Tay-Sachs disease is a rare genetic disorder where a deficiency in the Hex A gene results in excessive accumulation of certain fats in the brain and nerve cells and causes progressive dysfunction.
There are several forms of Tay-Sachs disease, including an infant, juvenile, and adult forms. Over a hundred mutations in the disease-causing Hex A gene have been identified that result in enzyme disfunction. There are currently no effective therapies or cures for Tay-Sachs.
The UC Davis team will genetically modify the patient’s own blood stem cells to restore the Hex A enzyme that is missing in the disease.
The goal is to complete safety studies and to apply to the US Food and Drug Administration for an Investigational New Drug (IND), the authorization needed to begin a clinical trial in people.
“The successful development of this therapy will not only help patients with Tay-Sachs but will demonstrate the use case of this therapeutic approach for other monogenic neurodegenerative diseases,” the UC Davis team said.
This work is a continuation of aCIRM grantthat the team received.
Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly. Now, new research using 3D organoid models of the eye has uncovered clues as to what happens in AMD, and how to stop it.
In AMD, a person loses their central vision because the light sensitive cells in the macula, a part of the retina, are damaged or destroyed. This impacts a person’s ability to see fine details, recognize faces or read small print, and means they can no longer drive.
AMD causes blurry and distorted vision
No one is quite sure what causes AMD, but in a study in the journal Nature Communications, German researchers used miniature human retina organoids to get some clues.
Building a better model for research
Organoids are 3D models made from human cells that are grown in the lab. Because they have some of the characteristics of a human organ—in this case the retina—they help researchers better understand what is happening in the AMD-affected eye.
In this study they found that photoreceptors, the light sensitive cells at the back of the retina, were missing but there was no sign of dead cells in the organoid. This led them to suspect that something called cell extrusion was at play.
Cell extrusion is where a cell exports or sends large particles outside the cell. In this case it appeared that something was causing these photoreceptors to be extruded, leading to the impaired visual ability.
In a news release Mark Karl, one of the authors of the study, said, “This was the starting point for our research project: we observed that photoreceptors are lost, but we could not detect any cell death in the retina. Half of all photoreceptors disappeared from the retinal organoid within ten days, but obviously they did not die in the retina. That made us curious.”
Using snakes to fight AMD
Further research identified two proteins that appeared to play a key role in the process, triggering the degeneration of the retinal organoid. They also tested a potential therapy to see if they could stop the process and save the photoreceptors. The therapy they tried, a snake venom, not only stopped the photoreceptors from being ejected, but it also prevented further damage to the retinal cells.
Karl says this is the starting point for the next step in the research. “This gives hope for the development of future preventive and therapeutic treatments for complex neurodegenerative diseases such as AMD.”
CIRM’s fight against blindness
The California Institute for Regenerative Medicine (CIRM) has funded six clinical trials targeting vision loss, including one for AMD. We recently interviewed Dr. Dennis Clegg, one of the team trying to develop a treatment for AMD and he talked about the encouraging results they have seen so far. You can hear that interview on our podcast “Talking ‘Bout (re)Generation.”
Earlier this year, CIRM welcomed many energetic and enthusiastic high school students at the 2022 SPARK Program annual conference in Oakland. The SPARK program is one of the California Institute for Regenerative Medicine’s (CIRM) many programs dedicated to building a diverse and highly-skilled workforce to support the growing regenerative medicine economy right here in California.
At the SPARK conference, a handful of students presented the stem cell research they did over the summer. It was a great opportunity to share their experiences as well as findings to their high school peers.
Just recently, Simran Ovalekar—a 2022 SPARK program intern—had the unique opportunity to share her research and findings with a wider audience, including undergraduate and PhD students at STEM Shadow Day in San Diego. The event aims to provide college prep students from San Diego and Imperial Valley counties with a unique experience to witness the “real world” of work in an engineering or scientific environment.
