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.”
I thought that headline would grab your attention. The idea behind it grabbed my attention when I read about a new study in the journal Cell Metabolismthat explored that idea and came away with a rather encouraging verdict of “perhaps”.
The research team from the University of Helsinki say that on average people lose 1.5 grams of hair every day, which over the course of a year adds up to more than 12 pounds (I think, sadly, this is the one area where I’m above average.) Normally all that falling hair is replaced by stem cells, which generate new hair follicles. However, as we get older, those stem cells don’t work as efficiently which explains why so many men go bald.
In a news release, lead author Sara Wickstrom says this was the starting point for their study.
“Although the critical role of stem cells in ageing is established, little is known about the mechanisms that regulate the long-term maintenance of these important cells. The hair follicle with its well understood functions and clearly identifiable stem cells was a perfect model system to study this important question.”
Previous studies have shown that after stem cells create new hair follicles they essentially take a nap (resume a quiescent state in more scientific parlance) until they are needed again. This latest study found that in order to do that the stem cells have to change their metabolism, reducing their energy use in response to the lower oxygen tissue around them. The team identified a protein called Rictor that appears to be the key in this process. Cells with low levels of Rictor were less able to wake up when needed and generate more hair follicles. Fewer replacements, bigger gaps in the scalp.
The team then created a mouse model to test their theory. Sure enough, mice with low or no Rictor levels were less able to regenerate hair follicles. Not surprisingly this was most apparent in older mice, who showed lower Rictor levels, decreased stem cell activity and greater hair loss.
Sara Wickstrom says this could point to new approaches to reversing the process.
“We are particularly excited about the observation that the application of a glutaminase inhibitor was able to restore stem cell function in the Rictor-deficient mice, proving the principle that modifying metabolic pathways could be a powerful way to boost the regenerative capacity of our tissues,”
It’s early days in the research so don’t expect them to be able to put the Hair Club for Men out of business any time soon. But a follicle-challenged chap can dream can’t he.
At CIRM we are modest enough to know that we can’t do everything by ourselves. To succeed we need partners. And in UC Davis we have a terrific partner. The work they do in advancing stem cell research is exciting and really promising. But it’s not just the science that makes them so special. It’s also their compassion and commitment to caring for patients.
What follows is an excerpt from an article by Lisa Howard on the work they do at UC Davis. When you read it you’ll see why we are honored to be a part of this research.
Gene therapy research at UC Davis
UC Davis’ commitment to stem cell and gene therapy research dates back more than a decade.
In 2010, with major support from the California Institute for Regenerative Medicine (CIRM), UC Davis launched the UC Davis Institute for Regenerative Cures, which includes research facilities as well as a Good Manufacturing Practice (GMP) facility.
Led by Jan Nolta, a professor of cell biology and human anatomy and the director of the UC Davis Institute for Regenerative Cures, the new center leverages UC Davis’ network of expert researchers, facilities and equipment to establish a center of excellence aimed at developing lifelong cures for diseases.
Nolta began her career at the University of Southern California working with Donald B. Kohn on a cure for bubble baby disease, a condition in which babies are born without an immune system. The blood stem cell gene therapy has cured more than 50 babies to date.
Work at the UC Davis Gene Therapy Center targets disorders that potentially can be treated through gene replacement, editing or augmentation.
“The sectors that make up the core of our center stretch out across campus,” said Nolta. “We work with the MIND Institute a lot. We work with the bioengineering and genetics departments, and with the Cancer Center and the Center for Precision Medicine and Data Sciences.”
A recent UC Davis stem cell study shows a potential breakthrough for healing diabetic foot ulcers with a bioengineered scaffold made up of human mesenchymal stem cells (MSCs). Another recent study revealed that blocking an enzyme linked with inflammation enables stem cells to repair damaged heart tissue. A cell gene therapy study demonstrated restored enzyme activity in Tay-Sachs disease affected cells in humanized mouse models.
“Some promising and exciting research right now at the Gene Therapy Center comes from work with hematopoietic stem cells and with viral vector delivery,” said Nolta.
Hematopoietic stem cells give rise to other blood cells. A multi-institutional Phase I clinical trial using hematopoietic stem cells to treat HIV-lymphoma patients is currently underway at UC Davis.
