Going the extra mile to save a patient’s life

You can tell an awful lot about a company by the people it hires and the ability it gives them to do their job in an ethical, principled way. By that measure Rocket Pharma is a pretty darn cool company.

Rocket Pharma is running a CIRM-funded clinical trial for Leukocyte Adhesion Deficiency-I (LAD-I), a rare genetic immune disorder that leaves patients vulnerable to repeated infections that often results in death within the first two years of life. The therapy involves taking some of the child’s own blood stem cells and, in the lab, correcting the mutation that causes LAD-I, then returning those cells to the patient. Hopefully those blood stem cells then create a new, healthy blood supply and repair the immune system.

So far, they have treated the majority of the nine patients in this Phase 1/2 clinical trial. Here’s the story of three of those children, all from the same family. Every patient’s path to the treatment has been uniquely challenging. For one family, it’s been a long, rough road, but one that shows how committed Rocket Pharma (Rocket) is to helping people in need.

The patient, a young girl, is from India. The family has already lost one child to what was almost certainly LAD-I, and now they faced the very real prospect of losing their daughter too. She had already suffered numerous infections and the future looked bleak. Fortunately, the team at Rocket heard about her and decided they wanted to help enroll her in their clinical trial.

Dr. Gayatri Rao, Rocket Pharmaceuticals

Dr. Gayatri Rao, the Global Program Head for the LAD-I therapy, this patient was about 6 months old when they heard about her: “She had already been in and out of the hospital numerous times so the family were really interested in enrolling the patient. But getting the family to the US was daunting.”

Over the course of several months, the team at Rocket helped navigate the complicated immigration process. Because the parents and child would need to make several trips to the US for treatment and follow-up exams they would need multiple-entry visas. “Just to get all the paper work necessary was a monumental task. Everything had to be translated because the family didn’t speak English. By the time the family flew to Delhi for their visa interview they had a dossier that filled a 3 inch binder.”  Rocket worked closely with partners in India to provide the family on-the-ground support every step of the way.  To help ensure the family received the visas they needed, Rocket also reached out to members of Congress and six members wrote in support of the family’s application.

Finally, everything fell into place. The family had the visas, all the travel arrangements were made. The Rocket team had even found an apartment near the UCLA campus where the family would stay during the treatment and stocked it with Indian food.

But on the eve of their flight to the US, the coronavirus pandemic hit. International flights were cancelled. Borders were closed. A year of work was put on hold and, more important, the little girl’s life hung in the balance.

Over the course of the next few months the little girl suffered several infections and had to be hospitalized. The family caught COVID and had to undergo quarantine till they recovered. But still the Rocket team kept working on a plan to bring them to the US. Finally, in late January, as vaccines became available and international flights opened up once again, the family were able to come to the US. One west-coast based Rocket team member even made sure that upon arriving to the apartment in UCLA, there was a home-cooked meal, a kitchen stocked with groceries, and handmade cards welcoming them to help transition the family into their new temporary “home.” They are now in living in that apartment near UCLA, waiting for the treatment to start.

Gayatri says it would have been easy to say: “this is too hard” and try to find another patient in the trial, but no one at Rocket wanted to do that: “Once a patient gets identified, we feel like we know them and the team feels invested in doing everything we can for them. We know it may not work out. But at the end of the day, we recognize that this child often has no other choices, and that motivates us to keep going despite the challenges.  If anything, this experience has taught us that with persistence and creativity, we can surmount these challenges.”

Maybe doing the right thing brings its own rewards, because this earlier this month Rocket was granted Regenerative Medicine Advanced Therapy (RMAT) designation for their treatment for LAD-I. This is a big deal because it means the therapy has already shown it appears to be safe and potentially beneficial to patients, so the designation means that if it continues to be safe and effective it may be eligible for a faster, more streamlined approval process. And that means it can get to the patients who need it, outside of a clinical trial, faster.