“At first I was nervous because I understood that I would be presenting not only in front of high school students, but also undergraduates and PhD candidates,” Simran says. “After reviewing my research, I felt solid and excited to present. I absolutely loved working in the lab so I knew all I had to do was be myself and show my enthusiasm.”
During the SPARK summer internship, Simran joined the Sacco Lab to study Duchenne Muscular Dystrophy (DMD) and how stem cells can be used to provide treatment. DMD is a progressive muscle wasting disorder with life expectancy of approximately age 20. There are around 17,000 people, the vast majority of them boys, diagnosed with DMD in the US.
Dr. Sacco’s lab—which has also received CIRM funding—is researching ways to generate healthy adult muscle stem cells using the patient’s own cells to generate healthy skeletal muscle.
For Simran, conducting research for DMD was personal, as her sister was born with a defect affecting the heart.
“When I began this program, I had a superficial understanding of what a stem cell was. Now, however, I am amazed at the possibilities stem cells provide, and with certainty, can say stem cells are the future of medicine.”
After her presentation at STEM Shadow Day, Simran says she received a positive response from attendees and was reminded why she loves science and of her passion for pursuing a career in stem cell research.
“I am looking forward to continue skeletal stem cell research and am even open to experimenting with other avenues of molecular medicine,” Simran says. “I am eager to have the opportunity to pursue the hands-on research I enjoyed this past summer.”
CIRM has also funded a clinical trial for people with DMD. We blogged about that work and how the impact it is having on some people’s lives.
El bebé, Tobi recibió un tratamiento de células madre, financiado por el CIRM, mientras aún estaba en el útero.To read this blog in English, click here.
Michelle y Jeff se llenaron de felicidad cuando se enteraron de que iban a tener un bebé.
Luego, un examen de ultrasonido a las 20 semanas del embarazo reveló que el feto tenía espina bífida, una malformación congénita que ocurre cuando la columna vertebral y la médula espinal no se forman de manera adecuada. La espina bífida puede causar parálisis y otras complicaciones serias.
Se derivó a la pareja a un ensayo clínico en la Universidad de California, Davis, que lleva a cabo la Dra. Diana Farmer, cirujana fetal y neonatal reconocida a nivel internacional, y su colega, el Dr. Aijun Wang.
En este ensayo clínico, que se basó en una previa investigación financiada por el CIRM, se repara el defecto espinal aplicando células madre de una placenta donada, las cuales se insertan en una estructura sintética y se aplican al defecto de la médula espinal mientras el bebé se encuentra todavía en el útero.
El hijo de Michelle y Jeff, Tobi, fue el segundo paciente que recibió este tratamiento. Michelle dijo que la cirugía fue difícil, pero el nacimiento de su bebé valió la pena.
“Cuando lo abrazamos por primera vez dijimos, ‘No puedo creer que hayamos hecho esto. Lo logramos. Lo hicimos sin saber si funcionaría’.”
A los tres meses, el progreso de Tobi parece promisorio. Jeff y Michelle saben que pueden surgir problemas más adelante, pero por ahora se sienten agradecidos de haber formado parte de este ensayo.
A study by Stanford Medicine researchers in older mice may lead to treatments that help seniors regain muscle strength lost to aging.
Muscle stem cells—which are activated in response to muscle injury to regenerate damaged muscle tissue—lose their potency with age. A study from the National Health and Nutrition Examination Survey showed that five percent of adults aged 60 and over had weak muscle strength, and thirteen percent had intermediate muscle strength.
Now, researchers at Stanford Medicine are seeing that old mice regain the leg muscle strength of younger animals after receiving an antibody treatment that targets a pathway mediated by a molecule called CD47.
CD47 is a protein found on the surface of many cells in the body. Billed as the “don’t eat me” molecule, it is better known as a target for cancer immunotherapy. It’s common on the surface of many cancer cells and protects them from immune cells that patrol the body looking for dysfunctional or abnormal cells.