“We are genetically engineering a patient’s own blood stem cells with genes that block HIV infection,” said Joseph Anderson, an associate professor in the UC Davis Department of Internal Medicine. The clinical trial is a collaboration with Mehrdad Abedi, the lead principal investigator.
“When the patients receive the modified stem cells, any new immune system cell, like T-cell or macrophage, that is derived from one of these stem cells, will contain the HIV-resistant genes and block further infection,” said Anderson.
He explained that an added benefit with the unique therapy is that it contains an additional gene that “tags” the stem cells. “We are able to purify the HIV-resistant cells prior to transplantation, thus enriching for a more protective cell population.
Kyle David Fink
Kyle David Fink, an assistant professor of neurology at UC Davis, is affiliated with the Stem Cell Program and Institute for Regenerative Cures. His lab is focused on leveraging institutional expertise to bring curative therapies to rare, genetically linked neurological disorders.
“We are developing novel therapeutics targeted to the underlying genetic condition for diseases such as CDKL5 deficiency disorder, Angelman, Jordan and Rett syndromes, and Juvenile Huntington’s disease,” said Fink.
The lab is developing therapies to target the underlying genetic condition using DNA-binding domains to modify gene expression in therapeutically relevant ways. They are also creating novel delivery platforms to allow these therapeutics to reach their intended target: the brain.
“The hope is that these highly innovative methods will speed up the progress of bringing therapies to these rare neurodegenerative disease communities,” said Fink.
Jasmine Carter, a graduate research assistant at the UC Davis Stem Cell Program, October 18, 2019. (AJ Cheline/UC Davis)
Developing potential lifetime cures
Among Nolta’s concerns is how expensive gene therapy treatments can be.
“Some of the therapies cost half a million dollars and that’s simply not available to everyone. If you are someone with no insurance or someone on Medicare, which reimburses about 65 percent, it’s harder for you to get these life-saving therapies,” said Nolta.
To help address that for cancer patients at UC Davis, Nolta has set up a team known as the “CAR T Team.”
Chimeric antigen receptor (CAR) T-cell therapy is a type of immunotherapy in which a patient’s own immune cells are reprogrammed to attack a specific protein found in cancer cells.
“We can develop our own homegrown CAR T-cells,” said Nolta. “We can use our own good manufacturing facility to genetically engineer treatments specifically for our UC Davis patients.”
Although safely developing stem cell treatments can be painfully slow for patients and their families hoping for cures, Nolta sees progress every day. She envisions a time when gene therapy treatments are no longer considered experimental and doctors will simply be able to prescribe them to their patients.
“And the beauty of the therapy is that it can work for the lifetime of a patient,” said Nolta.
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.
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.
Sometimes you read about a new study where the researchers did something that just leaves you gob smacked. That’s how I felt when I read a study in the journal Cell Stem Cell about a possible new approach to helping people with Parkinson’s Disease (PD).
More on the gob smacking later. But first the reason for the study.
We know that one of the causes of Parkinson’s disease is the death of dopamine-producing neurons, brain cells that help plan and control body movement. Over the years, researchers have tried different ways to try and replace those cells but getting the cells where they need to be and getting them to integrate into the brain has proved challenging.
A team at the University of Wisconsin-Madison think they may have found a way to fix that. In an article in Drug Target Review lead researcher Dr. Su-Chun Zhang, explained their approach:
“Our brain is wired in such an accurate way by very specialized nerve cells in particular locations so we can engage in all our complex behaviors. This all depends on circuits that are wired by specific cell types. Neurological injuries usually affect specific brain regions or specific cell types, disrupting circuits. In order to treat those diseases, we have to restore these circuits.”
The researchers took human embryonic stem cells and transformed them into dopamine-producing neurons, then they transplanted those cells into mice specially bred to display PD symptoms. After several months the team were able to show that not only had the mice improved motor skills but that the transplanted neurons were able to connect to the motor-control regions of the brain and also establish connections with regulatory regions of the brain, which prevented over stimulation. In other words, the transplanted cells looked and behaved the way they would in a healthy human brain.
