Scientists Engineer Stem Cells to Fight HIV

Image of the virus that causes AIDS – courtesy NIH

If that headline seems familiar it should. It came from an article in MIT Technology Review back in 2009. There have been many other headlines since then, all on the same subject, and yet here we are, in 2020, and still no cure for HIV/AIDS. So what’s the problem, what’s holding us back?

First, the virus is incredibly tough and wily. It is constantly mutating so trying to target it is like playing a game of ‘whack a mole’. Secondly not only can the virus evade our immune system, it actually hijacks it and uses it to help spread itself throughout the body. Even new generations of anti-HIV medications, which are effective at controlling the virus, can’t eradicate it. But now researchers are using new tools to try and overcome those obstacles and tame the virus once and for all.

Dr. Scott Kitchen: Photo David Geffen School of Medicine, UCLA

UCLA researchers Scott Kitchen and Irvin Chen have been awarded $13.65 million by the National Institutes of Health (NIH) to see if they can use the patient’s own immune system to fight back against HIV.

Dr. Irvin Chen: Photo UCLA

Dr. Kitchen and Dr. Chen take the patient’s own blood-forming stem cells and then, in the lab, they genetically engineer them to carry proteins called chimeric antigen receptors or CARs. Once these blood cells are transplanted back into the body, they combine with the patient’s own immune system T cells (CAR T). These T cells now have a newly enhanced ability to target and destroy HIV.

That’s the theory anyway. Lots of research in the lab shows it can work. For example, the UCLA team recently showed that these engineered CAR T cells not only destroyed HIV-infected cells but also lived for more than two years. Now the team at UCLA want to take the lessons learned in the lab and apply them to people.

In a news release Dr. Kitchen says the NIH grant will give them a terrific opportunity to do that: “The overarching goal of our proposed studies is to identify a new gene therapy strategy to safely and effectively modify a patient’s own stem cells to resist HIV infection and simultaneously enhance their ability to recognize and destroy infected cells in the body in hopes of curing HIV infection. It is a huge boost to our efforts at UCLA and elsewhere to find a creative strategy to defeat HIV.”

By the way, CIRM helped get this work off the ground with an early-stage grant. That enabled Dr. Kitchen and his team to get the data they needed to be able to apply to the NIH for this funding. It’s a great example of how we can kick-start projects that no one else is funding. You can read a blog about that early stage research here.

CIRM has already funded three clinical trials targeting HIV/AIDS. Two of these are still active; Dr. Mehrdad Abedi at UC Davis and Dr. John Zaia at City of Hope.

Parkinson’s Disease and Stem Cells

Lila Collins, PhD

A few weeks ago we held a Facebook Live “Ask the Stem Cell Team About Parkinson’s Disease” event. As you can imagine we got lots of questions but, because of time constraints, only had time to answer a few. Thanks to my fabulous CIRM colleagues, Dr. Lila Collins and Dr. Kent Fitzgerald, for putting together answers to some of the other questions. Here they are.

Kent Fitzgerald, PhD

Q: It seems like we have been hearing for years that stem cells can help people with Parkinson’s, why is it taking so long?

A: Early experiments in Sweden using fetal tissue did provide a proof of concept for the strategy of replacing dopamine producing cells damaged or lost in Parkinson’s disease (PD) . At first, this seemed like we were on the cusp of a cell therapy cure for PD, however, we soon learned based on some side effects seen with this approach (in particular dyskinesias or uncontrollable muscle movements) that the solution was not as simple as once thought. 

While this didn’t produce the answer it did provide some valuable lessons.

The importance of dopaminergic (DA) producing cell type and the location in the brain of the transplant.  Simply placing the replacement cells in the brain is not enough. It was initially thought that the best site to place these DA cells is a region in the brain called the SN, because this area helps to regulate movement. However, this area also plays a role in learning, emotion and the brains reward system. This is effectively a complex wiring system that exists in a balance, “rewiring” it wrong can have unintended and significant side effects. 

Another factor impacting progress has been understanding the importance of disease stage. If the disease is too advanced when cells are given then the transplant may no longer be able to provide benefit.  This is because DA transplants replace the lost neurons we use to control movement, but other connected brain systems have atrophied in response to losing input from the lost neurons. There is a massive amount of work (involving large groups and including foundations like the Michael J Fox Foundation) seeking to identify PD early in the disease course where therapies have the best chance of showing an effect.   Clinical trials will ultimately help to determine the best timing for treatment intervention.