Stanford researchers are finding that old muscle stem cells may use a similar approach to avoid being targeted by the immune system.
It’s been difficult to determine why muscle stem cells lose their ability to divide rapidly in response to injury or exercise as they age. Dr. Ermelinda Porpiglia, the lead author of the study, used a technique called “single-cell mass cytometry” to study mouse muscle stem cells.
Using the technique, Porpiglia focused on CD47, and found that the molecule was found at high levels on the surface of some muscle stem cells in older mice, but at lower levels in younger animals. Porpiglia also found that high levels of CD47 on the surface of muscle stem cells correlate with a decrease in their function.
“This finding was unexpected because we primarily think of CD47 as an immune regulator,” Porpiglia said. “But it makes sense that, much like cancer cells, aged stem cells might be using CD47 to escape the immune system.”
Testing an Antibody
Further investigation revealed that a molecule called thrombospondin, which binds to CD47 on the surface of the muscle stem cells, suppresses the muscle stem cells’ activity.
Porpiglia showed that an antibody that recognizes thrombospondin and blocks its ability to bind to CD47 dramatically affected the function of muscle stem cells. Cells from older animals divided more robustly when growing in a laboratory dish in the presence of the antibody, and when the antibody was injected into the leg muscles of old mice the animals developed bigger and stronger leg muscles than control animals.
When given prior to injury, the antibody helped the aged animals recover in ways similar to younger mice.
Porpiglia said, “We are hopeful that it might one day be possible to inject an antibody to thrombospondin at specific sites in the body to regenerate muscle in older people or to counteract functional problems due to disease or surgery.”
These results are significant because they could one day make it possible to boost muscle recovery in humans after surgery and reduce the decline in muscle strength as people age, but researchers say more work is needed.
“Rejuvenating the muscle stem cell population in older mice led to a significant increase in strength,” said Dr. Helen Blau, a senior author of the study. “This is a localized treatment that could be useful in many clinical settings, although more work needs to be done to determine whether this approach will be safe and effective in humans.”
CIRM has previously funded work with researchers using CD47 that led to clinical trials targeting cancer. You can read about that work here and here. That work led to the creation of a company, Forty Seven Inc, which was eventually bought by Gilead for $4.9 billion.
Dr. Diana Farmer (right) meets with Emily Lofton and her baby Robbie who had stem cell treatment for spina bifida in the womb. Photo: UC Davis Health
The California Institute for Regenerative Medicine (CIRM) recently shared some encouraging news on The Stem Cellar about a CIRM-funded stem cell clinical trial for spina bifida at UC Davis Health.
Spina bifida is a birth defect that occurs when the spine and spinal cord don’t form properly and can result in life-long walking and mobility problems for the child, even paralysis.
Now, UC Davis has released more details about the clinical trial and the babies born after receiving the world’s first spina bifida treatment combining surgery with stem cells. The story was featured in BBC News and The Sacramento Bee.
The first phase of the trial is funded by a $9 million grant from the California Institute for Regenerative Medicine.
The one-of-a-kind treatment, delivered while a fetus is still developing in the mother’s womb, could improve outcomes for children with this birth defect.
A Decade’s Work
“I’ve been working toward this day for almost 25 years now,” said Dr. Diana Farmer, the world’s first woman fetal surgeon, professor and chair of surgery at UC Davis Health and principal investigator on the study.
In previous clinical trial, Farmer had helped to prove that fetal surgery reduced neurological deficits from spina bifida. Many children in that study showed improvement but still required wheelchairs or leg braces.
Dr. Diana Farmer and Dr. Aijun Wang. Photo courtesy UC Davis Health
Farmer recruited bioengineer Dr. Aijun Wang to help take that work to the next level. Together, they researched and tested ways to use stem cells and bioengineering to advance the effectiveness and outcomes of the surgery.