Hitting our goals: regulatory reform

Way, way back in 2015 – seems like a lifetime ago doesn’t it – the team at CIRM sat down and planned out our Big 6 goals for the next five years. The end result was a Strategic Plan that was bold, ambitious and set us on course to do great things or kill ourselves trying. Well, looking back we can take some pride in saying we did a really fine job, hitting almost every goal and exceeding them in some cases. So, as we plan our next five-year Strategic Plan we thought it worthwhile to look back at where we started and what we achieved. We are going to start with Regulatory Reform.

The political landscape in 2015 was dramatically different than it is today. Compared to more conventional drugs and therapies stem cells were considered a new, and very different, approach to treating diseases and disorders. At the time the US Food and Drug Administration (FDA) was taking a very cautious approach to approving any stem cell therapies for a clinical trial.

A survey of CIRM stakeholders found that 70% said the FDA was “the biggest impediment for the development of stem cell treatments.” One therapy, touted by the FDA as a success story, had such a high clinical development hurdle placed on it that by the time it was finally approved, five years later, its market potential had significantly eroded and the product failed commercially. As one stakeholder said: “Is perfect becoming the enemy of better?”

So, we set ourselves a goal of establishing a new regulatory paradigm, working with Congress, academia, industry, and patients, to bring about real change at the FDA and to find ways to win faster approval for promising stem cell therapies, without in any way endangering patients.

It seemed rather ambitious at the time, but achieving that goal happened much faster than any of us anticipated. With a sustained campaign by CIRM and other industry leaders, working with the patient advocacy groups, the FDA, Congress, and President Obama, the 21st Century Cures Act was signed into law on December 13, 2016.

President Obama signs the 21st Century Cures Act.
Photo courtesy of NBC News

The law did something quite radical; it made the perspectives of patients an integral part of the FDA’s decision-making and approval process in the development of drugs, biological products and devices. And it sped up the review process by:

In a way the FDA took its foot off the brake but didn’t hit the accelerator, so the process moved faster, but in a safe, manageable way.

Fast forward to today and eight projects that CIRM funds have been granted RMAT designation. We have become allies with the FDA in helping advance the field. We have created a unique partnership with the National Heart, Lung and Blood Institute (NHLBI) to support the Cure Sickle Cell initiative and accelerate the development of cell and gene therapies for sickle cell disease.

The landscape has changed since we set a goal of regulatory reform. We still have work to do. But now we are all working together to achieve the change we all believe is both needed and possible.

A Match Made in Heaven, if heaven were in Oakland!

The Matchmaker – by Gerrit van Honthorst

Throughout history, matchmakers have played an important role in bringing together couples for arranged marriages. Fast forward to today and CIRM is now playing a similar role. We’re not looking to get anyone hitched, what we are trying to do is create partnerships between people we are funding and companies looking for the next hot thing.

So far, I’d say we are doing a pretty decent job. Over the years we have leveraged our funding to bring in some $13 billion in additional investments in stem cell research. But there’s still a lot of untapped potential out there. That’s why tomorrow, March 9th, we’re joining with BIOCOM to host a Partner Day.

The idea is to highlight some of the most promising programs we are funding and see if we can find partners for them, partners who want to help advance the research and ultimately – we hope – bring those therapies to patients.

The webinar and panel discussion will feature a presentation from the CIRM Business Development team about our portfolio. That’s a pretty extensive list because it covers all stages of research from Discovery or basic, through Translational and all the way to Clinical. We’ll show how our early investment in these programs has helped de-risk them and given them the chance to get the data needed to demonstrate their promise and potential.

So, who are we interested in having join us? Pretty nearly everyone involved in the field:

  • Academic institutions
  • Research organizations
  • Entrepreneurs
  • Venture capital firms
  • Companies

And the areas of interest are equally broad:

  • Stem or progenitor cell-based therapy
  • Cell Therapy
  • Gene therapy
  • Biologic
  • Small molecule
  • Medical Device
  • Diagnostic
  • Tools/Tech
  • Other

And for those who are really interested and don’t want to waste any time, there’s an opportunity to set up one-on-one meetings right away. After all, if you have found the perfect match, why wait!