Ideally, in addition to the cell therapies that would replace lost or damaged cells we also want to find a therapy that slows or stops the underlying biology causing progression of the disease.

So, I think we’re going to see more gene therapy trials including those targeting the small minority of PD that is driven by known mutations.  In fact, Prevail Therapeutics will soon start a trial in patients with GBA1 mutations. Hopefully, replacing the enzyme in this type of genetic PD will prevent degeneration.

And, we are also seeing gene therapy approaches to address forms of PD that we don’t know the cause, including a trial to rescue sick neurons with GDNF which is a neurotrophic factor (which helps support the growth and survival of these brain cells) led by Dr Bankiewicz  and trials by Axovant and Voyager, partnered with Neurocrine aimed at restoring dopamine generation in the brain.

 A small news report came out earlier this year about a recently completed clinical trial by Roche Pharma and Prothena. This addressed the build up in the brain of what are called lewy bodies, a problem common to many forms of PD. While the official trial results aren’t published yet, a recent press release suggests reason for optimism.  Apparently, the treatment failed to statistically improve the main clinical measurement, but other measured endpoints saw improvement and it’s possible an updated form of this treatment will be tested again in the hopes of seeing an improved effect.

Finally, I’d like to call attention to the G force trials. Gforce is a global collaborative effort to drive the field forward combining lessons learned from previous studies with best practices for cell replacement in PD.  These first-in-human safety trials to replace the dopaminergic neurons (DANs) damaged by PD have shared design features including identifying what the best goals are and how to measure those.

The CIRA trial, Dr Jun Takahashi

The NYSTEM PD trial, Dr Lorenz Studer

The EUROSTEMPD trial, Dr Roger Barker.

And the Summit PD trial, Dr Jeanne Loring of Aspen Neuroscience.

Taken together these should tell us quite a lot about the best way to replace these critical neurons in PD.

As with any completely novel approach in medicine, much validation and safety work must be completed before becoming available to patients

The current approach (for cell replacement) has evolved significantly from those early studies to use cells engineered in the lab to be much more specialized and representing the types believed to have the best therapeutic effects with low probability of the side effects (dyskinesias) seen in earlier trials. 

If we don’t really know the cause of Parkinson’s disease, how can we cure it or develop treatments to slow it down?

PD can now be divided into major categories including 1. Sporadic, 2. Familial. 

For the sporadic cases, there are some hallmarks in the biology of the neurons affected in the disease that are common among patients.  These can be things like oxidative stress (which damages cells), or clumps of proteins (like a-synuclein) that serve to block normal cell function and become toxic, killing the DA neurons. 

The second class of “familial” cases all share one or more genetic changes that are believed to cause the disease.  Mutations in genes (like GBA, LRRK2, PRKN, SNCA) make up around fifteen percent of the population affected, but the similarity in these gene mutations make them attractive targets for drug development.

CIRM has funded projects to generate “disease in a dish” models using neurons made from adults with Parkinson’s disease.   Stem cell-derived models like this have enabled not only a deep probing of the underlying biology in Parkinson’s, which has helped to identify new targets for investigation, but have also allowed for the testing of possible therapies in these cell-based systems. 

iPSC-derived neurons are believed to be an excellent model for this type of work as they can possess known familial mutations but also show the rest of the patients genetic background which may also be a contributing factor to the development of PD. They therefore contain both known and unknown factors that can be tested for effective therapy development.

I have heard of scientists creating things called brain organoids, clumps of brain cells that can act a little bit like a brain. Can we use these to figure out what’s happening in the brain of people with Parkinson’s and to develop treatments?

There is considerable excitement about the use of brain organoids as a way of creating a model for the complex cell-to-cell interactions in the brain.  Using these 3D organoid models may allow us to gain a better understanding of what happens inside the brain, and develop ways to treat issues like PD.

The organoids can contain multiple cell types including microglia which have been a hot topic of research in PD as they are responsible for cleaning up and maintaining the health of cells in the brain.  CIRM has funded the Salk Institute’s Dr. Fred Gage’s to do work in this area.

If you go online you can find lots of stem cells clinics, all over the US, that claim they can use stem cells to help people with Parkinson’s. Should I go to them?

