In the middle of a pandemic, stress can run really high and you might be tempted to light up a cigarette to decompress from the world around you. However, a CIRM-funded study revealed that you might want to think twice before lighting up.
It is already known that cigarette smoke is one of the most common causes of lung diseases, including lung cancer, but Dr. Brigitte Gomperts and Vaithilingaraja Arumugaswami at UCLA have pinpointed how smoking cigarettes may worsen infection by SARS-CoV-2, the virus that causes COVID-19, in the airways of the lungs.
The team used airway stem cells from the lungs of healthy non-smoking donors to create a tissue model that replicates the way that airways behave and function in humans. The researchers then exposed these newly created airways to cigarette smoke to mimic the effects of smoking.
Next, the team infected the airway tissue exposed with cigarette smoke with SARS-CoV-2 and also infected tissue not exposed to cigarette smoke. In the tissue model exposed to smoke, the researchers saw between two and three times more infected cells.
The UCLA team determined that smoking resulted in more severe SARS-CoV-2 infection. This was due to the smoke blocking the activity of immune system messenger proteins called interferons, which play an important role in the body’s early immune response. They trigger infected cells to produce proteins to attack the virus, summon additional support from the immune system, and alert uninfected cells to prepare to fight the virus. Cigarette smoke is known to reduce the interferon response in the airways.
In a UCLA news release, Dr. Gomperts explains the results with a simple analogy.
“If you think of the airways like the high walls that protect a castle, smoking cigarettes is like creating holes in these walls. Smoking reduces the natural defenses and that allows the virus to set in.”
The hope is that these findings will help researchers better understand COVID-19 risks for smokers and could inform the development of new therapeutic strategies to help reduce smokers’ chances of developing severe disease.
The full results to this study were published in Cell Stem Cell.
This past Thursday the governing Board of the California Institute for Regenerative Medicine (CIRM) approved four new clinical trials in addition to ten new discovery research awards.
These new awards bring the total number of CIRM-funded clinical trials to 68. Additionally, these new additions have allowed the state agency to exceed the goal of commencing 50 new trials outlined in its five year strategic plan.
$8,970,732 was awarded to Dr. Steven Deeks at the University of California San Francisco (UCSF) to conduct a clinical trial that modifies a patient’s own immune cells in order to treat and potentially cure HIV.
Current treatment of HIV involves the use of long-term antiretroviral therapy (ART). However, many people are not able to access and adhere to long-term ART.
Dr. Deeks and his team will take a patient’s blood and extract T cells, a type of immune cell. The T cells are then genetically modified to express two different chimeric antigen receptors (CAR), which enable the newly created duoCAR-T cells to recognize and destroy HIV infected cells. The modified T cells are then reintroduced back into the patient.
The goal of this one time therapy is to act as a long-term control of HIV with patients no longer needing to take ART, in effect a form of HIV cure. This approach would also address the needs of those who are not able to respond to current approaches, which is estimated to be 50% of those affected by HIV globally.
$3,728,485 was awarded to Dr. Gayatri Rao from Rocket Pharmaceuticals to conduct a clinical trial using a gene therapy for infantile malignant osteopetrosis (IMO), a rare and life-threatening disorder that develops in infancy. IMO is caused by defective bone cell function, which results in blindness, deafness, bone marrow failure, and death very early in life.
The trial will use a gene therapy that targets IMO caused by mutations in the TCIRG1 gene. The team will take a young child’s own blood stem cells and inserting a functional version of the TCIRG1 gene. The newly corrected blood stem cells are then introduced back into the child, with the hope of halting or preventing the progression of IMO in young children before much damage can occur.
Rocket Pharmaceuticals has used the same gene therapy approach for modifying blood stem cells in a separate CIRM funded trial for a rare pediatric disease, which has shown promising results.
$8,996,474 was awarded to Dr. Diana Farmer at UC Davis to conduct a clinical trial of in utero repair of myelomeningocele (MMC), the most severe form of spina bifida. MMC is a birth defect that occurs due to incomplete closure of the developing spinal cord, resulting in neurological damage to the exposed cord. This damage leads to lifelong lower body paralysis, and bladder and bowel dysfunction.