But here’s the catch. Space is limited so you need to register ahead. Here’s where you go to find out all the details and sign up for the event.

A little history in the making by helping the tiniest patients

Dr. Diana Farmer stands with Dr. Aijun Wang and their UC Davis research team.

It’s appropriate that at the start of Women’s History Month, UC Davis’ Dr. Diana Farmer is making a little history of her own. She launched the world’s first clinical trial using stem cells to treat spina bifida before the child is born.

Spina bifida is a birth defect caused when a baby’s spinal cord fails to develop properly in the womb. In myelomeningocele, the most severe form of spina bifida, a portion of the spinal cord or nerves is exposed in a sac through an opening in the spine. Most people with myelomeningocele have changes in their brain structure, leg weakness, and bladder and bowel dysfunction. 

Illustration of spina bifida

While surgery can help, Dr. Farmer says it is far from perfect: “Currently, the standard of care for our patients is fetal surgery, which, while promising, still leaves more than half of children with spina bifida unable to walk independently. There is an extraordinary need for a treatment that prevents or lessens the severity of this devastating condition. Our team has spent more than a decade working up to this point of being able to test such a promising therapy.” 

The team at UC Davis – in a CIRM-funded study – will use a stem cell “patch” that is placed over the exposed spinal cord, then surgically close the opening, hopefully allowing the stem cells to regenerate and protect the spinal cord.

In a news release Dr. Aijun Wang, a stem cell bioengineer, says the team has been preparing for this trial for years, helping show in animals that it is safe and effective. He is hopeful it will prove equally safe and effective in people: “Our cellular therapy approach, in combination with surgery, should encourage tissue regeneration and help patients avoid devastating impairments throughout their lives.” 

Dr. Farmer says the condition, while rare, disproportionately affects Latinx babies and if the procedure works could have an enormous impact on their lives and the lives of their families: “A successful treatment for MMC would relieve the tremendous emotional and economic cost burden on families. We know it initially costs approximately $532,000 per child with spina bifida. But the costs are likely several million dollars more due to ongoing treatments, not to mention all the pain and suffering, specialized childcare, and lost time for unpaid caregivers such as parents.”

Here is video of two English bulldogs who had their spinal injuries repaired at UC Davis using stem cells. This was part of the research that led to the clinical trial led by Dr. Farmer and Dr. Wang.

Stem cell gene therapy for Fabry disease shows positive results in patients

Darren Bidulka rests after his modified blood stem cells were transplanted into him at the Foothills Medical Centre in Calgary in 2017, allowing him to stop his enzyme therapy. (From left): Dr. Jeffrey Medin, Medical College of Wisconsin, Dr. Aneal Khan, the experimental trial lead in Calgary, and Darren Bidulka. Image Credit: Darren Bidulka

Fabry disease is an X-linked genetic disorder that can damage major organs and shorten lifespan. Without a functional version of a gene called GLA, our bodies are unable to make the correct version of an enzyme that breaks down a fat, and that in turn can lead to problems in the kidneys, heart and brain. It is estimated that one person in 40,000 to 60,000 has the disease and it affects men more severely than women since men only have one copy of the X chromosome. Current treatment consists of enzyme therapy infusions every two weeks but there is currently no cure for Fabry disease. 

However, a Canadian research team is conducting the world’s first pilot study to treat Fabry disease using a stem cell gene therapy approach. The researchers collected the patient’s own blood stem cells and used gene therapy to insert copies of the fully functional gene into the stem cells, allowing them to make the correct version of the enzyme. The newly modified stem cells were then transplanted back into each patient.

Five men participated in this trial and the results so far have been very encouraging. After treatment with the stem cell gene therapy, all patients began producing the corrected version of the enzyme to near normal levels within one week. With these initial results, all five patients were allowed to stop their biweekly enzyme therapy infusions. So far, only three patients decided to do so and are stable.