In a word, no! These clinics offer a wide variety of therapies using different kinds of cells or tissues (including the patient’s own blood or fat cells) but they have one thing in common; none of these therapies have been tested in a clinical trial to show they are even safe, let alone effective. These clinics also charge thousands, sometimes tens of thousands of dollars these therapies, and because it’s not covered by insurance this all comes out of the patient’s pocket.

These predatory clinics are peddling hope, but are unable to back it up with any proof it will work. They frequently have slick, well-designed websites, and “testimonials” from satisfied customers. But if they really had a treatment for Parkinson’s they wouldn’t be running clinics out of shopping malls they’d be operating huge medical centers because the worldwide need for an effective therapy is so great.

Here’s a link to the page on our website that can help you decide if a clinical trial or “therapy” is right for you.

Is it better to use your own cells turned into brain cells, or cells from a healthy donor?

This is the BIG question that nobody has evidence to provide an answer to. At least not yet.

Let’s start with the basics. Why would you want to use your own cells? The main answer is the immune system.  Transplanted cells can really be viewed as similar to an organ (kidney, liver etc) transplant. As you likely know, when a patient receives an organ transplant the patient’s immune system will often recognize the tissue/organ as foreign and attack it. This can result in the body rejecting what is supposed to be a life-saving organ. This is why people receiving organ transplants are typically placed on immunosuppressive “anti-rejection “drugs to help stop this reaction. 

In the case of transplanted dopamine producing neurons from a donor other than the patient, it’s likely that the immune system would eliminate these cells after a short while and this would stop any therapeutic benefit from the cells.  A caveat to this is that the brain is a “somewhat” immune privileged organ which means that normal immune surveillance and rejection doesn’t always work the same way with the brain.  In fact analysis of the brains collected from the first Swedish patients to receive fetal transplants showed (among other things) that several patients still had viable transplanted cells (persistence) in their brains.

Transplanting DA neurons made from the patient themselves (the iPSC method) would effectively remove this risk of the immune system attack as the cells would not be recognized as foreign.

CIRM previously funded a discovery project with Jeanne Loring from Scripps Research Institute that sought to generate DA neurons from Parkinson’s patients for use as a potential transplant therapy in these same patients.   This project has since been taken on by a company formed, by Dr Loring, called Aspen Neuroscience.  They hope to bring this potential therapy into clinical trials in the near future.    

A commonly cited potential downside to this approach is that patients with genetic (familial) Parkinson’s would be receiving neurons generated with cells that may have the same mutations that caused the problem in the first place. However, as it can typically take decades to develop PD, these cells could likely function for a long time. and prove to be better than any current therapies.

Creating cells from each individual patient (called autologous) is likely to be very expensive and possibly even cost-prohibitive. That is why many researchers are working on developing an “off the shelf” therapy, one that uses cells from a donor (called allogeneic)would be available as and when it’s needed.

When the coronavirus happened, it seemed as if overnight the FDA was approving clinical trials for treatments for the virus. Why can’t it work that fast for Parkinson’s disease?

While we don’t know what will ultimately work for COVID-19, we know what the enemy looks like.  We also have lots of experience treating viral infections and creating vaccines.  The coronavirus has already been sequenced, so we are building upon our understanding of other viruses to select a course to interrupt it.  In contrast, the field is still trying to understand the drivers of PD that would respond to therapeutic targeting and therefore, it’s not precisely clear how best to modify the course of neurodegenerative disease.  So, in one sense, while it’s not as fast as we’d like it to be, the work on COVID-19 has a bit of a head start.

Much of the early work on COVID-19 therapies is also centered on re-purposing therapies that were previously in development.  As a result, these potential treatments have a much easier time entering clinical trials as there is a lot known about them (such as how safe they are etc.).  That said, there are many additional therapeutic strategies (some of which CIRM is funding) which are still far off from being tested in the clinic. 

The concern of the Food and Drug Administration (FDA) is often centered on the safety of a proposed therapy.  The less known, the more cautious they tend to be. 

As you can imagine, transplanting cells into the brain of a PD patient creates a significant potential for problems and so the FDA needs to be cautious when approving clinical trials to ensure patient safety.

Two rare diseases, two pieces of good news

Dr. Stephanie Cherqui

Last week saw a flurry of really encouraging reports from projects that CIRM has supported. We blogged about two of them last Wednesday, but here’s another two programs showing promising results.

UC San Diego researcher Dr. Stephanie Cherqui is running a CIRM-funded clinical trial for cystinosis. This is a condition where patients lack the ability to clear an amino acid called cystine from their cells. As the cystine builds up it can lead to multi-organ failure affecting the kidneys, eyes, thyroid, muscle, and pancreas.

