transplant.
Why are blood stem cells important? Well, they help create our red and white blood cells and platelets, critical elements in carrying oxygen to all our organs and fighting infections. They have also become one of the most important weapons we have to combat deadly diseases like leukemia and lymphoma. Unfortunately, today we depend on finding a perfect or near-perfect match to make bone marrow transplants as safe and effective as possible and without a perfect match many patients miss out. That’s why this news is so exciting.
Researchers at UCSD found that the process of creating new blood stem cells depends on the action of three molecules, not two as was previously thought.
Zebrafish
Here’s where it gets
a bit complicated but stick with me. The team worked with zebrafish, which use
the same method to create blood stem cells as people do but also have the
advantage of being translucent, so you can watch what’s going on inside them as
it happens. They noticed that a molecule
called Wnt9a touches down on a receptor called Fzd9b and brings along with it
something called the epidermal growth factor receptor (EGFR). It’s the
interaction of these three together that turns a stem cell into a blood cell.
In a news release, Stephanie Grainger, the first author of the
study published in Nature Cell Biology, said this discovery could help lead to new
ways to grow the cells in the lab.
“Previous attempts to develop blood stem cells in a
laboratory dish have failed, and that may be in part because they didn’t take
the interaction between EGFR and Wnt into account.”
If this new approach helps the team generate blood stem cells in the lab these could be used to create off-the-shelf blood stem cells, instead of bone marrow transplants, to treat people battling leukemia and/or lymphoma.
Dr. Theodore Nowicki, physician in the division of pediatric hematology/oncology at UCLA. Photo courtesy of Milo Mitchell/UCLA Jonsson Comprehensive Cancer Center
The
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.
This project
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.
This project will add to CIRM’s portfolio in stem cell approaches for difficult to treat cancers. A previously funded a clinical trial at UCLA uses this same approach to treat patients with multiple myeloma. CIRM has also previously funded two clinical trials using different approaches to target other types of solid tumors, one of which was conducted at Stanford and the other at UCLA. Lastly, two additional CIRM funded trials conducted by City of Hope and Poseida Therapeutics, Inc. used modified T cells to treat brain cancer and multiple myeloma, respectively.
“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.”
Dr. Matthew Porteus, professor of pediatrics at Stanford University. Photo courtesy of Stanford Medicine.
Our immune system is an important and essential part of everyday life. It is crucial for fighting off colds and, with the help of vaccinations, gives us immunity to potentially lethal diseases. Unfortunately, for some infants, this innate bodily defense mechanism is not present or is severely lacking in function.
This condition is known as severe combined immunodeficiency (SCID), commonly nicknamed “bubble baby” disease because of the sterile plastic bubble these infants used to be placed in to prevent exposure to bacteria, viruses, and fungi that can cause infection. There are several forms of SCID, one of which involves a single genetic mutation on the X chromosome and is known as SCID-X1
Many infants with SCID-X1 develop chronic diarrhea, a fungal infection called thrush, and skin rashes. Additionally, these infants grow slowly in comparison to other children. Without treatment, many infants with SCID-X1 do not live beyond infancy.
SCID-X1 occurs almost predominantly in males since they only carry one X chromosome, with at least 1 in 50,000 baby boys born with this condition. Since females carry two X chromosomes, one inherited from each parent, they are unlikely to inherit two X chromosomes with the mutation present since it would require the father to have SCID-X1.
What if there was a way to address this condition by correcting the single gene mutation? Dr. Matthew Porteus at Stanford University is leading a study that has developed an approach to treat SCID-X1 that utilizes this concept.
By using CRISPR-Cas9 technology, which we have discussed in detail in a previous blog post, it is possible to delete a problematic gene and insert a corrected gene. Dr. Porteus and his team are using CRISPR-Cas9 to edit blood stem cells, which give rise to immune cells, which are the foundation of the body’s defense mechanism. In a study published in Nature, Dr. Porteus and his team have demonstrated proof of concept of this approach in an animal model.
The Stanford team was able to take blood stem cells from six infants with SCID-X1 and corrected them with CRISPR-Cas9. These corrected stem cells were then introduced into mice modeled to have SCID-X1. It was found that these mice were not only able to make immune cells, but many of the edited stem cells maintained their ability to continuously create new blood cells.
In a press release, Dr. Mara Pavel-Dinu, a member of the research team, said:
“To our knowledge, it’s the first time that human SCID-X1 cells edited with CRISPR-Cas9 have been successfully used to make human immune cells in an animal model.”
CIRM has previously awarded Dr. Porteus with a preclinical development award aimed at developing gene correction therapy for blood stem cells for SCID-X1. In addition to this, CIRM has funded two other projects conducted by Dr. Porteus related to CRISPR-Cas9. One of these projects used CRISPR-Cas 9 to develop a treatment for chronic sinusitis due to cystic fibrosis and the second project used the technology to develop an approach for treating sickle cell disease.
CIRM has also funded four clinical trials related to SCID. Two of these trials are related to SCID-X1, one being conducted at St. Jude Children’s Research Hospital and the other at Stanford University. The third trial is related to a different form of SCID known as ADA-SCID and is being conducted at UCLA in partnership with Orchard Therapeutics. Finally, the last of the four trials is related to an additional form of SCID known as ART-SCID and is being conducted at UCSF.
The Stem Cellar 