In a news release, Darren Bidulka, the first patient to be treated in the study, talked about how life changing this stem cell gene therapy has been for him.

“I’m really happy that this worked. What an amazing result in an utterly fascinating experience. I consider this a great success. I can lead a more normal life now without scheduling enzyme therapy every two weeks. This research is also incredibly important for many patients all over the world, who will benefit from these findings.”

CIRM is no stranger to stem cell gene therapy and its potential having funded clinical trials in various areas such as severe combined immunodeficiency (bubble baby disease), cystinosis, sickle cell disease, and various others. The broad range of genetic diseases it has been used in to treat patients further highlights its importance in scientific research.

The full results of this study were published in Nature Communications.

Tipping our hat to the good guys (& gals)

A search on Google using the term “stem cell blogs” quickly produces a host of sites offering treatments for everything from ankle, hip and knee problems, to Parkinson’s disease and asthma. Amazingly the therapies for those very different conditions all use the same kind of cells produced in the same way. It’s like magic. Sadly, it’s magic that is less hocus pocus and more bogus bogus.

The good news is there are blogs out there (besides us, of course) that do offer good, accurate, reliable information about stem cells. The people behind them are not in this to make a quick buck selling snake oil. They are in this to educate, inform, engage and enlighten people about what stem cells can, and cannot do.

So, here’s some of our favorites.

The Niche

This blog has just undergone a face lift and is now as colorful and easy to read as it is informative. It bills itself as the longest running stem cell blog around. It’s run by UC Davis stem cell biologist Dr. Paul Knoepfler – full disclosure, we have funded some of Paul’s work – and it’s a constant source of amazement to me how Paul manages to run a busy research lab and post regular updates on his blog.

The power of The Niche is that it’s easy for non-science folk – like me – to read and understand without having to do a deep dive into Google search or Wikipedia. It’s well written, informative and often very witty. If you are looking for a good website to check whether some news about stem cells is real or suspect, this is a great place to start.

Stem Cell Battles

This site is run by another old friend of CIRM’s, Don Reed. Don has written extensively about stem cell research in general, and CIRM in particular. His motivation to do this work is clear. Don says he’s not a doctor or scientist, he’s something much simpler:

“No. I am just a father fighting for his paralyzed son, and the only way to fix him is to advance cures for everyone. Also, my mother died of breast cancer, my sister from leukemia, and I myself am a prostate cancer survivor. So, I have some very personal reasons to support the California Institute for Regenerative Medicine and to want state funding for stem cell and other regenerative medicine research to continue in California!”

The power of Don’s writing is that he always tells human stories, real tales about real people. He makes everything he does accessible, memorable and often very funny. If I’m looking for ways to explain something complex and translate it into everyday English, I’ll often look at Don’s work, he knows how to talk to people about the science without having their eyes cloud over.

A Closer Look at Stem Cells

This is published by the International Society for Stem Cell Research (ISSCR), the leading professional organization for stem cell scientists. You might expect a blog from such a science-focused organization to be heavy going for the ordinary person, but you’d be wrong.

A Closer Look at Stem Cells is specifically designed for people who want to learn more about stem cells but don’t have the time to get a PhD. They have sections explaining what stem cells are, what they can and can’t do, even a glossary explaining different terms used in the field (I used to think the Islets of Langerhans were small islands off the coast of Germany till I went to this site).

One of the best, and most important, parts of the site is the section on clinical trials, helping people understand what’s involved in these trials and the kinds of things you need to consider before signing up for one.

Signals

Of course, the US doesn’t have a monopoly on stem cell research and that’s reflected in the next two choices. One is the Signals Blog from our friends to the north in Canada. This is an easy-to-read site that describes itself as the “Insiders perspective on the world of stem cells and regenerative medicine.” The ‘Categories ‘dropdown menu allows you to choose what you want to read, and it gives you lots of options from the latest news to a special section for patients, even a section on ethical and legal issues. 

