Leukocyte Adhesion Deficiency-I (LAD-I) is a rare pediatric disease caused by a mutation in a specific gene that causes low levels of a protein called CD18. Due to low levels of CD18, the adhesion of immune cells is affected, which negatively impacts the body’s ability to combat infections.
Rocket Pharmaceuticals has announced positive results from a CIRM-funded clinical trial that is testing a treatment that uses a gene therapy called RP-L201. The therapy 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. The goal is to establish functional immune cells, enabling the body to combat infections.
The two patients enrolled in the CIRM funded trial have shown restored levels of CD18. Previous studies have indicated that an increase in CD18 to 4-10% is associated with survival into adulthood. The two patients demonstrated CD18 levels that exceeded this threshold.
In a news release, Jonathan Schwartz, M.D. Chief Medical Officer and Senior Vice President of Rocket, elaborated on these positive results.
“Patients with LAD-I have markedly diminished expression of the integrin CD18 and suffer from life-threatening bacterial and fungal infections. Natural history studies indicate that an increase in CD18 expression to 4-10% is associated with survival into adulthood. The two patients enrolled in our Phase 1 trial demonstrated restored CD18 expression substantially exceeding this threshold. In addition, we continue to observe a durable treatment effect in the patient followed through one year, with improvement of multiple disease-related skin lesions after therapy and no further requirements for prophylactic anti-infectives.”
Battling the virus that causes COVID-19 is something that is top of everyone’s mind right now. That’s why CIRM is funding 17 different projects targeting the virus. But one of the most valuable tools in helping develop vaccines against a wide variety of diseases in the past is now coming under threat. We’ll talk about both issues in a live broadcast we’re holding on Wednesday, October 14th at noon (PDT).
That date is significant because it’s Stem Cell Awareness Day and we thought it appropriate to host a meeting looking at two of the most important issues facing the field.
The first part of the event will focus on the 17 projects that CIRM is funding that target COVID-19. This includes three clinical trials aiming to treat people who have been infected with the virus and are experiencing some of the more severe effects, such as damaged lungs.
We’ll also look at some of the earlier stage research that includes:
Work to help develop a vaccine
Using muscle stem cells to help repair damage to the diaphragm in patients who have spent an extended period on a ventilator
Boosting immune system cells to help fight the virus
The second part of the event will look at ways that funding for stem cell research at the federal level is once again coming into question. The federal government has already imposed new restrictions on funding for fetal tissue research, and now there are efforts in Congress to restrict funding for embryonic stem cell research.
The impacts could be significant. Fetal tissue has been used for decades to help develop some of the most important vaccines used today including rubella, chickenpox, hepatitis A, and shingles. They have also been used to make approved drugs against diseases including hemophilia, rheumatoid arthritis, and cystic fibrosis.
We’ll look at some of the reasons why we are seeing these potential restrictions on the medical research and what impact they could have on the ability to develop new treatments for the coronavirus and other deadly diseases.
This past Friday the governing Board of the California Institute for Regenerative Medicine (CIRM) approved two new discovery research project as part of the $5 million in emergency funding for COVID-19 related projects. This brings the number of COVID-19 projects CIRM is supporting to 17, including three clinical trials.
$249,974 was awarded to Dr. Karen Christman at UC San Diego to develop a treatment for Acute Respiratory Distress Syndrome (ARDS), a life-threatening lung injury that occurs when fluid leaks into the lungs and is prevalent in COVID-19 patients. Dr. Christman and her team will develop extracellular matrix (ECM) hydrogels, a kind of structure that provides support to surrounding cells. The goal is to develop a treatment that can be delivered directly to site of injury, where the ECM would recruit stem cells, treat lung inflammation, and promote lung healing.
$250,000 was awarded to Dr. Lili Yang at UCLA to develop a treatment for COVID-19. Dr. Yang and her team will use blood stem cells to create invariant natural killer T (iNKT) cells, a powerful kind of immune cell with the potential to clear virus infection and mitigate harmful inflammation. The goal is to develop these iNKT cells as an off the shelf therapy to treat patients with COVID-19.
These awards are part of CIRM’s Quest Awards Program (DISC2), which promotes promising new technologies that could be translated to enable broad use and improve patient care.
“The harmful lung inflammation caused by COVID-19 can be dangerous and life threatening,” says Maria T. Millan, M.D., the President and CEO of CIRM. “Early stage discovery projects like the ones approved today are vital in developing treatments for patients severely affected by the novel coronavirus.”
Earlier in the week the Board also approved changes to both DISC2 and clinical trial stage projects (CLIN2). These were in recognition of the Agency’s remaining budget and operational timeline and the need to launch the awards as quickly as possible.
For DISC2 awards the changes include:
Award limit of $250,000
Maximum award duration of 12 months
Initiate projects within 30 days of approval
All proposals must provide a statement describing how their overall study plan and design has considered the influence of race, ethnicity, sex and gender diversity.
All proposals should discuss the limitations, advantages, and/or challenges in developing a product or tools that addresses the unmet medical needs of California’s diverse population, including underserved communities.
Under the CLIN2 awards, to help projects carry out a clinical trial, the changes include:
Adjust award limit to the following:
Phase 1, Phase 1/2, Feasability Award Cap
Phase 2 Award Cap
Phase 3 Award Cap
Adjust the award duration to not exceed 3 years with award completion no later than November 2023
Initiate projects within 30 days of approval
All proposals must include a written plan in the application for outreach and study participation by underserved and disproportionately affected populations. Priority will be given to projects with the highest quality plans in this regard.
The changes outlined above for CLIN2 awards do not apply to sickle cell disease projects expected to be funded under the CIRM/NHLBI Cure Sickle Cell Disease joint Initiative.
