Celebrating a life that almost didn’t happen

Evie Vaccaro

You can’t look at this photo and not smile. This is Evie Vaccaro, and it’s clear she is just bursting with energy and vitality. Sometimes it feels like I have known Evie all her life. In a way I have. And I feel so fortunate to have done so, and that’s why this photo is so powerful, because it’s a life that almost ended before it had a chance to start.

Evie was born with a rare condition called Severe Combined Immunodeficiency (SCID). Children with this condition lack a functioning immune system so even a simple cold or diaper rash can prove fatal. Imagine how perilous their lives are in a time of COVID-19. These children used to be called “bubble babies” because they were often kept inside sterile plastic bubbles to keep them alive. Many died before their second birthday.

Today there is no need for plastic bubbles. Today, we have a cure. That’s a word we use very cautiously, but in Evie’s case, and the case of more than 40 other children, we use it with pride.

Dr. Don Kohn and a child born with SCID

Dr. Don Kohn at UCLA has developed a method of taking the child’s own blood stem cells and, in the lab, inserting a corrected copy of the gene that caused SCID, and then returning those cells to the child. Because they are stem cells they multiply and renew and replicate themselves, creating a new blood supply, one free of the SCID mutation. The immune system is restored. The children are cured.

This is a story we have told several times before, but we mention it again because, well, it never gets old, and because Evie is on the front and back cover of our upcoming Annual Report. The report is actually a look back on the last 18 months in CIRM’s life, reporting on the progress we have made in advancing stem cell research, in saving and changing lives, and in producing economic benefits for California (billions of dollars in sales revenue and taxes and thousands of jobs).  

Evie’s story, Evie’s photo, is a reminder of what is possible thanks to the voters of California who created CIRM back in 2004. Hers is just one of the stories in the report. I think,  you’ll enjoy reading all of them.

Of course, I might be just a little bit biased.

Encouraging news for treatment targeting retinitis pigmentosa

While most people probably wouldn’t put 2020 in their list of favorite years, it’s certainly turning out to be a good one for jCyte. Earlier this year jCyte entered into a partnership with global ophthalmology company Santen Pharmaceuticals worth up to $252 million. Then earlier this week they announced some encouraging results from their Phase 2b clinical trial.

Let’s back up a bit and explain what jCyte does and why it’s so important. They have developed a therapy for retinitis pigmentosa (RP), a rare vision destroying disease that attacks the light sensitive cells at the back of the eye. People are often diagnosed when they are in their teens and most are legally blind by middle age. CIRM has supported this therapy from its early stages into clinical trials.

This latest clinical trial is one of the largest of its kind anywhere in the world. They enrolled 84 patients (although only 74 were included in the final analysis). The patients had vision measuring between 20/80 and 20/800. They were split into three groups: one group was given a sham or placebo treatment; one was given three million human retinal progenitor cells (hRPCs), the kind attacked by the disease; and one was given six million hRPCs.

jCyte CEO Paul Bresge

In an article in Endpoints News, jCyte’s CEO Paul Bresge said there was a very specific reason for this approach. “We did enroll a very wide patient population into our Phase IIb, including patients that had vision anywhere from 20/80 to 20/800, just to learn which patients would potentially be the best responders.”

The results showed that the treatment group experienced improved functional vision and greater clarity of vision compared to the sham or placebo group. Everyone had their vision measured at the start and again 12 months later. For the placebo group the mean change in their ability to read an eye chart (with glasses on) was an improvement of 2.81 letters; for the group that got three million hRPCs it was 2.96 letters, and for the group that got six million hRPCs it was 7.43 letters.

When they looked at a very specific subgroup of patients the improvement was even more dramatic, with the six million cell group experiencing an improvement of 16.27 letters.

Dr. Henry Klassen

Dr. Henry Klassen, one of the founders of jCyte, says the therapy works by preserving the remaining photoreceptors in the eye, and helping them bounce back.