Dr. Cherqui uses the patient’s own blood stem cells, that have been genetically corrected in the lab to remove the defective gene that causes the problem. It’s hoped these new cells will help reduce the cystine buildup.

The data presented at the annual meeting of the American Society of Cell and Gene Therapy (ASCGT) focused on the first patient treated with this approach. Six months after being treated the patient is showing positive trends in kidney function. His glomerular filtration rate (a measure of how well the kidneys are working) has risen from 38 (considered a sign of moderate to severe loss of kidney function) to 52 (mild loss of kidney function). In addition, he has not had to take the medication he previously needed to control the disorder, nor has he experienced any serious side effects from the therapy.

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Dr. Linda Marban of Capricor

Capricor Therapeutics also had some positive news about its therapy for people with Duchenne’s Muscular Dystrophy (DMD). This is a progressive genetic disorder that slowly destroys the muscles. It affects mostly boys. By their teens many are unable to walk, and most die of heart or lung failure in their 20’s. 

Capricor is using a therapy called CAP-1002, using cells derived from heart stem cells, in the HOPE-2 clinical trial.

In a news release Capricor said 12-month data from the trial showed improvements in heart function, lung function and upper body strength. In contrast, a placebo control group that didn’t get the CAP-1002 treatment saw their condition deteriorate.

Craig McDonald, M.D., the lead investigator on the study, says these results are really encouraging.  “I am incredibly pleased with the outcome of the HOPE-2 trial which demonstrated clinically relevant benefits of CAP-1002 which resulted in measurable improvements in upper limb, cardiac and respiratory function. This is the first clinical trial which shows benefit to patients in advanced stages of DMD for which treatment options are limited.”

You can read the story of Caleb Sizemore, one of the patients treated in the CIRM-funded portion of this trial.

Living proof science can find a cure

Like many kids, let’s face it, many adults too, Ronav “Ronnie” Kashyap is getting a little bored stuck inside all day during the coronavirus pandemic. This video, shot by his dad Pawash, shows Ronnie trying to amuse himself by pretending to be hard at work.

https://www.instagram.com/p/B_BSQaonFXb/

It’s a lovely moment. It’s also a moment that just a few years ago seemed almost impossible. That’s because Ronnie was born with severe combined immunodeficiency (SCID). SCID kids have no functioning immune system so even a simple infection, such as a cold, can be life-threatening.

Many of those hardest hit by COVID-19 have compromised immune systems. But try fighting the virus if you have no immune system at all. The odds would not be good.

Happily, we don’t have to imagine it because Ronnie is one of around 60 children who have undergone CIRM-supported stem cell/gene therapies that have helped repair their immune system.

In Ronnie’s case he was rushed to UC San Francisco shortly after his birth when a newborn screening test showed he had SCID. He spent the next several months there, in isolation with his parents, preparing for the test. Doctors took his own blood stem cells and, in the lab, corrected the genetic mutation that causes SCID. The cells were then re-infused into Ronnie where they created a new blood supply and repaired his immune system.

How good is his immune system today? Last year his parents, Upasana and Pawash, were concerned about taking Ronnie to a crowded shopping mall for fear he might catch a cold. Their doctor reassured them that he would be fine. So, they went. The doctor was right, Ronnie was fine. However, Upasana and Pawash both caught colds!

Just a few weeks ago Ronnie started pre-school. He loves it. He loves having other kids to play with and his parents love it because it helps him burn off some energy. But they also love it because it showed Ronnie is now leading a normal life, one where they don’t have to worry about everything he does, every person he comes into contact with.

Sounds a bit like how the rest of us are living right now doesn’t it. And the fears that Ronnie’s parents had, that even a casual contact with a friend, a family member or stranger, might prove life-threatening, are ones many of us are experiencing now.

When Ronnie was born he faced long odds. At the time there were only a handful of scientists working to find treatments for SCID. But they succeeded. Now, Ronnie, and all the other children who have been helped by this therapy are living proof that good science can overcome daunting odds to find treatments, and even cures, for the most life-threatening of conditions.

Today there are thousands, probably tens of thousands of scientists around the world searching for treatments and cures for COVID-19. And they will succeed.

Till then the rest of us will have to be like Ronnie. Stay at home, stay safe, and enjoy the luxury of being bored.