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.”
In a previous blog post, we talked about how scientists at the Gladstone Institutes have shifted their current operations towards helping with the current coronavirus pandemic. Now scientists at Gladstone and U.C. San Francisco have formed two new research institutes to broaden its impact on unsolved diseases such as COVID-19.
One of these institutes is the Gladstone Institute of Virology and will be lead by Dr. Melanie Ott. The immediate focus of this newly formed institution will be the current coronavirus pandemic. Additionally, it will focus on searching for new therapies against future infectious diseases. The Gladstone Institute of Virology will focus on how viruses interact with human cells to cause disease and how to intervene in that process. Dr. Ott’s goal is to identify pathways these viruses use to infect human cells as a way to develop innovative treatments.
In a press release from Gladstone Institutes, Dr. Ott talks about the goal of her work in more detail.
“Contrary to the current strategy of combining several drugs to treat one virus, we want to develop one drug against multiple viruses. As antibiotic resistance becomes an increasingly urgent problem, we will also delve into how we can use viruses as therapeutics, which involves using viruses against themselves or to fight bacteria.”
The second institute is a collaboration between UCSF and Gladstone Institutes and is called the Gladstone-UCSF Institute of Genomic Immunology. It will be lead by Dr. Alexander Marson and will combine the study of genomics and immunology to develop new therapies. One of the primary goals will be to understand the role that genetics play in human immune cells. By manipulating these cells, the immune system could potentially be altered to treat cancer, infectious diseases, autoimmune diseases, and even neurological conditions such as Alzheimer’s.
In the same press release from Gladstone Institutes, Dr. Marson discusses the importance these collaborations hold for pushing scientific innovation.
“These rapidly advancing fields are starting to converge in ways that are too big for any single lab to take on. The impetus to start a new institute was the realization that we need to create an ecosystem to bring together people with different perspectives to think about transformative opportunities for how patients can be treated in the future.”
This past Friday, the CIRM Board approved funding for its first clinical study for COVID-19. In addition to this, the Board also approved two discovery stage research projects, which support promising new technologies that could be translated to enable broad use and improve patient care. Before we go into more detail, the two awards are summarized in the table below:
The discovery grant for $150,000 was given to Dr. Gay Crooks at UCLA to study how specific immune cells called T cells respond to COVID-19. The goal of this is to inform the development of vaccines and therapies that harness T cells to fight the virus. Typically, vaccine research involves studying the immune response using cells taken from infected people. However, Dr. Crooks and her team are taking T cells from healthy people and using them to mount strong immune responses to parts of the virus in the lab. They will then study the T cells’ responses in order to better understand how T cells recognize and eliminate the virus.
This method uses blood forming stem cells and then converts them into specialized immune cells called dendritic cells, which are able to devour proteins from viruses and chop them into fragments, triggering an immune response to the virus.
In a press release from UCLA, Dr. Crooks says that, “The dendritic cells we are able to make using this process are really good at chopping up the virus, and therefore eliciting a strong immune response”
The discovery grant for $149,998 was given to Dr. Brigitte Gomberts at UCLA to study a lung organoid model made from human stem cells in order to identify drugs that can reduce the number of infected cells and prevent damage in the lungs of patients with COVID-19. Dr. Gomberts will be testing drugs that have been approved by the U.S. Food and Drug Administration (FDA) for other purposes or have been found to be safe in humans in early clinical trials. This increases the likelihood that if a successful drug is found, it can be approved more rapidly for widespread use.
In the same press release from UCLA, Dr. Gomberts discusses the potential drugs they are evaluating.
“We’re starting with drugs that have already been tested in humans because our goal is to find a therapy that can treat patients with COVID-19 as soon as possible.”
Our immune system is the first line of defense our bodies use to fight off infections and disease. One crucial component of this defense mechanism are lymphocytes, which are specialized cells that give rise to various kinds of immune cells, such as a T cell, designed to attack and destroy harmful foreign bodies. Problems in how certain immune cells are formed can lead to diseases such as leukemia and other immune system related disorders.
But how exactly do immune cells form early on in the body?
Dr. Andrew Elfanty and Dr. Ed Stanley at Murdoch Children’s Research Institute in Australia have reproduced and visualized a method in the laboratory used to create human immune cells from pluripotent stem cells, a kind of stem cell that can make virtually any kind of cell in the body. Not only can this unlock a better understanding of leukemia and other immune related diseases, it could potentially lead to a patient’s own skin cells being used to produce new cells for cancer immunotherapy or to test autoimmune disease therapies.
Dr. Elefanty and Dr. Stanley used genetic engineering and a unique way of growing stem cells to make this discovery.
As observed in this video, the team was able to engineer pluripotent stem cells to glow green when they expressed a specific protein found in early immune cells. These cells can be seen migrating along blood vessels outlined in red. These cells go on to populate the thymus, which as we discussed in an earlier blog, is an organ that is crucial in developing functional T cells.
In a press release from Murdoch Children’s Research Institute, Dr. Stanley talks about the important role these early immune cells might play.
“We think these early cells might be important for the correct maturation of the thymus, the organ that acts as a nursery for T-cells”
In addition to this, the team also isolated the green, glowing pluripotent stem cells and showed that they could be used for multiple immune cell types, including those necessary for shaping the development of the immune system as a whole.
In the same press release, Dr. Elefanty discusses the future direction that their research could lead to.
“Although a clinical application is likely still years away, we can use this new knowledge to test ideas about how diseases like childhood leukemia and type 1 diabetes develop. Understanding more about the steps these cells go through, and how we can more efficiently nudge them down a desired pathway, is going to be crucial to that process.”
The full results to this study were published in Nature Cell Biology.