“Typically, people think about the disease as a narrowing of this peripheral vision in a very nice granular way, but that’s actually not what happens. What happens in the disease is that patients lose like islands of vision. So, what we’re doing in our tests is actually measuring […] islands that the patients have at baseline, and then what we’re seeing after treatment is that the islands are expanding. It’s similar to the way that one would track, let’s say a tumor, in oncology of course we’re looking for the opposite effect. We’re looking for the islands of vision to expand.”

One patient did experience some serious side effects in the trial but they responded well to treatment.

The team now plan on carrying out a Phase 3 clinical trial starting next year. They hope that will provide enough evidence showing the treatment is both safe and effective to enable them to get approval from the US Food and Drug Administration to make it available to all who need it.

CIRM Board Approves Two New Discovery Research Projects for COVID-19

Dr. Karen Christman (left) and Dr. Lili Yang (right)

This past Friday the governing Board of the California Institute for Regenerative Medicine (CIRM) approved two new discovery research project as part of the $5 million in emergency funding for COVID-19 related projects.  This brings the number of COVID-19 projects CIRM is supporting to 17, including three clinical trials.

$249,974 was awarded to Dr. Karen Christman at UC San Diego to develop a treatment for Acute Respiratory Distress Syndrome (ARDS), a life-threatening lung injury that occurs when fluid leaks into the lungs and is prevalent in COVID-19 patients.  Dr. Christman and her team will develop extracellular matrix (ECM) hydrogels, a kind of structure that provides support to surrounding cells.  The goal is to develop a treatment that can be delivered directly to site of injury, where the ECM would recruit stem cells, treat lung inflammation, and promote lung healing.

$250,000 was awarded to Dr. Lili Yang at UCLA to develop a treatment for COVID-19.  Dr. Yang and her team will use blood stem cells to create invariant natural killer T (iNKT) cells, a powerful kind of immune cell with the potential to clear virus infection and mitigate harmful inflammation.  The goal is to develop these iNKT cells as an off the shelf therapy to treat patients with COVID-19.

These awards are part of CIRM’s Quest Awards Program (DISC2), which promotes promising new technologies that could be translated to enable broad use and improve patient care.

“The harmful lung inflammation caused by COVID-19 can be dangerous and life threatening,” says Maria T. Millan, M.D., the President and CEO of CIRM. “Early stage discovery projects like the ones approved today are vital in developing treatments for patients severely affected by the novel coronavirus.”

Earlier in the week the Board also approved changes to both DISC2 and clinical trial stage projects (CLIN2). These were in recognition of the Agency’s remaining budget and operational timeline and the need to launch the awards as quickly as possible.

For DISC2 awards the changes include:

  • Award limit of $250,000
  • Maximum award duration of 12 months
  • Initiate projects within 30 days of approval
  • All proposals must provide a statement describing how their overall study plan and design has considered the influence of race, ethnicity, sex and gender diversity.
  • All proposals should discuss the limitations, advantages, and/or challenges in developing a product or tools that addresses the unmet medical needs of California’s diverse population, including underserved communities.

Under the CLIN2 awards, to help projects carry out a clinical trial, the changes include:

  • Adjust award limit to the following:
Applicant typePhase 1, Phase 1/2, Feasability Award CapPhase 2 Award CapPhase 3 Award Cap
Non-profit$9M$11.25M$7.5M
For-profit$6M$11.25M$7.5M
  • Adjust the award duration to not exceed 3 years with award completion no later than November 2023
  • Initiate projects within 30 days of approval
  • All proposals must include a written plan in the application for outreach and study participation by underserved and disproportionately affected populations. Priority will be given to projects with the highest quality plans in this regard.

The changes outlined above for CLIN2 awards do not apply to sickle cell disease projects expected to be funded under the CIRM/NHLBI Cure Sickle Cell Disease joint Initiative.