CIRM-funded treatment for Cystinosis receives orphan drug designation

Dr. Stephanie Cherqui, UC San Diego

Orphan drug designation is a special status given by the Food and Drug Administration (FDA) for potential treatments of rare diseases that affect fewer than 200,000 in the U.S. This type of status can significantly help advance treatments for rare diseases by providing financial incentives in the form of tax credits towards the cost of clinical trials and prescription drug user fee waivers.

Fortunately for us, a stem cell-gene therapy approach used in a CIRM-funded clinical trial for Cystinosis has just received orphan drug designation. The trial is being conducted by Dr. Stephanie Cherqui at UC San Diego, which is an academic collaborator for AVROBIO, Inc.

Cystinosis is a rare disease that primarily affects children and young adults, and leads to premature death, usually in early adulthood.  Patients inherit defective copies of a gene called CTNS, which results in abnormal accumulation of an amino acid called cystine in all cells of the body.  This buildup of cystine can lead to multi-organ failure, with some of earliest and most pronounced effects on the kidneys, eyes, thyroid, muscle, and pancreas.  Many patients suffer end-stage kidney failure and severe vision defects in childhood, and as they get older, they are at increased risk for heart disease, diabetes, bone defects, and neuromuscular defects. 

Dr. Cherqui’s clinical trial uses a gene therapy approach to modify a patient’s own blood stem cells with a functional version of the defective CTNS gene. The goal of this treatment is to reintroduce the corrected stem cells into the patient to give rise to blood cells that will reduce cystine buildup in affected tissues.  

In an earlier blog, we shared a story by UCSD news that featured Jordan Janz, the first patient to participate in this trial, as well as the challenges promising approaches like this one face in terms of getting financial support. Our hope is that in addition to the funding we have provided, this special designation gives additional support to what appears to be a very promising treatment for a very rare disease.

You can read the official press release from AVROBIO, Inc. related to the orphan drug designation status here.

‘A Tornado at the Front Door, a Tsunami at the Back Door’

CIRM funds a lot of research and all of it has life-saving potential. But every once in a while you come across a story about someone benefiting from CIRM-supported research that highlights why the work we do is so important. This story is about a brilliant researcher at UC San Diego developing a treatment for a really rare disease, one that was unlikely to get funding from a big pharmaceutical company because it offered little chance for a return on its investment. At CIRM we don’t have to worry about things like that. Stories like this are our return on investment.

Our thanks to our colleagues at UCSD News for allowing us to run this piece in full.

Jordan Janz and Dr. Stephanie Cherqui in her lab at the UC San Diego School of Medicine: Photo courtesy UC San Diego

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By Heather Buschman, PhD

Born with a rare disease called cystinosis, 20-year-old Jordan Janz arrived at a crossroads: continue life as-is, toward a future most likely leading to kidney failure and an early death or become the first patient in the world to undergo a new gene-and-stem cell therapy developed over more than a decade by UC San Diego School of Medicine researchers

For the majority of Jordan Janz’s 20 years of life, most neighbors in his tiny Canadian town never knew he was sick. Janz snowboarded, hunted and fished. He hung with friends, often playing ice hockey video games. He worked in shipping and receiving for a company that makes oil pumps.

But there were times when Janz was younger that he vomited up to 13 times each day. He received a growth hormone injection every day for six years. He needed to swallow 56 pills every day just to manage his symptoms. And the medication required around-the-clock administration, which meant his mother or another family member had to get up with him every night.

“I was tired for school every day,” Janz said. “I was held back in second grade because I missed so much school. And because the medication had a bad odor to it, when I did go to school kids would ask, ‘What’s that smell?’ It was hard.”

Janz was born with cystinosis, a rare metabolic disorder that’s detected in approximately one in 100,000 live births worldwide. People with cystinosis inherit a mutation in the gene that encodes a protein called cystinosin. Cystinosin normally helps cells transport the amino acid cystine. Because cells in people with cystinosis don’t produce the cystinosin protein, cystine accumulates. Over the years, cystine crystals build up and begin to damage tissues and organs, from the kidneys and liver to muscles, eyes and brain. Numerous symptoms and adverse consequences result.

These days, Janz manages his condition. There’s a time-release version of the symptom-relieving medication now that allows him to go 12 hours between doses, allowing for a good night’s sleep. But there’s no stopping the relentless accumulation of cystine crystals, no cure for cystinosis.  

