Lab-made retinas offer a new approach to battling vision loss

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.” 

Bubble baby treatment cleared to restart clinical trial

Evie Vaccaro: Photo courtesy Nancy Ramos

Three families battling a life-threatening immune disorder got some great news last week. A clinical trial that could save the life of their child has once again been given the go-ahead by the US Food and Drug Administration (FDA).

The clinical trial is the work of UCLA’s Dr. Don Kohn, and was strongly supported by CIRM. It is targeting ADA-SCID, a condition where the child is born without a functioning immune system so even a simple infection could prove fatal. In the past they were called “bubble babies” because some had been placed inside sterile plastic bubbles to protect them from germs.

Dr. Kohn’s approach – using the patient’s own blood stem cells, modified in the lab to correct the genetic mutation that causes the problem – had shown itself to be amazingly effective.  In a study in the prestigious New England Journal of Medicine, the researchers showed that of 50 patients treated all had done well and 97 percent were considered cured.

UCLA licensed the therapy to Orchard Therapeutics, who planned to complete the testing needed to apply for permission to make it more widely available. But Orchard ran into problems and shelved the therapy.

After lengthy negotiations Orchard returned the therapy to UCLA last year and now the FDA has given clearance for UCLA to resume treating patients. That is expected to start early next year using CIRM funds left over when Orchard halted its work.

One of the people who played a big role in helping persuade Orchard to return the therapy to UCLA is Alysia Vaccaro. She is the mother of Evie, a child born with ADA-SCID who was cured by Dr. Kohn and his team and is now a thriving 9 year old.

You can watch an interview we did with Alysia about the impact this research has had on her family, and how important it is for other families with ADA-SCID kids.

High school SPARK intern presents stem cell research to academic audience 

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.  

 

Tratando malformaciones congénitas antes del nacimiento 

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.

To read this blog in English, click here.

Making transplants easier for kids, and charting a new approach to fighting solid tumors.

Every year California performs around 100 kidney transplants in children but, on average, around 50 of these patients will have their body reject the transplant. These children then have to undergo regular dialysis while waiting for a new organ. Even the successful transplants require a lifetime of immunosuppression medications. These medications can prevent rejection but they also increase the risk of infection, gastrointestinal disease, pancreatitis and cancer.

Dr. Alice Bertaina and her team at Stanford University were awarded $11,998,188 to test an approach that uses combined blood stem cell (HSC) and kidney transplantation with the goal to improve outcomes with kidney transplantation in children. This approach seeks to improve on the blood stem cell preparation through an immune-based purification process.

In this approach, the donor HSC are transplanted into the patient in order to prepare for the acceptance of the donor kidney once transplanted. Donor HSC give rise to cells and conditions that re-train the immune system to accept the kidney. This creates a “tolerance” to the transplanted kidney providing the opportunity to avoid long-term need for medications that suppress the immune system.

Pre-clinical data support the idea that this approach could enable the patient to stop taking any immunosuppression medications within 90 days of the surgery.

Dr. Maria T. Millan, President and CEO of CIRM, a former pediatric transplant surgeon and tolerance researcher states that “developing a way to ensure long-term success of organ transplantation by averting immune rejection while avoiding the side-effects of life-long immunosuppression medications would greatly benefit these children.”

The CIRM Board also awarded $7,141,843 to Dr. Ivan King and Tachyon Therapeutics, Inc to test a drug showing promise in blocking the proliferation of cancer stem cells in solid tumors such as colorectal and gastrointestinal cancer.

Patients with late-stage colorectal cancer are typically given chemotherapy to help stop or slow down the progression of the disease. However, even with this intervention survival rates are low, usually not more than two years.

Tachyon’s medication, called TACH101, is intended to target colorectal cancer (CRC) stem cells as well as the bulk tumor by blocking an enzyme called KDM4, which cancer stem cells need to grow and proliferate.

In the first phase of this trial Dr. King and his team will recruit patients with advanced or metastatic solid tumors to assess the safety of TACH101, and determine what is the safest maximum dose. In the second phase of the trial, patients with gastrointestinal tumors and colorectal cancer will be treated using the dose determined in the first phase, to determine how well the tumors respond to treatment.  

The CIRM Board also awarded $5,999,919 to Dr. Natalia Gomez-Ospina and her team at Stanford University for a late-stage preclinical program targeting Severe Mucopolysaccharidosis type 1, also known as Hurler syndrome. This is an inherited condition caused by a faulty gene. Children with Hurler syndrome lack an enzyme that the body needs to digest sugar. As a result, undigested sugar molecules build up in the body, causing progressive damage to the brain, heart, and other organs. There is no effective treatment and life expectancy for many of these children is only around ten years.