Farmer, Wang and their research team have been working on their novel approach using stem cells in fetal surgery for more than 10 years. Over that time, animal modeling has shown it is capable of preventing the paralysis associated with spina bifida.
Preliminary work by Farmer and Wang proved that prenatal surgery combined with human placenta-derived mesenchymal stromal cells, held in place with a biomaterial scaffold to form a “patch,” helped lambs with spina bifida walk without noticeable disability. When the team refined their surgery and stem cells technique for canines, the treatment also improved the mobility of dogs with naturally occurring spina bifida.
The CuRe Trial
When Emily and her husband Harry learned that they would be first-time parents, they never expected any pregnancy complications. But the day that Emily learned that her developing child had spina bifida was also the day she first heard about the CuRe trial, as the clinical trial is known.
Participating in the trial would mean that she would need to temporarily move to Sacramento for the fetal surgery and then for weekly follow-up visits during her pregnancy.
After screenings, MRI scans and interviews, Emily received the news that she was accepted into the trial. Her fetal surgery was scheduled for July 12, 2021, at 25 weeks and five days gestation.
Farmer and Wang’s team manufactured clinical grade stem cells—mesenchymal stem cells—from placental tissue in the UC Davis Health’s CIRM-funded Institute for Regenerative Cures. The lab is a Good Manufacturing Practice (GMP) Laboratory for safe use in humans. It is here that they made the stem cell patch for Emily’s fetal surgery.
The Procedure
During Emily’s historic procedure, a small opening was made in her uterus and they floated the fetus up to that incision point so they could expose its spine and the spina bifida defect.
Then, the stem cell patch was placed directly over the exposed spinal cord of the fetus. The fetal surgeons then closed the incision to allow the tissue to regenerate. The team declared the first-of-its-kind surgery a success.
On Sept. 20, 2021, at 35 weeks and five days gestation, Robbie was born at 5 pounds, 10 ounces, 19 inches long via C-section.
For Farmer, this day is what she had long hoped for, and it came with surprises. If Robbie had remained untreated, she was expected to be born with leg paralysis.
Baby Robbie underwent treatment for spina bifida while in the womb. Photo credit: UC David Health
“It was very clear the minute she was born that she was kicking her legs and I remember very clearly saying, ‘Oh my God, I think she’s wiggling her toes!’” said Farmer. “It was amazing. We kept saying, ‘Am I seeing that? Is that real?’”
Both mom and baby are at home and in good health. Robbie just celebrated her first birthday.
Emily Lofton and her baby daughter Robbie who underwent treatment for spina bifida while in the womb.
The CuRe team is cautious about drawing conclusions and says a lot is still to be learned during this safety phase of the trial. The team will continue to monitor Robbie and the other babies in the trial until they are 6 years old, with a key checkup happening at 30 months to see if they are walking and potty training.
“This experience has been larger than life and has exceeded every expectation. I hope this trial will enhance the quality of life for so many patients to come,” Emily said. “We are honored to be part of history in the making.”
Read the official release from UC Davis Health here.
Senior author of the study Clive Svendsen, PhD (center)
With funding support from the California Institute for Regenerative Medicine (CIRM), Cedars-Sinai investigators have developed an investigational therapy using support cells and a protective protein that can be delivered past the blood-brain barrier. This combined stem cell and gene therapy can potentially protect diseased motor neurons in the spinal cord of patients with amyotrophic lateral sclerosis, a fatal neurological disorder known as ALS or Lou Gehrig’s disease.
In the first trial of its kind, the Cedars-Sinai team showed that delivery of this combined treatment is safe in humans. The findings were reported in the peer-reviewed journal Nature Medicine.
What causes ALS?
ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. About 6,000 people are diagnosed with ALS each year in the U.S., and the average survival time is two to five years.
The disease results when the cells in the brain or spinal cord that instruct muscles to move—called motor neurons—die off. People with the disease lose the ability to move their muscles and, over time, the muscles atrophy and people become paralyzed and eventually die. There is no effective therapy for the disease.