In October 2019, Janz became the first patient to receive treatment as part of a Phase I/II clinical trial to test the safety and efficacy of a unique gene therapy approach to treating cystinosis. The treatment was developed over more than a decade of research by Stephanie Cherqui, PhD, associate professor of pediatrics, and her team at University of California San Diego School of Medicine.

“The day they started looking for people for the trial, my mom picked up the phone, found a number for Dr. Cherqui, called her and put my name in as a candidate,” Janz said.

Janz’s mom, Barb Kulyk, has long followed Cherqui’s work. Like many parents of children with cystinosis, Kulyk has attended conferences, read up on research and met many other families, doctors and scientists working on the condition. Kulyk says she trusts Cherqui completely. But she was understandably nervous for her son to be the first person ever to undergo a completely new therapy.

“It’s like giving birth,” she said shortly before Janz received his gene therapy. “You’re really looking forward to the outcome, but dreading the process.”

The treatment

Cherqui’s gene therapy approach involves genetical modifying the patient’s own stem cells. To do this, her team obtained hematopoietic stem cells from Janz’s bone marrow. These stem cells are the precursors to all blood cells, including both red blood cells and immune cells. The scientists then re-engineered Janz’s stem cells in a lab using gene therapy techniques to introduce a normal version of the cystinosin gene. Lastly, they reinfused Janz with his own now-cystinosin-producing cells. The approach is akin to a bone marrow transplant — the patient is both donor and recipient.

“A bone marrow transplant can be very risky, especially when you take hematopoietic stem cells from a another person. In that case, there’s always the chance the donor’s immune cells will attack the recipient’s organs, so-called graft-versus-host disease,” Cherqui explained. “It’s a great advantage to use the patient’s own stem cells.”

As is the case for other bone marrow transplants, Janz’s gene-modified stem cells are expected to embed themselves in his bone marrow, where they should divide and differentiate to all types of blood cells. Those cells are then expected to circulate throughout his body and embed in his tissues and organs, where they should produce the normal cystinosin protein. Based on Cherqui’s preclinical data, she expects the cystinosin protein will be transferred to the surrounding diseased cells. At that point, Janz’s cells should finally be able to appropriately transport cystine for disposal — potentially alleviating his symptoms.

Before receiving his modified stem cells, Janz had to undergo chemotherapy to make space in his bone marrow for the new cells. Not unexpectedly, Janz experienced a handful of temporary chemotherapy-associated side-effects, including immune suppression, hair loss and fatigue. He also had mucositis, an inflammation of mucous membranes lining the digestive tract, which meant he couldn’t talk or eat much for a few days.

Now, only three months after his transfusion of engineered stem cells, Cherqui reports that Janz is making a good recovery, though it’s still too early to see a decrease in his cystinosis-related symptoms.

“I’ve been sleeping at least 10 hours a day for the last few weeks,” Janz said. “It’s crazy, but I know my body is just working hard to, I guess, create a new ‘me.’ So it’s no wonder I’m tired. But I’m feeling okay overall.

“One of the hardest parts for me is being inactive for so long. I’m not used to doing nothing all day. But I’m taking an online course while I wait for my immune system to rebuild. And I’m getting pretty good at video games.”

Like all Phase I/II clinical trials, the current study is designed to first test the safety and tolerability of the new treatment. Janz knows the treatment might not necessarily help him.

“When we started this trial, my mom explained it like this: ‘We have a tornado at the front door and a tsunami at the back door, and we have to pick one to go through. Neither will be any fun and we don’t know what’s going to happen, but you have to believe you will make it and go.

“So we weighed the pros and cons and, basically, if I don’t do this trial now, when I’m older I might not be healthy and strong enough for it. So I decided to go for it because, even if there are consequences from the chemotherapy, if it works I could live 20 years longer than I’m supposed to and be healthy for the rest of my life. That’s worth it.”

Besides the possible benefit to himself, Janz also sees his participation in the clinical trial as a way to contribute to the tight-knit community of families with children who have cystinosis.

“I’m willing to do if it helps the kids,” he said. “Somebody has to do it. I don’t have the money to donate to scientific conferences and stuff like that, but I can do this trial.”

The trial

If the treatment continues to meet certain criteria for safety and efficacy for Janz and one other participant after three months, two more adult participants will be enrolled. Three months after that, if the treatment continues to be safe and effective, the trial might enroll two adolescent participants. To participate in the clinical trial, individuals must meet specific eligibility requirements.