Now here comes the gob smack part. The team wanted to make sure the cells they transplanted were the reason for the improved motor control in the mice. So, they had inserted a genetic on-and-off switch into the stem cells. By using specially designed drugs the researchers were able to switch the cells on or off.
When the cells were switched off the mice’s motor improvements stopped. When they were switched back on, they were restored.
Brilliant right! Well, I thought it was.
Next step is to test this approach in larger animals and, if all continues to look promising, to move into human clinical trials.
CIRM is already funding one clinical trial in Parkinson’s disease. You can read about it here.
COVID-19 and social and racial injustice are two of the biggest challenges facing the US right now. This Thursday, October 8th, we are holding a conversation that explores finding answers to both.
The CIRM Alpha Stem Cell Clinic Network Symposium is going to feature presentations about advances in stem cell and regenerative research, highlighting treatments that are already in the clinic and being offered to patients.
But we’re also going to dive a little deeper into the work we support, and use it to discuss two of the most pressing issues of the day.
One of the topics being featured is research into COVID-19. To date CIRM has funded 17 different projects, including three clinical trials. We’ll talk about how these are trying to find ways to help people infected with the virus, seeing if stem cells can help restore function to organs and tissues damaged by the virus, and if we can use stem cells to help develop safe and effective vaccines.
Immediately after that we are going to use COVID-19 as a way of exploring how the people most at risk of being infected and suffering serious consequences, are also the ones most likely to be left out of the research and have most trouble accessing treatments and vaccines.
Study after study highlights how racial and ethnic minorities are underrepresented in clinical trials and disproportionately affected by debilitating diseases. We have a responsibility to change that, to ensure that the underserved are given the same opportunity to take part in clinical trials as other communities.
How do we do that, how do we change a system that has resisted change for so long, how do we overcome the mistrust that has built up in underserved communities following decades of abuse? We’ll be talking about with experts who are on the front lines of this movement.
It promises to be a lively meeting. We’d love to see you there. It’s virtual – of course – it’s open to everyone, and it’s free.
Timothy Ray Brown, a man who was the first person to be cured of HIV, giving hope to millions of people around the world, died at his home in Palm Springs this week. He was just 54 years old.
For years Brown was known simply as “the Berlin patient” because that was where he was living when he made medical history. He was diagnosed with HIV in 1995 and began taking medications to keep the virus under control. He was later also diagnosed with leukemia. He underwent several rounds of treatment for the leukemia, but it kept recurring.
By 2007 Brown’s physician decided the best way to treat the leukemia was with a blood stem cell transplant. But the doctor also wanted to see if using the stem cells from a donor who had a natural immunity to the AIDS virus could help treat Brown’s HIV. While such donors are very rare, the doctor succeeded in finding one whose bone marrow carried the CCR5 gene, a mutation that is believed to provide resistance to HIV. The transplant was a success, putting Brown’s leukemia into remission and eliminating detectable traces of HIV. For the first time in years he was able to stop taking the medications that had helped keep the virus under control.
The procedure quickly garnered world-wide attention. But not everyone was convinced it was real. Some questioned if Brown’s HIV had really been eradicated and speculated that the virus was merely suppressed. But with each passing year, and no signs of the virus recurring, more and more people came to believe it was a cure.
Initially Brown remained in the background, preferring not to be identified. But three years after his transplant he decided he had to come forward and put a face on “the Berlin patient”. In an interview with the website ContagionLive he explained why:
“At some point, I decided I didn’t want to be the only person in the world cured of H.I.V.,” I wanted there to be more. And the way to do that was to show the world who I am and be an advocate for H.I.V.”
He proved to be a powerful advocate, talking at international conferences and serving as living-proof that stem cells could help lead to a cure for HIV.
But while he managed to beat HIV, he could not beat leukemia. He suffered relapses that required another transplant and a difficult recovery. When it returned again this time, there was little physicians could do.
But Timothy Ray Brown did get to see his hope of not being the only patient cured seemingly come true. In September of last year researchers announced they had successfully treated a second person, known as “the London patient” using the same technique that cured Brown.
While it wasn’t the role he would have chosen Brown was a pioneer. His experience showed that a deadly virus could be cured. His courage in not just overcoming the virus but in overcoming his own reluctance to take center stage and becoming a symbol of hope for millions remain and will never die.