Dr. Farmer and her team will use placenta tissue to generate mesenchymal stem cells (MSCs). The newly generated MSCs will be seeded onto an FDA approved dural graft and the product will be applied to the spinal cord while the infant is still developing in the womb. The goal of this therapy is to help promote proper spinal cord formation and improve motor function, bladder function, and bowel function.
$8,333,581 was awarded to Dr. David Williams at Boston Children’s Hospital to conduct a gene therapy clinical trial for sickle cell disease (SCD). This is the second project that is part of an agreement between CIRM and the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, to co-fund cell and gene therapy programs under the NHLBI’s “Cure Sickle Cell” Initiative. The goal of this agreement is to markedly accelerate clinical development of cell and gene therapies to cure SCD.
SCD is an inherited disease caused by a single gene mutation resulting in abnormal hemoglobin, which causes red blood cells to ‘sickle’ in shape. Sickling of red blood cells clogs blood vessels and leads to progressive organ damage, pain crises, reduced quality of life, and early death.
The team will take a patient’s own blood stem cells and insert a novel engineered gene to silence abnormal hemoglobin and induce normal fetal hemoglobin expression. The modified blood stem cells will then be reintroduced back into the patient. The goal of this therapy is to aid in the production of normal shaped red blood cells, thereby reducing the severity of the disease.
“Today is a momentus occasion as CIRM reaches 51 new clinical trials, surpassing one of the goals outlined in its five year strategic plan,” says Maria T. Millan, M.D., President and CEO of CIRM. “These four new trials, which implement innovative approaches in the field of regenerative medicine, reflect CIRM’s ever expanding and diverse clinical portfolio.”
The Board also approved ten awards that are part of CIRM’s Quest Awards Prgoram (DISC2), which promote promising new technologies that could be translated to enable broad use and improve patient care.
The awards are summarized in the table below:
Human-induced pluripotent stem cell-derived glial enriched progenitors to treat white matter stroke and vascular dementia.
Development of COVID-19 Antiviral Therapy Using Human iPSC-Derived Lung Organoids
UC San Diego
Hematopoietic Stem Cell Gene Therapy for X-linked Agammaglobulinemia
Development of a SYF2 antisense oligonucleotide (ASO) treatment for ALS
University of Southern California
Dual angiogenic and immunomodulating nanotechnology for subcutaneous stem cell derived islet transplantation for the treatment of diabetes
Human iPSC-derived chimeric antigen receptor-expressing macrophages for cancer treatment
UC San Diego
Optimization of a human interneuron cell therapy for traumatic brain injury
Combating COVID-19 using human PSC-derived NK cells
City of Hope
The First Orally Delivered Cell Therapy for the Treatment of Inflammatory Bowel Disease
Transplantation of Pluripotent Stem Cell Derived Microglia for the Treatment of Adult-onset Leukoencephalopathy (HDLS/ALSP)
Canavan disease is a fatal neurological disorder, the most prevalent form of which begins in infancy. It is caused by mutation of the ASPA gene, resulting in the deterioration of white matter (myelin) in the brain and preventing the proper transmission of nerve signals. The mutated ASPA gene causes the buildup of an amino acid called NAA and is typically found in neurons in the brain. As a result of the NAA buildup, Canavan disease causes symptoms such as impaired motor function, mental retardation, and early death. Currently, there is no cure or standard of treatment for this condition.
Fortunately, CIRM-funded research conducted at City of Hope by Yanhong Shi, Ph.D. is developing a stem cell-based treatment for Canavan disease. The research is part of CIRM’s Translational Stage Research Program, which promotes the activities necessary for advancement to clinical study of a potential therapy.
The results from the study are promising, with the therapy improving motor function, reducing degeneration of various brain regions, and expanding lifespan in a Canavan disease mouse model.
For this study, induced pluripotent stem cells (iPSCs), which can turn into virtually any type of cells, were created from skin cells of Canavan disease patients. The newly created iPSCs were then used to create neural progenitor cells (NPCs), which have the ability to turn into various types of neural cells in the central nervous system. A functional version of the ASPA gene was then introduced into the NPCs. These newly created NPCs were then transplanted inside the brains of Canavan disease mice.
The study also used iPSCs engineered to have a functional version of the ASPA gene. The genetically modified iPSCs were then used to create oligodendrocyte progenitor cells (OPCs), which have the ability to turn into myelin. The OPCs were also transplanted inside the brains of mice.