Later in the trial, Cherqui and team will begin measuring how well the treatment actually works. The specific objectives include assessing the degree to which gene-modified stem cells establish themselves in  bone marrow, how they affect cystine levels and cystine crystal counts in blood and tissues.

“This trial is the first to use gene-modified hematopoietic stem cell gene therapy to treat a multi-organ degenerative disorder for which the protein is anchored in the membrane of the lysosomes, as opposed to secreted enzymes,” Cherqui said. “We were amazed when we tested this approach in the mouse model of cystinosis — autologous stem cell transplantation reversed the disease. The tissues remained healthy, even the kidneys and the eyes.”

Trial participants are closely monitored for the first 100 days after treatment, then tested again at six, nine, 12, 18 and 24 months post-gene therapy for a variety of factors, including vital signs, cystine levels in a number of organs, kidney function, hormone function and physical well-being.

“If successful in clinical trials, this approach could provide a one-time, lifelong therapy that may prevent the need for kidney transplantation and long-term complications caused by cystine buildup,” Cherqui said.

The future

For the trial participants, all of the pre-treatment tests, the treatment itself, and monitoring afterward means a lot of travel to and long stays in San Diego.

It’s tough on Kulyk and Janz. They have to fly in from Alberta, Canada and stay in a San Diego hotel for weeks at a time. Kulyk has two older adult children, as well as a 12-year-old and a seven-year-old at home. 

“I’ve missed a lot of things with my other kids, but none of them seem to hold any grudges,” she said. “They seem to be totally fine and accepting. They’re like, ‘We’re fine, mom. You go and take care of Jordan.’”

Janz is looking forward to getting back home to his friends, his dog and his job, which provided him with paid leave while he received treatment and recovers.

For Cherqui, the search for a cystinosis cure is more than just a scientific exercise. Cherqui began working on cystinosis as a graduate student more than 20 years ago. At the time, she said, it was simply a model in which to study genetics and gene therapy.

“When you read about cystinosis, it’s just words. You don’t put a face to it. But after I met all the families, met the kids, and now that I’ve seen many of them grow up, and some of them die of the disease — now it’s a personal fight, and they are my family too.”

Patients with cystinosis typically experience kidney failure in their 20s, requiring kidney dialysis or transplantation for survival. For those born with cystinosis who make it into adulthood, the average lifespan is approximately 28 years old.

“I’m optimistic about this trial because it’s something we’ve worked so hard for and now it’s actually happening, and these families have so much hope for a better treatment,” Cherqui said. “After all the years of painstaking laboratory research, we now need to move into the clinic. If this works, it will be wonderful. If it doesn’t, we will all be disappointed but a least we’ll be able to say we tried.”

Nancy Stack, who founded the Cystinosis Research Foundation after her own daughter, Natalie, was diagnosed with the disease, calls Cherqui “the rock star of our community.”

“She cares deeply about the patients and is always available to talk, to explain her work and to give us hope,” Stack said. “She said years ago that she would never give up until she found the cure — and now we are closer to a cure than ever before.” (Read more about Natalie here.)

In addition to cystinosis, Cherqui says this type of gene therapy approach could also lead to treatment advancements for other multi-organ degenerative disorders, such as Friedreich’s ataxia and Danon disease, as well as other kidney, genetic and systemic diseases similar to cystinosis.

While they wait for the long-term results of the treatment, Kulyk is cautiously hopeful.

“Moms are used to being able to fix everything for their children — kiss boo-boos make them better, make cupcakes for school, whip up Halloween costumes out of scraps, pull a coveted toy out of thin air when it has been sold out for months.

“But we have not been able to fix this, to take it away. I not only want this disease gone for my child, I want cystinosis to be nothing more than a memory for all the children and adults living with it. I know that even if and when Jordan is cured, there will still be so much work to do, in terms of regulatory approvals and insurance coverage.

“Having hope for your child’s disease to be cured is a slippery slope. We have all been there, held hope in our hands and had to let go. But, I find myself in a familiar place, holding onto hope again and this time I am not letting go.”

Video of Dr. Cherqui and Jordan Janz talking about the therapy

For more information about the Phase I/II clinical trial for cystinosis and to learn how to enroll, call 1-844-317-7836 or email alphastemcellclinic@ucsd.edu.