Since Brown’s transplant many other scientists have attempted to replicate the procedure that cured Brown, in the hopes of making it available to many more people.
CIRM has funded three clinical trials targeting HIV, two of which are still active. Dr. Mehrdad Abedi at UC Davis and Dr. John Zaia at City of Hope are both using the patient’s own blood forming stem cells to try and defeat the virus.
If they succeed, some of the credit should go to Timothy Ray Brown, the man who led the way.
Recently, The New York Times released a powerful article that tells the stories of four different families navigating the challenges of having a family member with a rare disease. One of these stories focused on Matt Wilsey, a tech entrepreneur and investor in California’s Silicon Valley, and his daughter Grace, who was born with an extremely rare genetic disorder named NGLY1 deficiency. This genetic disorder causes developmental delay, intellectual disability, seizures, and other movement issues.
Matt decided to put his entrepreneurial and networking skills to good use in order to form Grace Science Foundation, an organization whose focus is to pioneer approaches to scientific discovery in order to develop a cure for NGLY1 deficiency. One researcher that Matt brought on board was Carolyn Bertozzi, Ph.D., a chemist from Stanford University. A graduate student in her laboratory, Ian Blong, Ph.D., decided to study NGLY1 and was able to complete his dissertation while working on this topic at Stanford University.
In exploring the various options afforded to him by the CIRM, Ian found Dr. Bertozzi’s lab at UC Berkeley, where he focused on early stage discovery research. His master’s thesis project focused on how to generate rare neuronal and and neural crest cells from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs). Both of these stem cell types can generate virtually any kind of cell, but iPSCs are unique in that they can be generated from the adult cells (such as skin) of a patient.
Ian decided to continue his studies in Dr. Bertozzi’s lab by continuing his research in a Ph.D. program at UC Berkeley. He credits the SFSU CIRM Bridges Program with giving him the opportunity to work under a prestigious PI and in her lab at UC Berkeley, which allowed him to continue his studies there.
“The CIRM Bridges Program gave me the confidence and resources to pursue my dreams. Being able to have the capability of going to Berkeley and do research with top tier scientists along with the support from CIRM. Without CIRM, I wouldn’t have had the courage to go to those universities to get my foot in the door.”
Eventually, Dr. Bertozzi move her operations to Stanford University and Ian continued his Ph.D. studies there. Stanford provided him the opportunity to focus more on the translational stage, which is an area of research aimed at developing a therapeutic candidate. Going into his Ph.D. work, Ian was able to build upon his previous “discovery stage” knowledge of generating neuronal and neural crest cells from iPSCS and hESCs.
An area of his work at Stanford focused on generating neural crest cells from iPSCs of those with NGLY1 deficiency. The goal was to identify a phenotype, which is an observable characteristic such as physical form. Identifying this would help better understand potential differentiation pathways that underlie NGLY1 deficiency, which could lead to the development a potential treatment for the condition.
Flash forward to present day and Ian is still using the knowledge he learned from his time in the SFSU CIRM Bridges to Stem Cell Research Program. He is currently a scientist at the healthcare company Roche, where his focus is on manufacturing future diagnostics and therapeutics on a much larger scale, a complex and extremely critical process necessary in widely distributing potential stem cell-based treatments.
Ian’s experience and opportunities provided to him is just one of the many examples of how the various CIRM Bridges Programs across California have given students the resources needed to become the next generation of scientists.
When people ask me what I do at CIRM I sometimes half-jokingly tell them that I’m the official translator: I take complex science and turn it into everyday English. That’s important. The taxpayers of California have a right to know how their money is being spent and how it might benefit them. But that message can be even more effective when it comes from the scientists themselves.
Recently we asked some of the scientists we are funding to do research into COVID-19 to record what’s called an “elevator pitch”. This is where they prepare an explanation of their work that is in ordinary English and is quite short, short enough to say it to someone as you ride in an elevator. Hence the name.
It sounds easy enough. But it’s not. When you are used to talking in the language of science day in and day out, suddenly switching codes to talk about your work in plain English can take some practice. Also, you have spent years, often decades, on this work and to have to explain it in around one minute is no easy thing.
But our researchers rose to the challenge. Here’s some examples of just how well they did.