Dr. Gomez-Ospina will use the patient’s own blood stem cells that have been genetically edited to restore the missing enzyme. The goal of this preclinical program is to show the team can manufacture the needed cells, 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.

Finally the Board awarded $20,401,260 to five programs as part of its Translational program. The goal of the Translational program is to support promising stem cell-based or gene projects that accelerate completion of translational stage activities necessary for advancement to clinical study or broad end use. Those can include therapeutic candidates, diagnostic methods  or devices and novel tools that address critical bottlenecks in research.

The successful applicants are:

APPLICATIONTITLEPRINCIPAL INVESTIGATOR – INSTITUTIONAMOUNT  
TRAN4-14124Cell Villages and Clinical Trial in a Dish with Pooled iPSC-CMs for Drug DiscoveryNikesh Kotecha — Greenstone Biosciences  $1,350,000
TRAN1-14003Specific Targeting Hypoxia Metastatic Breast Tumor with Allogeneic Off-the-Shelf Anti-EGFR CAR NK Cells Expressing an ODD domain of HIF-1αJianhua Yu — Beckman Research Institute of City of Hope  $6,036,002  
TRAN1-13983CRISPR/Cas9-mediated gene editing of Hematopoietic
stem and progenitor cells for Friedreich’s ataxia
Stephanie Cherqui — University of California, San Diego  $4,846,579
TRAN1-13997Development of a Gene Therapy for the Treatment of
Pitt Hopkins Syndrome (PHS) – Translating from Animal Proof of Concept to Support Pre-IND Meeting
Allyson Berent — Mahzi Therapeutics  $4,000,000
TRAN1-13996Overcoming resistance to standard CD19-targeted CAR
T using a novel triple antigen targeted vector
William J Murphy — University of California, Davis  $4,168,679

Neurona Therapeutics Update: First two patients who received treatment experienced significantly less seizures

Nearly 3.5 million Americans suffer from some form of epilepsy. It can affect people in different ways from stiff muscles or staring spells, to violent shaking and loss of consciousness.

The impact it has on people’s lives extends far beyond the condition itself. People who suffer from epilepsy experience a higher frequency of depression and other mood disorders, social isolation, challenges in school and with living independently, higher unemployment, limitations on driving, and higher risk of early death.

Medications can help control the seizures in some people, but around one-third of patients don’t respond to those drugs. The alternative is surgery, which is invasive and can cause damage to delicate brain tissue.

Neurona Therapeutics —a clinical stage biotherapeutics company— has developed a therapy called NRTX-1001, which consists of a specialized type of neuronal or brain cell derived from embryonic stem cells. These cells are injected into the brain in the area affected by the seizures where they release a neurotransmitter or chemical messenger that will block the signals in the brain causing the epileptic seizures.

So far, the first two patients treated in the groundbreaking clinical trial—both of whom entered the study with a history of significant monthly seizures that were not controlled by anti-seizure medications—have seen encouraging signs of reduction which suggest that a single dose of NRTX-1001 may have a long-lasting ability to suppress seizures.

The first patient had a 9-year history of seizures and in the six months prior to the administration of NRTX-1001, the patient experienced an average of 32 seizures per month, despite being on several antiepileptic medications. The patient received a single administration of NRTX-1001, the treatment was well tolerated, and there have been no serious or severe adverse events associated with the treatment to date. The patient reported four seizures during the first three months since receiving NRTX-1001.

The second patient treated in the trial also had drug-resistant seizures, with an average of 14 seizures per month in the six months prior to treatment. This individual received NRTX-1001 and in the first week post-treatment had not experienced any serious or severe adverse events, or seizures.

“The early clinical results with NRTX-1001 in epilepsy are very encouraging, and we look forward to enrolling additional patients in the study,” said Dr. Cory Nicholas, Neurona’s president and chief executive officer. “NRTX-1001 is designed to be an off-the-shelf, one-time administration therapy with the potential to durably eliminate seizures and provide a new regenerative cell therapeutic approach in patients for whom anti-seizure medication has failed.”

Dr. Nicholas added, “It has the potential to be disease-modifying without the tissue-destructive procedural risks associated with lobectomy. Further, there are many who are not currently eligible for lobectomy surgery who may be eligible for NRTX-1001 in the future. We are sincerely grateful to everyone involved in the development of NRTX-1001, including the first participants in this pioneering study, their families, and the respective clinical site teams.”