Using Stem Cells to Treat ALS
In a news release, senior author Clive Svendsen, PhD, executive director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute, says using stem cells shows lots of promise in treating patients with ALS.
“We were able to show that the engineered stem cell product can be safely transplanted in the human spinal cord. And after a one-time treatment, these cells can survive and produce an important protein for over three years that is known to protect motor neurons that die in ALS,” Svendsen says.
Aimed at preserving leg function in patients with ALS, the engineered cells could pave the way to a therapeutic option for this disease that causes progressive muscle paralysis, robbing people of their ability to move, speak and breathe.
The study used stem cells originally designed in Svendsen’s laboratory to produce a protein called glial cell line-derived neurotrophic factor (GDNF). This protein can promote the survival of motor neurons, which are the cells that pass signals from the brain or spinal cord to a muscle to enable movement.
In patients with ALS, diseased glial cells can become less supportive of motor neurons, and these motor neurons progressively degenerate, causing paralysis.
By transplanting the engineered protein-producing stem cells in the central nervous system, where the compromised motor neurons are located, these stem cells can turn into new supportive glial cells and release the protective protein GDNF, which together helps the motor neurons stay alive.
Ensuring Safety in the Trial
The primary goal of the trial was to ensure that delivering the cells releasing GDNF to the spinal cord did not have any safety issues or negative effects on leg function.
In this trial, none of the 18 patients treated with the therapy—developed by Cedars-Sinai scientists and funded by CIRM—had serious side effects after the transplantation, according to the data.
Because patients with ALS usually lose strength in both legs at a similar rate, investigators transplanted the stem cell-gene product into only one side of the spinal cord so that the therapeutic effect on the treated leg could be directly compared to the untreated leg.
After the transplantation, patients were followed for a year so the team could measure the strength in the treated and untreated legs. The goal of the trial was to test for safety, which was confirmed, as there was no negative effect of the cell transplant on muscle strength in the treated leg compared to the untreated leg.
What’s Next?
Investigators expect to start a new study with more patients soon. They will be targeting lower in the spinal cord and enrolling patients at an earlier stage of the disease to increase the chances of seeing effects of the cells on the progression of ALS.
“We are very grateful to all the participants in the study,” said Svendsen. “ALS is a very tough disease to treat, and this research gives us hope that we are getting closer to finding ways to slow down this disease.”
The Cedars-Sinai team is also using the GDNF-secreting stem cells in another CIRM-funded clinical trial for ALS, transplanting the cells into a specific brain region, called the motor cortex that controls the initiation of movement in the hand. The clinical trial is also funded by CIRM.
The California Institute for Regenerative Medicine (CIRM) remains committed to funding research and clinical trials to treat ALS. To date, CIRM has provided $93 million in funding for research to treat ALS.
Read the original source release of the study here.
David Anjakos in the lab. Photo courtesy Sarah White/SDSU.
When he was younger, David Anjakos experienced kidney failure due to an autoimmune disease, leaving him without kidneys in his body. As a trainee in the California Institute for Regenerative Medicine’s Bridges to Stem Cell Research Internship Program, Anjakos is researching methods of growing organs for transplantation to help people on a transplant list, himself included.
By now, Anjakos thought he’d have his own kidney and that he would be off the transplant list and dialysis. That’s not the case, so he realized he wanted to try and do something about it.
“Fifteen years later, we haven’t really gotten there. It just shows how complex the problem is and how even with thousands of hours and scientists working on this, we still haven’t quite got there,” he says. “What that showed me is that I needed to step in. We need more people on these problems.”
David Anjakos in the lab. Photo courtesy Sarah White/SDSU.
That’s what inspired him to join the CIRM Bridges Program at San Diego State University. Specifically, he wanted to get into stem cells to try to control them to do what he wanted them to do. He’s completing his internship at the Sanford Consortium for Regenerative Medicine, where he is working toward developing a protein that will be able to activate stem cells to turn into different organs.