Using mini lungs to test potential COVID-19 therapies

Dr. Evan Snyder

If someone told you they were working on lungs in a dish you might be forgiven for thinking that’s the worst idea for a new recipe you have ever heard of. But in the case of Dr. Evan Snyder and his team at Sanford Burnham Prebys Medical Discovery Institute it could be a recipe for a powerful new tool against COVID-19. 

Earlier this month the CIRM Board approved almost $250,000 for Dr. Snyder and his team to use human induced pluripotent stem cells (hiPSCs), a type of stem cell that can be created by reprogramming skin or blood cells, to create any other cell in the body, including lung cells.

These cells will then be engineered to become 3D lung organoids or “mini lungs in a dish”. The importance of this is that these cells resemble human lungs in a way animal models do not. They have the same kinds of cells, structures and even blood vessels that lungs do.

These cells will then be infected with the coronavirus and then be used to test two drugs to see if those drugs are effective against the virus.

In a news release Dr. Snyder says these cells have some big advantages over animal models, the normal method for early stage testing of new therapies.

“Mini lungs will also help us answer why some people with COVID-19 fare worse than others. Because they are made from hiPSCs, which come from patients and retain most of the characteristics of those patients, we can make ‘patient-specific’ mini lungs. We can compare the drug responses of mini lungs created from Caucasian, African American, and Latino men and women, as well as patients with a reduced capacity to fight infection to make sure that therapies work effectively in all patients. If not, we can adjust the dose or drug regime to help make the treatment more effective.

“We can also use the mini lungs experimentally to evaluate the effects of environmental toxins that come from cigarette smoking or vaping to make sure the drugs are still effective; and emulate the microenvironmental conditions in the lungs of patients with co-morbidities such as diabetes, and heart or kidney disease.”

To date CIRM has funded 15 projects targeting COVID-19, including three that are in clinical trials.

Cord blood transplants help children fighting deadly diseases

Dr. Paul Szabolcs: Photo courtesy of UPMC

A simple blood stem cell transplant is showing tremendous promise in treating a wide range of metabolic, blood and immune disorders such as thalassemia and some leukodystrophies.

These are considered rare diseases – meaning there are fewer than 200,000 people with them in the US – so there is often little funding available to develop new therapies to help people suffering from them. So, researchers at UPMC Children’s Hospital of Pittsburgh set out to develop a therapy that could help several different disorders without having to craft individual approaches for each condition.

The team used blood stem cells from donated umbilical cords and placentas. In a news article, study senior author Dr. Paul Szabolcs, said they then used a combination of chemotherapy and immunotherapy to prepare the patients for the transplant and increase the chance of success.

“We approached the topic with the mindset to design a regimen that carefully balances low-intensity chemo (bringing safety) with sufficiently effective immunotherapy to blast away the patients’ immune system, therefore preventing rejection. Rejection has been a common failure when other centers explored the reduced-intensity conditioning (RIC) approach with cord blood. We are the first to prove the RIC is able to give reliable results in long-term engraftment.”

Szabolcs says another advantage to their approach was that it meant there didn’t need to be a perfect immune system match of donor and recipient.

“That’s huge for ethnic minorities. The probability of a perfect match is very low, but with a cord blood graft, we have a chance to overcome this discrepancy over the course of a couple months and then taper immunosuppressants away.”

Altogether 44 children were treated this way. After undergoing the preparation, they had the blood stem cells transfused into them and, once those cells had integrated into the body they got a second, smaller, transfusion a few weeks later to help kick start their immune system.

Most of the complications from the infusions were mild, and while around 5 percent of children died from viral infection due to the immune suppression this was much lower than in earlier studies. Another encouraging sign was that none of the children suffered severe Graft vs Host disease which can be fatal.

Thirty of the children in the trial suffered from metabolic disorders, meaning their bodies were unable to remove dangerous toxins, and this led to developmental delays in their brains. One year after the treatment all 30 children had normal enzyme levels and their neurological decline had stopped. Some of the children even showed improvements and gained new skills.