EuroStemCell

As you may have guessed from the title this is by our chums across the pond in Europe. They lay out their mission on page one saying they want to help people make sense of stem cells:

“As a network of scientists and academics, we provide independent, expert-reviewed information and road-tested educational resources on stem cells and their impact on society. We also work with people affected by conditions, educators, regulators, media, healthcare professionals and policymakers to foster engagement and develop material that meets their needs.”

True to their word they have great information on the latest research, broken down by different types of disease, different types of stem cell etc. And like CIRM they also have some great educational resources for teachers to use in the classroom.

U.C. San Diego Scientist Larry Goldstein Joins Stem Cell Agency’s Board

Larry Goldstein, PhD.

Larry Goldstein PhD, has many titles, one of which sums up his career perfectly, “Distinguished Professor”. Dr. Goldstein has distinguished himself on many fronts, making him an ideal addition to the governing Board of the California Institute for Regenerative Medicine (CIRM).

Dr. Goldstein – everyone calls him Larry – is a Cell Biologist, Geneticist and Neuroscientist. He worked with many colleagues to launch the UC San Diego Stem Cell program, the Sanford Consortium for Regenerative Medicine and the Sanford Stem Cell Clinical Center. He has received the Public Service Award from the American Society for Cell Biology and has had a Public Policy Fellowship named for him by the International Society for Stem Cell Research. He is a member of the American Academy of Arts and Sciences and last year was named a member of the prestigious National Academy of Sciences.

“I look forward to working with the ICOC and CIRM staff to ensure that the best and most promising stem cell research and medicine is fostered and funded,” Larry said.

For more than 25 years Larry’s work has targeted the brain and, in particular, Alzheimer’s disease and amyotrophic lateral sclerosis (ALS) better known as Lou Gehrig’s disease.

In 2012 his team was the first to create stem cell models for two different forms of Alzheimer’s, the hereditary and the sporadic forms. This gave researchers a new way of studying the disease, helping them better understand what causes it and looking at new ways of treating it.

He was appointed to the CIRM Board by Pradeep Khosla, the Chancellor of U.C. San Diego saying he is “gratified you are assuming this important role.”

Jonathan Thomas, JD, PhD., Chair of the CIRM Board, welcome the appointment saying “I have known Larry for many years and have nothing but the highest regard for him as a scientist, a leader, and a great champion of stem cell research. He is also an innovative thinker and that will be invaluable to us as we move into a second chapter in the life of CIRM.”

Larry was born in Buffalo, New York and grew up in Thousand Oaks, California. He graduated from UC San Diego with a degree in Biology in 1976 and from the University of Washington with a Ph. D. in Genetics in 1980. He joined the faculty in Cell and Developmental Biology at Harvard University in 1984 where he was promoted to Full Professor with tenure in 1990. He returned to UC San Diego and the Howard Hughes Medical Institute in 1993. After 45 years pursuing cutting edge lab-based research Larry is now transitioning to an administrative and executive role at UC San Diego where he will serve as the Senior Advisor for Stem Cell Research and Policy to the Vice Chancellor of Health Sciences.

He replaces David Brenner who is standing down after completing two terms on the Board.

De-stressing stem cells and the Bonnie & Clyde of stem cells

Dr. John Cashman

The cells in our body are constantly signalling with each other, it’s a critical process by which cells communicate not just with other cells but also with elements within themselves. One of the most important signalling pathways is called Wnt. This plays a key role in early embryonic and later development. But when Wnt signalling goes wrong, it can also help spur the growth of cancer.

Researchers at the Human BioMolecular Research Institute (HBRI) and Stanford University, have reported on a compound that can trigger a cascade of events that create stress and ultimately impact Wnt’s ability to control the ability of cells to repair themselves.

In a news release Dr. Mark Mercola, a co-author of a CIRM-funded study – published in the journal Cell Chemical Biology – says this is important: “because it explains why stressed cells cannot regenerate and heal tissue damage. By blocking the ability to respond to Wnt signaling, cellular stress prevents cells from migrating, replicating and differentiating.”