If successful, this will be important for drug discovery, growing organs and vascularization, the process of growing blood vessels into a tissue to improve oxygen and nutrient supply.
“CIRM’s Bridges to Stem Cell Research program has really been a huge opportunity for me to get into science, to practice science, to practice the skills that I’ll need,” said Anjakos. “It has really helped me in my confidence in my ability to do science.”
After finishing his Bridges internship at the Sanford Consortium, Anjakos plans to start a PhD program so he can apply all he has learned from creating approximations of the Wnt protein that is essential for turning stem cells into organs with functioning vessels.
To date, there are 1,663 Bridges alumni, and another 109 Bridges trainees are completing their internships in 2022.
Started in 2009, the Bridges program provides paid stem cell research internships to students at universities and colleges that don’t have major stem cell research programs. Each Bridges internship includes thorough hands-on training and education in regenerative medicine and stem cell research, and direct patient engagement and outreach activities that engage California’s diverse communities. Click here to learn more about CIRM’s educational programs.
This story was first covered by Sarah White and Susanne Clara Bard. Read the original release on the San Diego State University website.
The California Institute for Regenerative Medicine (CIRM) is seeking applications for its next round of Quest Awards (DISC2) for discovery stage research.
Applications are due August 2nd, 2022, at 2:00 PM PDT. Please visit the CIRM website for full details.
The purpose of the Quest Awards is to promote the discovery of promising new stem cell-based or gene therapy technologies that could be translated to enable broad use and ultimately, improve patient care.
Applications should propose technology that is uniquely enabled by human stem/progenitor cells or directly reprogrammed cells, or that is uniquely enabling for the advancement of stem cell-based therapies or aimed at developing a genetic therapy approach.
The expected outcome, at the end of the award, is a candidate therapeutic or technology that can immediately progress to translational stage activities. For projects that culminate in a candidate that is a diagnostic, medical device or tool, the proposed project period must not exceed 2 years and direct project costs can be up to $500,000 per award. For projects that culminate in a candidate that is a therapeutic, an applicant may request up to $1,500,000 in direct project costs for up to 3 years duration.
Important Update: Please note that the DISC2 Program Announcement has been updated since the last round of applications. Please read the new program announcement on the CIRM funding website before submitting your application.
To receive updates about future funding opportunities through CIRM, please visit our e-mail newsletter page to sign up.
We spend around one third of our life sleeping—or at least we should. Not getting enough sleep can have serious consequences on many aspects of our health and has been linked to high blood pressure, heart disease and stroke.
A study by the American Sleep Apnea Association found that some 70 percent of Americans report getting too little sleep at least one night a month, and 11 percent report not enough sleep every night. Over time that can take a big toll on your mental and physical health. Now a new study says that impact can also put you at increased risk for eye disease.
The study published in the journal Stem Cell Reports, looked at how sleep deprivation affects corneal stem cells. These cells are essential in replacing diseased or damaged cells in the cornea, the transparent tissue layer that covers and protects the eye.
Researchers Wei Li, Zugou Liu and colleagues from Xiamen University, China and Harvard Medical School, USA, found that, in mice short-term sleep deprivation increased the rate at which stem cells in the cornea multiplied. Having too many new cells created vision problems.
They also found that long-term sleep deprivation had an even bigger impact on the health of the cornea. Sleep-deprived mice had fewer active stem cells and so were not as effective in replacing damaged or dying cells. That in turn led to a thinning of the cornea and a loss of transparency in the remaining cells.
The cornea— the transparent tissue layer covering the eye—is maintained by stem cells, which divide to replace dying cells and to repair small injuries.
The findings suggest that sleep deprivation negatively affects the stem cells in the cornea, possibly leading to vision impairment in the long run. It’s not clear if these findings also apply to people, but if they do, the implications could be enormous.
The Stem Cellar 