Most of the children with metabolic disorders had leukodystrophies. These are usually fatal within a few years of diagnosis. Even with a cord blood transplant the three-year survival rate is only 60 percent. In this trial more than 90 percent of children with leukodystrophies were alive after three years.

Dr. Szabolcs says this approach has a lot of advantages over existing approaches, including cost.

“There has been a lot of emphasis placed on cool new technologies that might address these diseases, but — even if they prove effective — those aren’t available to most centers. The regimen we developed is more robust, readily applicable and will remain significantly less expensive.”

The study was published in the journal Blood Advances.

Researchers 3D print a heart pump using stem cells

This image used on the cover of the American Heart Association’s Circulation Research journal is a 3D rendering of the printed heart pump developed at the University of Minnesota. The discovery could have major implications for studying heart disease. 
Credit: Kupfer, Lin, et al., University of Minnesota

According to the Centers for Disease Control and Prevention (CDC), heart disease is the leading cause of death for men, women, and people of most racial and ethnic groups in the United States. About 647,000 Americans die from heart disease each year, which is roughly one out of every four deaths total in the US.

In order to better study heart disease, Dr. Brenda Ogle and her team at the University of Minnesota have successfully 3D printed a functioning centimeter-scale human heart pump.

Previously, researchers have attempted to 3D print heart muscle cells within a 3D structure called an extracellular matrix. The heart muscle cells were made from induced pluripotent stem cells (iPSCs), a type of stem cell that can turn into virtually any kind of cell. Unfortunately, the cell density needed for the heart cells to function was never reached.

In this study. Dr. Ogle and her team made some slight changes to the process that had failed previously. First, they optimized a specialized ink made from extracellular matrix proteins. They then mixed the newly created ink with human iPSCs and used this new mixture to 3D print the chambered structure. The iPSCS were expanded to high cell densities in the structure first, and then were differentiated into heart muscle cells. The heart muscle model is about 1.5 centimeters long and was specifically designed to fit into the abdominal cavity of a mouse for future studies.

A video of this process can be seen below:

The team of researchers found that for the first time ever they could achieve the goal of high cell density to allow the cells to beat together, just like a human heart. Furthermore, this study shows how heart muscle cells can organize and work together. The iPSCs differentiating into heart muscle cells right next to each other is comparable to how stem cells grow in the body and then undergo specification to heart muscle cells.

A video of the heart pump contractions can be seen below as well:

In a press release from the University of Minnesota, Dr. Ogle elaborates on the implications of this study.

“We now have a model to track and trace what is happening at the cell and molecular level in pump structure that begins to approximate the human heart. We can introduce disease and damage into the model and then study the effects of medicines and other therapeutics.”

The full results of this study were published in Circulation Research.

Lab-grown human sperm cells could unlock treatments for infertility

Dr. Miles Wilkinson: Photo courtesy UCSD

Out of 100 couples in the US, around 12 or 13 will have trouble starting a family. In one third of those cases the problem is male infertility (one third is female infertility and the other third is a combination of factors). In the past treatment options for men were often limited. Now a new study out of the University of California San Diego (UCSD) could help lead to treatments to help these previously infertile men have children of their own.

The study, led by Dr. Miles Wilkinson of UCSD School of Medicine, targeted spermatogonial stem cells (SSCs), which are the cells that develop into sperm. In the past it was hard to isolate these SSCs from other cells in the testes. However, using a process called single cell RNA sequencing – which is like taking a photo of all the gene expression happening in one cell at a precise moment – the team were able to identify the SSCs.

In a news release Dr. Wilkinson, the senior author of the study, says this is a big advance on previous methods: “We think our approach — which is backed up by several techniques, including single-cell RNA-sequencing analysis — is a significant step toward bringing SSC therapy into the clinic.”

Identifying the SSCs was just the first step. Next the team wanted to find a way to be able to take those cells and grow and multiply them in the lab, an important step in having enough cells to be able to treat infertility.