The researchers discovered a compound PAWI-2 that shows promise in blocking the compound that causes this cascade of problems. Co-author Dr. John Cashman says PAWI-2 could lead to treatments in a wide variety of cancers such as pancreatic, breast, prostate and colon cancer.

“As anti-cancer PAWI-2 drug development progresses, we expect PAWI-2 to be less toxic than current therapeutics for pancreatic cancer, and patients will benefit from improved safety, less side effects and possibly with significant cost-savings.”

Dr. Catriona Jamieson: Photo courtesy Moores Cancer Center, UCSD

Speaking of cancer….

Stem cells have many admirable qualities. However, one of their less admirable ones is their ability to occasionally turn into cancer stem cells. Like regular stem cells these have the ability to renew and replicate themselves over time, but as cancer stem cells they use that ability to help fuel the growth and spread of cancer in the body. Now, researchers at U.C. San Diego are trying to better understand how those regular stem cells become cancer stem cells, so they can stop that process.

In a CIRM-funded study Dr. Catriona Jamieson and her team identified two molecules, APOBEC3C and ADAR1, that play a key role in this process.

In a news release Jamieson said: “APOBEC3C and ADAR1 are like the Bonnie and Clyde of pre-cancer stem cells — they drive the cells into malignancy.”

So they studied blood samples from 54 patients with leukemia and 24 without. They found that in response to inflammation, APOBEC3C promotes the rapid production of pre-leukemia stem cells. That in turn enables ADAR1 to go to work, interfering with gene expression in a way that helps those pre-leukemia stem cells turn into leukemia stem cells.

They also found when they blocked the action of ADAR1 or silenced the gene in patient cells in the laboratory, they were able to stop the formation of leukemia stem cells.

The study is published in the journal Cell Reports.

Surviving with Joy

Dr. Tippi MacKenzie (left) of UCSF Benioff Children’s Hospital San Francisco, visits with newborn Elianna and parents Nichelle Obar and Chris Constantino. Photo by Noah Berger

Alpha thalassemia major is, by any stretch of the imagination, a dreadful, heart breaker of a disease. It’s caused by four missing or mutated genes and it almost always leads to a fetus dying before delivery or shortly after birth. Treatments are limited and in the past many parents were told that all they can do is prepare for the worst.

Now, however, there is new hope with new approaches, including one supported by CIRM, helping keep these children alive and giving them a chance at a normal life.

Thalassemias are a group of blood disorders that affect the way the body makes hemoglobin, which helps in carrying oxygen throughout the body. In alpha thalassemia major it’s the lack of alpha globin, a key part of hemoglobin, that causes the problem. Current treatment requires in blood transfusions to the fetus while it is still in the womb, and monthly blood transfusions for life after delivery, or a bone marrow transplant if a suitable donor is identified.

A clinical trial run by University of California San Francisco’s Dr. Tippi MacKenzie – funded by CIRM – is using a slightly different approach. The team takes stem cells from the mother’s bone marrow and then infuses them into the fetus. If accepted by the baby’s bone marrow, these stem cells can then mature into healthy blood cells. The hope is that one day this method will enable children to be born with a healthy blood supply and not need regular transfusions.

Treating these babies, saving their lives, is the focus of a short film from UCSF called “Surviving with Joy”. It’s a testament to the power of medicine, and the courage and resilience of parents who never stopped looking for a way to help their child.

Tissues are optional but advised.

CIRM funded researchers discover link between Alzheimer’s gene and COVID-19

Dr. Yanhong Shi (left) and Dr. Vaithilingaraja Arumugaswami (right)

All this month we are using our blog and social media to highlight a new chapter in CIRM’s life, thanks to the voters approving Proposition 14. We are looking back at what we have done since we were created in 2004, and also looking forward to the future. Today we focus on groundbreaking CIRM funded research related to COVID-19 that was recently published.