The rationale for evaluating both NPCs and OPCs was that NPCs typically stayed at the site of injection while OPCs tend to migrate, which might have been important in terms of the effectiveness of the therapy. However, the results of the study show that both NPCs and OPCs were effective, with both being able to reduce levels of NAA, presumably because NAA can move to where the ASPA enzyme is although NPCs do not migrate. This resulted in improved motor function, recovery of myelin, and reduction of brain degeneration, in both the NPC and OPC-transplanted Canavan disease mice.
“Thanks to funding from CIRM and the hard work of my team here at City of Hope and collaborators at Center for Biomedicine and Genetics, Department of Molecular Imaging and Therapy, and Diabetes and Metabolism Institute at City of Hope, as well as collaborators from the University of Texas Medical Branch at Galveston, University of Rochester Medical Center, and Aarhus University, we were able to carry out this study which has demonstrated promising results,” said Dr. Shi. “I hope that these findings can one day bring about an effective therapy for Canavan disease patients, who currently have no treatment options.”
Dr. Shi and her team will build on this research by starting IND-enabling studies using their NPC therapy soon. This is the final step in securing approval from the Food and Drug Administration (FDA) in order to test the therapy in patients.
Last year, CIRM awarded $5.53 million to Rosa Bacchetta, M.D. at Stanford University to complete the work necessary to conduct a clinical trial for IPEX syndrome. This is a rare disease caused by mutations in the FOXP3 gene, which leaves people with the condition vulnerable to immune system attacks on their organs and tissues. These attacks can be devastating, even fatal.
Flash forward to the present day and the CIRM-funded treatment that Dr. Bacchetta has been working on has received both an orphan drug and a rare pediatric disease designation from the Food and Drug Administration (FDA).
Orphan drug designation is a special status given by the Food and Drug Administration (FDA) for potential treatments of rare diseases that affect fewer than 200,000 in the U.S. This type of status can significantly help advance treatments for rare diseases by providing financial incentives in the form of tax credits towards the cost of clinical trials and prescription drug user fee waivers.
Under the FDA’s rare pediatric disease designation program, the FDA may grant priority review to Dr. Bacchetta if this treatment eventually receives FDA approval. The FDA defines a rare pediatric disease as a serious or life-threatening disease in which the serious or life-threatening manifestations primarily affect individuals aged from birth to 18 years and affects fewer than 200,000 people in the U.S.
“The designations granted by the FDA are a strong encouragement for our team to meet the goal of submitting the IND in 2021 and start the clinical trial for IPEX patients who are so much looking forward to new therapeutic options.” said Dr. Bacchetta.
But this begs the question, what exactly is IPEX syndrome? What is the approach that Dr. Bacchetta is working on? For those of you interested in the deeper scientific dive, we will elaborate on this complex disease and promising approach.
IPEX syndrome is a rare disease that primarily affects males and is caused by a genetic mutation that leads to lack of function of specialized immune cells called regulatory T cells (Tregs).
Without functional Tregs, a patient’s own immune cells attack the body’s own tissues and organs, a phenomenon known as autoimmunity. This affects many different areas such as the intestines, skin, and hormone-producing glands and can be fatal in early childhood.
Current treatment options include a bone marrow transplant and immune suppressing drugs. However, immune suppression is only partially effective and can cause severe side effects while bone marrow transplants are limited due to lack of matching donors.
Dr. Rosa Bacchetta and her team at Stanford will take a patient’s own blood in order to obtain CD4+ T cells. Then, using gene therapy, they will insert a normal version of the mutated gene into the CD4+ T cells, allowing them to function like normal Treg cells. These Treg-like cells would then be reintroduced back into the patient, hopefully creating an IPEX-free blood supply and resolving the autoimmunity.
Furthermore, if successful, this treatment could be adapted for treatment of other, more common, autoimmune conditions where Treg cells are the underlying problem.
The same day that CIRM approved funding for this approach, Taylor Lookofsky, a young man with IPEX syndrome, talked about the impact the condition has had on his life.
It’s a powerful reminder that syndromes like this, because they affect a small number of people, are often overlooked and have few resources devoted to finding new treatments and cures. After hearing Taylor’s story, you come to appreciate his courage and determination, and why the funding CIRM provides is so important in helping researchers like Dr. Bacchetta find therapies to help people like Taylor.