The California Institute for Regenerative Medicine has a vested interest in seeing this therapy succeed. CIRM has invested more than $14 million over four different awards in helping this research progress from a basic or Discovery level through to the current clinical trial.

Reasons to be thankful this Thanksgiving: creative nerds

We at the California Institute for Regenerative Medicine have a lot to be thankful for this Thanksgiving. We get to work with some extraordinary colleagues, we get to know some remarkable patient advocates who are pioneers in volunteering for stem cell and gene therapies, and we have a front row seat in a movement that is changing the face of medicine.

We also get to work with some brilliant scientists and help support their research. As if we needed any reminders of how important that funding is, we thought we would share this video with you. It’s from the talented post docs and researchers at the University of California San Diego. It’s a delightful parody of the Cyndi Lauper classic “Girls Just Wanna Have Fun”. Only in this case it’s “Nerds Just Wanna Have Funds.”

Enjoy, and Happy Thanksgiving.

A timeless message about stem cells

Dr. Daniel Kota

The world of stem cell research is advancing rapidly, with new findings and discoveries seemingly every week. And yet some things that we knew years ago are still every bit as relevant today as they were then.

Take for example a TEDx talk by Dr. Daniel Kota, a stem cell researcher and the Director, Cellular Therapy – Research and Development at Houston Methodist.

Dr. Kota’s talk is entitled: “Promises and Dangers of Stem Cell Therapies”. In it he talks about the tremendous potential of stem cells to reverse the course of disease and help people battle previously untreatable conditions.

But he also warns about the gap between what the science can do, and what people believe it can do. He says too many people have unrealistic expectations of what is available right now, fueled by many unscrupulous snake oil salesmen who open clinics and offer “treatments” that are both unproven and unapproved by the Food and Drug Administration.

He says we need to “bridge the gap between stem cell science and society” so that people have a more realistic appreciation of what stem cells can do.

Sadly, as the number of clinics peddling these unproven therapies grows in the US, Dr. Kota’s message remains all too timely.

Myocarditis in Cancer Patients Is Driven by Specific Immune Cells

In a new study, researchers from UC San Francisco and Vanderbilt University Medical Center have identified specific immune cells that cause a potentially lethal heart inflammation -called myocarditis- in a small fraction of patients treated with powerful cancer immunotherapy drugs.

Myocarditis is inflammation of the heart muscle. It can cause chest pain, shortness of breath, and rapid or irregular heart rhythms. Myocarditis can weaken the heart and its electrical system. As a result, the heart’s ability to pump blood declines. In severe cases, myocarditis causes clots and may lead to stroke, heart attack, heart failure and even death.

The form of myocarditis the researchers studied is a rare but deadly side effect of cancer immunotherapy drugs called immune checkpoint inhibitors (ICIs). 

ICI is a type of therapy method that can improve the anti-tumor immune response by regulating the activity of T cells. ICI treatment has proven lifesaving for many cancer patients and fewer than one percent of patients who receive ICI develop myocarditis.

However, according to Javid Moslehi, MD, chief of Cardio-Oncology and Immunology for the UCSF Heart and Vascular Center, nearly half of patients who do experience ICI-caused myocarditis die as a result. 

Using genetically altered mice to mimic human ICI-caused myocarditis in the new study, the researchers found an excess of immune system cells called CD8 T lymphocytes in the inflamed heart tissue of mice with myocarditis. 

“We earlier observed many T cells in patients who had died, but in the mice we performed several key experiments to show that the T lymphocytes really are drivers of the disease process, and not merely innocent bystanders,” Moslehi said. “There are therapeutic implications to this study.” 

The results of the study led the researchers to conclude that activation of CD8 T cells is necessary to trigger myocarditis in ICI-treated cancer patients and therefore immunosuppressive therapies that affect CD8 T cells might play a beneficial role.

Their new findings already have led them to begin investigating better ways to prevent and treat myocarditis. The research team already has reported a case study in which they used Abatacept, a rheumatoid arthritis drug that suppresses the activation of CD8 T cells, to successfully treat myocarditis in a cancer patient. 

Study could pave the way in reducing decline in muscle strength as people age 

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.  

The study was published in Cell Stem Cell and is co-funded by the California Institute for Regenerative Medicine (CIRM).  

A Closer Look at 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.  

Read the original release by Krista Conger on the Stanford Medicine website.