So, they tested the cells in the lab and identified something called the AKT pathway, which controls cell division and survival. By blocking the AKT pathway they were able to keep the SSCs alive and growing for a month. Next they hope to build on the knowledge and expand the cells for even longer so they could be used in a clinical setting.

This image has an empty alt attribute; its file name is wilkinson-ssc-graphic_450px.jpg
Illustrations by Vishaala Wilkinson

The hope is that this could ultimately lead to treatments for men whose bodies don’t produce sperm cells, or enough sperms cells to make them fertile. It could also help children going through cancer therapy which can destroy their ability to have children of their own later in life. By taking sperm cells and freezing them, they could later be grown and expanded in the lab and injected back into the testes to restore sperm production.

The study is published in the journal Proceedings of the National Academy of Science.

CIRM Board Approves Two Discovery Research Projects for COVID-19

Dr. Steven Dowdy (left), Dr. Evan Snyder (center), and Dr. John Zaia (right)

This past Friday the governing Board of the California Institute for Regenerative Medicine (CIRM) approved two additional discovery research projects as part of the $5 million in emergency funding for COVID-19 related projects.  This brings the number of COVID-19 projects CIRM is supporting to 15, including three clinical trials.

The Board awarded $249,999 to Dr. Evan Snyder at the Sanford Burnham Prebys Medical Discovery Institute.  The study will use induced pluripotent stem cells (iPSCs), a type of stem cell that can be created by reprogramming skin or blood cells, to create lung organoids.  These lung organoids will then be infected with the novel coronavirus in order to test two drug candidates for treatment of the virus. The iPSCs and the subsequent lung organoids created will reflect diversity by including male and female patients from the Caucasian, African-American, and Latinx population.

This award is part of CIRM’s Quest Awards Program (DISC2), which promotes promising new technologies that could be translated to enable broad use and improve patient care.

The Board also awarded $150,000 to Dr. Steven Dowdy at UC San Diego for development of another potential treatment for COVID-19.  

Dr. Dowdy and his team are working on developing a new, and hopefully more effective, way of delivering a genetic medicine, called siRNA, into the lungs of infected patients. In the past trying to do this proved problematic as the siRNA did not reach the appropriate compartment in the cell to become effective. However, the team will use an iPSC lung model to help them identify ways past this barrier so the siRNA can attack the virus and stop it replicating and spreading throughout the lungs.

This award is part of CIRM’s Inception Awards Program (DISC1), which supports transformational ideas that require the generation of additional data.

A supplemental award of $250,000 was approved for Dr. John Zaia at City of Hope to continue support of a CIRM funded clinical study that is using convalescent plasma to treat COVID-19 patients.  The team recently launched a website to enroll patients, recruit plasma donors, and help physicians enroll their patients.

“The use of induced pluripotent stem cells has expanded the potential for personalized medicine,” says Dr. Maria T. Millan, the President & CEO of CIRM. “Using patient derived cells has enabled researchers to develop lung organoids and lung specific cells to test numerous COVID-19 therapies.”

Four teaspoons could save a life

Sometimes it’s the smallest things that make the biggest difference. In the case of a clinical trial that CIRM is funding, all it takes to be part of it is four teaspoons of blood.

The clinical trial is being run by Dr. John Zaia and his team at the City of Hope in Duarte, near Los Angeles, in partnership with tgen and the CIRM Alpha Stem Cell Clinic Network. They are going to use blood plasma from people who have recovered from COVID-19 to treat people newly infected with the virus. The hope is that antibodies in the plasma, which can help fight infections, will reduce the severity or length of infection in others.

Dr. John Zaia. Photo courtesy City of Hope

People who have had the virus and are interested in taking part are asked to give four teaspoons of blood, to see if they have enough antibodies. If they do they can then either donate plasma – to help newly infected people – or blood to help with research into COVID-19.