Since the first grant was issued in April 2006, CIRM has funded a wide range of research conducted by top scientists at UCLA for a wide range of diseases. To give a retrospective look at all the research, UCLA released a news article that describes all this work up until this past September. During this period, UCLA researchers were awarded 120 grants totaling more than $307 million. We’ll highlight some of these findings from the article below.
51 Basic Biology CIRM Grants
Basic biology research encompasses very early stage work that focuses on the very essentials such as how stem cells work, how to successfully turn a stem cell into another type of cell, and other basic mechanisms that underly the stem cell research field. This research is critical because they inform future therapies for dozens of conditions including heart disease, genetic and blood disorders, cancer, spinal cord injuries and neurological disorders.
3 Consecutive Year-Long CIRM Training Grants
These CIRM grants are essential in training the next generation of scientists and physicians in the regenerative medicine field. The CIRM training grants supported 146 graduate students, post‐doctoral fellows, and clinical fellows working in UCLA laboratories by providing them year-long training fellowships. This program was so successful that the UCLA Broad Stem Cell Research Center funded 26 additional fellowships to supplement CIRM’s support.
5 COVID-19 Related Grants
Shortly after the coronavirus pandemic, CIRM authorized $5 million in emergency funding to fund COVID-19 related projects. UCLA has received a $1.02 million to support four discovery research projects and one translational project. Discovery research promotes promising new technologies that could be translated to enable broad use and improve patient care. Translational research takes it a step further by promoting the activities necessary for advancement to clinical study of a potential therapy.
1 Alpha Stem Cell Clinic (ASCC) Grant
One award was used to establish the UCLA‐UCI Alpha Stem Cell Clinic. It is one of five leading medical centers throughout California that make up the CIRM ASSC Network, which specializes in the delivery of stem cell therapies by providing world-class, state of the art infrastructure to support clinical research.
The development of organoid modeling has significantly expanded our understanding of human organs and the diseases that can affect them. For those unfamiliar with the term, an organoid is a miniaturized, simplified version of an organ produced that is also three dimensional.
Recently, scientists from the University of Cambridge and the Korea Advanced Institute Science and Technology (KAIST) were able to develop ‘mini lungs’ from donated tissue and use them to uncover the mechanisms behind the new coronavirus infection and the early immune response in the lungs.
SARS-CoV-2, the name of the coronavirus that causes COVID-19, first appears in the alveoli, which are tiny air sacs in the lungs that take up the oxygen we breathe and exchange it with carbon dioxide.
To better understand how SARS-CoV-2 infects the lungs and causes COVID-19, the team used donated tissue to extract a specific type of lung cell. They then reprogrammed these cells to an earlier stem cell-like state and used them to grow the lung organoids.
The team then infected the ‘mini lungs’ with a strain of SARS-CoV-2 taken from a patient in South Korea who was diagnosed with COVID-19 after traveling to Wuhan, China.
Within the newly infected lung organoids, the team observed that the virus began to replicate rapidly, reaching full cellular infection in just six hours. Replication allows the virus to spread the infection throughout the body to other cells and tissue. The infected cells also began to produce interferons, which are proteins that act as warning signals to healthy cells, telling them to activate their antiviral defenses. After two days, the interferons triggered an immune response and the cells started fighting back against infection. Two and a half days after infection, some of the alveolar cells began to disintegrate, leading to cell death and damage to the lung tissue.
In a news release, Dr. Joo-Hyeon Lee, co-senior author of this study, elaborates on how he hopes this study can help more vulnerable sections of the population.
“We hope to use our technique to grow these 3D models from cells of patients who are particularly vulnerable to infection, such as the elderly or people with diseased lungs, and find out what happens to their tissue.”
CIRM has funded two discovery stage research projects that use lung organoids to look at potential treatments for COVID-19. One is being conducted by Dr. Brigitte Gomperts at UCLA and the other by Dr. Evan Snyder at the Sanford Burnham Prebys Medical Discovery Institute.
For many couples that are ready to start a family, infertility, which is the inability to conceive children, can be a devastating setback. In fact, according to the Mayo Clinic, about 15% of couples are infertile. Of those couples experiencing infertility, one in three are issues related to male infertility, which often involves problems with sperm development.