It’s been almost a year since the world started hearing about SARS-CoV-2, the virus that causes COVID-19.  In our minds, the pandemic has felt like an eternity, but scientists are still discovering new things about how the virus works and if genetics might play a role in the severity of the virus.  One population study found that people who have ApoE4, a gene type that has been found to increase the risk of developing Alzheimer’s, had higher rates of severe COVID-19 and hospitalizations.

It is this interesting observation that led to important findings of a study funded by two CIRM awards ($7.4M grant and $250K grant) and conducted by Dr. Yanhong Shi at City of Hope and co-led by Dr. Vaithilingaraja Arumugaswami, a member of the UCLA Broad Stem Cell Research Center.  The team found that the same gene that increases the risk for Alzheimer’s disease can increase the susceptibility and severity of COVID-19.

At the beginning of the study, the team was interested in the connection between SARS-CoV-2 and its effect on the brain.  Due to the fact that patients typically lose their sense of taste and smell, the team theorized that there was an underlying neurological effect of the virus.  

The team first created neurons and astrocytes.  Neurons are cells that function as the basic working unit of the brain and astrocytes provide support to them.  The neurons and astrocytes were generated from induced pluripotent stem cells (iPSCs), which are a kind of stem cell that can become virtually any type of cell and can be created by “reprogramming” the skin cells of patients.  The newly created neurons and astrocytes were then infected with SARS-CoV-2 and it was found that they were susceptible to infection.

Next, the team used iPSCs to create brain organoids, which are 3D models that mimic certain features of the human brain.  They were able to create two different organoid models: one that contained astrocytes and one without them.  They infected both brain organoid types with the virus and discovered that those with astrocytes boosted SARS-CoV-2 infection in the brain model. 

The team then decided to further study the effects of ApoE4 on susceptibility to SARS-CoV-2.  They did this by generating neurons from iPSCs “reprogrammed” from the cells of an Alzheimer’s patient.  Because the iPSCs were derived from an Alzheimer’s patient, they contained ApoE4.  Using gene editing, the team modified some of the ApoE4 iPSCs created so that they contained ApoE3, which is a gene type considered neutral.  The ApoE3 and ApoE4 iPSCs were then used to generate neurons and astrocytes.

The results were astounding.  The ApoE4 neurons and astrocytes both showed a higher susceptibility to SARS-CoV-2 infection in comparison to the ApoE3 neurons and astrocytes.  Moreover, while the virus caused damage to both ApoE3 and ApoE4 neurons, it appeared to have a slightly more severe effect on ApoE4 neurons and a much more severe effect on ApoE4 astrocytes compared to ApoE3 neurons and astrocytes. 

“Our study provides a causal link between the Alzheimer’s disease risk factor ApoE4 and COVID-19 and explains why some (e.g. ApoE4 carriers) but not all COVID-19 patients exhibit neurological manifestations” says Dr. Shi. “Understanding how risk factors for neurodegenerative diseases impact COVID-19 susceptibility and severity will help us to better cope with COVID-19 and its potential long-term effects in different patient populations.”

In the last part of the study, the researchers tested to see if the antiviral drug remdesivir inhibits virus infection in neurons and astrocytes.  They discovered that the drug was able to successfully reduce the viral level in astrocytes and prevent cell death.  For neurons, it was able to rescue them from steadily losing their function and even dying. 

The team says that the next steps to build on their findings is to continue studying the effects of the virus and better understand the role of ApoE4 in the brains of people who have COVID-19.  Many people that developed COVID-19 have recovered, but long-term neurological effects such as severe headaches are still being seen months after. 

“COVID-19 is a complex disease, and we are beginning to understand the risk factors involved in the manifestation of the severe form of the disease” says Dr. Arumugaswami.  “Our cell-based study provides possible explanation to why individuals with Alzheimer’s’ disease are at increased risk of developing COVID-19.”

The full results to this study were published in Cell Stem Cell.