As a sign of how quickly Dr. Zaia and his team are working, while we only approved the award in late April, they already have their website up and running, promoting the trial and trying to recruit both recovered COVID-19 survivors and current patients.

The site does a great job of explaining what they are trying to do and why people should take part. Here’s one section from the site.

Why should I participate in your study?

By participating in our study, you will learn whether you have developed antibodies against SARS-CoV-2, the virus responsible for COVID-19. To do so, you just need to donate a small sample of blood (approximately 4 teaspoons).

If testing show you have enough antibodies, you will have the option of donating plasma that will be used to treat severely ill COVID-19 patients and may help save lives.

If you don’t want to donate plasma, you can still donate blood (approximately 3.5 tablespoons), which will be studied and help researchers learn more about COVID-19.

By donating blood or plasma, you will help us gain information that may be of significant value for patient management in future epidemic seasons.

You don’t even have to live close to one of the clinical trial sites because the team can send you a blood collection kit and information about a blood lab near you so you can donate there. They may even send a nurse to collect your blood.

The team is also trying to ensure they reach communities that are often overlooked in clinical trials. That’s why the website is also in Spanish and Vietnamese.

Finally, the site is also being used to help recruit treating physicians who can collect the blood samples and help infuse newly infected patients.

We often read about clinical trials in newspapers and online. Now you get a chance to not only see one working in real time, you can get to be part of it.

Stem cells used to look at how COVID-19 attacks heart muscle

Human induced pluripotent stem cell-derived cardiomyocytes (heart cells) shown in green and blue, are infected by the novel coronavirus SARS-CoV-2 (red). Image provided by Cedars-Sinai Board of Governors Regenerative Medicine Institute.

There is still a lot that we don’t understand about SARS-CoV-2 (COVID-19), the new coronavirus that has caused a worldwide pandemic. Some patients that contract the virus experiences heart problems, but the reasons are not entirely clear. Pre-existing heart conditions or inflammation and oxygen deprivation that result from COVID-19 have all been implicated but more evidence needs to be collected.

To evaluate this, a joint study between Cedars-Sinai Board of Governors Regenerative Medicine Institute and the UCLA Broad Stem Cell Research Center used human induced pluripotent stem cells (iPSCs), a kind of stem cell that can become any kind of cell in the body and is usually made from skin cells. The iPSCS were converted into heart cells and infected with COVID-19 in order to study the effects of the virus.

The results of this study showed that the iPSC-derived heart cells are susceptible to COVID-19 infection and that the virus can quickly divide inside the heart cells. Furthermore, the infected heart cells showed changes in their ability to beat 72 hours after infection.

In a press release, Dr. Clive Svendsen, senior and co-corresponding author of the study and director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute, elaborated on the results.

“This viral pandemic is predominately defined by respiratory symptoms, but there are also cardiac complications, including arrhythmias, heart failure and viral myocarditis. While this could be the result of massive inflammation in response to the virus, our data suggest that the heart could also be directly affected by the virus in COVID-19.”

Although this study does not perfectly replicate the conditions inside the human body, the iPSC heart cells may also help identify and screen new potential drugs that could alleviate viral infection of the heart.

The research team has already found that treatment with an antibody called ACE2 was able to decrease viral replication on the iPSC heart cells.

In the same press release Dr. Arun Sharma, first author and another co-corresponding author of the study and a research fellow at the Cedars-Sinai Board of Governors Regenerative Medicine Institute, had this to say about the ACE2 antibody.

“By blocking the ACE2 protein with an antibody, the virus is not as easily able to bind to the ACE2 protein, and thus cannot easily enter the cell. This not only helps us understand the mechanisms of how this virus functions, but also suggests therapeutic approaches that could be used as a potential treatment for SARS-CoV-2 infection.”

The study’s third co-corresponding author was Dr. Vaithilingaraja Arumugaswami, an associate professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA and member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research.

The full results of this study were published in Cell Reports Medicine.