However, researchers at Seoul National University in South Korea have found a way to deliver an important protein to mouse testes to improve sperm development. This is the first demonstration of direct delivery of proteins into the testes to treat male infertility, which could one day help people.
Male infertility is often associated with a lack of sperm in the semen. This can occur because of damage to the blood-testis barrier (BTB), which protects reproductive cells from harm. A protein named PIN1 is important for proper BTB function.
For this study, male mice were genetically engineered to lack PIN1, making them infertile. The researchers then developed a delivery system called Fibroplex, which consists of sphere-shaped nanoparticles. The team then inserted PIN1 into the Fibroplex, which was subsequently injected into the testes of the infertile mice.
The results were remarkable. The scientists found that the treatment had restored nearly normal PIN1 levels and sperm stem cell numbers in addition to repairing the BTB. The treated mice were also able to father a similar number of pups in comparison to normal mice while untreated, infertile mice weren’t able to reproduce at all. However, the treated mice were only able to successfully reproduce until about 5 months after treatment, at which point the PIN1 was no longer present.
The full results of this study were published in ACS Nano 2020.
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.”
Due to the ongoing coronavirus pandemic, CIRM converted its 2020 Grantee Meeting with UC Irvine & UC San Diego to a completely virtual format this year. Held on September 14 & 15, we brought together stem cell scientists and trainees that have received CIRM funding. In addition to the complex science, we also heard from patients and patient advocates.
If you want a more extensive breakdown of the talks and sessions, we’ve got you covered there too! We have organized the videos by sessions and speakers on the CIRM website, which you can access by clicking here. The Grantee Meeting this year covered a wide variety of sessions including COVID-19 clinical trials, neurodegenerative diseases, eye diseases, immune disorders, cancer, and much more.
When Evie was born in 2012, she was diagnosed with a fatal immune disorder called ADA-SCID. Her mother, Alysia Vaccaro, spoke about how a CIRM funded stem cell and gene therapy clinical trial cured Evie and gave her daughter a new chance at life.
Brenden Whittaker was born with a rare genetic disorder called X-linked chronic granulomatous disease (X-CGD). This condition affects the immune system’s ability to fight off common germs, specifically bacteria and fungi, and can result in infections that would only be mild for healthy people. Unfortunately for Brenden, he has suffered life-threatening infections that have required him to be hospitalized hundreds of times throughout most of his childhood. At only 16 years old, he got a very bad case of pneumonia that resulted in having tissue from his right lung removed. By age 22, the treatments he had received to fight off infections had stopped working entirely.
His prognosis looked grim, but fortunately he was informed of a CIRM-funded clinical trial conducted by Dr. Don Kohn to treat his condition. He would go on to become the first participant in this trial, which involved taking his blood stem cells, using gene therapy to correct the X-CGD mutation, and reintroducing these modified cells back into his body. Following his treatment, blood tests confirmed that the treatment produced enough corrected cells for Brenden to now be protected from severe infection.
Before the CIRM-funded treatment, the chances of severe infection were virtually everywhere, something many of us might better understand given everything going on with COVID-19. But now with a new lease on life, Brenden is giving back to the very community that helped him in his time of need. He is currently working as a patient care associate at his local hospital in Ohio. Considered an essential worker, Brenden’s responsibilities include taking patients’ vital signs, helping them eat and get cleaned up, and going for walks around the unit with those who are able to do so. He also plans to attend nursing school in the future.
In a news release, Brenden talks about wanting to give back to those in similar situations as him and demonstrates true selflessness.
“My job entails doing anything I can to make a patient’s time in the hospital a little bit easier while at the same time helping the doctors and nurses monitor for any new health developments. From the nurses who sat with me holding my hand and telling me about their lives when I was up in the middle of the night with a fever, to the patient transporters who remembered my name and talked with me the whole way to surgery, to the doctors who wouldn’t give up until they found an option that worked for me, these people are the reason the hospital setting is the only place I want to work. If I can help even one person the way these people have helped me, I will be happy.”
In addition to Brenden, five additional patients who received the same treatment for X-CGD are also doing well. This same gene therapy approach for blood stem cells was used in another CIRM-funded trial for SCID, another kind of genetic immune disorder. The SCID trial resulted in over 50 babies being cured of the condition, including little Evie, who is featured on the cover of CIRM’s 18-month report.