Cherqui’s research has been funded by the Cystinosis Research Foundation, California Institute for Regenerative Medicine (CIRM), and National Institutes of Health. She receives additional support from the Sanford Stem Cell Clinical Center and CIRM-funded Alpha Stem Cell Clinic at UC San Diego Health, and AVROBIO.

Stem Cell/Gene Therapy combo heals patients battling rare disorder

Brenden Whittaker and his dog: Photo by Colin McGuire

A few years ago, Brenden Whittaker was running out of time. Brenden was born with a rare condition called x-linked chronic granulomatous disease or XCGD. It meant he lacked a critical part of his immune system that protects against bacterial or fungal infections.

Over 22 years Brenden was in and out of the hospital hundreds of times. Twice he almost died. When antibiotics failed to clear up persistent infections surgeons had to remove parts of his lungs and liver.

Brenden felt he was running out of options. Then he signed up for a clinical trial (funded by CIRM) that would use his own stem cells to correct the problem. More than four years later Brenden is doing just fine.

And he’s not the only one. A new study, published in the journal Nature Medicine, shows that six other patients in the clinical trial are now in remission and have stopped taking any other medications.

Dr. Don Kohn: Photo courtesy UCLA

Don Kohn, the lead researcher on the team from UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, says that in the past the only “cure” for people with CGD was a bone marrow transplant, but that was rarely an option for most patients. In a news release he said finding a perfect match for a transplant was difficult, and even then, patients had to take powerful anti-rejection medications to stop their body rejecting the transplant. So, they developed another approach, using genetically re-engineered stem cells from the patient themselves.

“With this gene therapy, you can use a patient’s own stem cells instead of donor cells for a transplant. This means the cells are perfectly matched to the patient and it should be a much safer transplant, without the risks of rejection.”

The team removed blood stem cells from the patients and, in the lab, corrected the genetic mutation that caused CGD. They then returned those cells to the patients which, because they are stem cells, multiplied and created a new blood supply – one free of CGD – and repaired the immune system.

Brenden was the first of five patients treated in the US. Another four were treated in Europe. All were between the ages of 2 and 27 (CGD patients often die in their 20’s because of the impact of repeated infections).

  • Two patients died because of previously incurred infections
  • Six of the seven surviving patients have discontinued previous treatments
  • Four new patients have since been treated and are currently free of infections

Dr. Kohn said the results are really encouraging: “None of the patients had complications that you might normally see from donor cells and the results were as good as you’d get from a donor transplant — or better.”

The next step is for the researchers to work with the US Food and Drug Administration to get permission to carry out a larger trial, with the eventual goal of getting approval to make it available to all patients who need it.  

Regular readers of our blog will remember that Don Kohn also pioneered a similar approach in treating, and curing, children battling another rare immune disorder, severe combined immunodeficiency or SCID. You can read about that here.

As for Brenden, he is now in college and has his sights set on medical school. In 2016 we profiled him in our Annual Report and ran a long interview with him on the blog where he talked about the joys of mowing the lawn and learning to live without a deadly disease stalking him.

Two studies identify a molecule that could be used to block Zika virus and kill cancer cells

Dr. Tariq Rana (left) and Dr. Jeremy Rich (right) both lead independent teams at UC San Diego that identified a molecule, αvβ5 integrin, as the Zika virus’ key to getting into brain stem cells

Zika virus is caused by a virus transmitted by Aedes mosquitoes. People usually develop mild symptoms that include fever, rash, and muscle and joint pain. However, Zika virus infection during pregnancy can lead to much more serious problems. The virus causes infants to be born with microcephaly, a condition in which the brain does not develop properly, resulting in an abnormally small head. In 2015-2016, the rapid spread of the virus was observed in Latin America and the Caribbean, increasing the urgency of understanding how the virus affected brain development.

Working independently, Dr. Tariq Rana and Dr. Jeremy Rich from UC San Diego identified the same molecule, αvβ5 integrin, as the Zika virus’ key to entering brain stem cells. The two studies, with the aid of CIRM funding, discovered how to take advantage of the molecule in order to block the Zika virus from infecting cells. In addition to this, they were able to turn it into something useful: a way to destroy brain cancer stem cells.

In the first study, Dr. Rana and his team used CRISPR gene editing on brain cancer stem cells to delete individual genes, which was done to see which genes are required for the Zika virus to enter the cells. They discovered that the gene responsible for αvβ5 integrin also enabled the Zika virus.

In a press release by UC San Diego, Dr. Rana elaborates on the importance of his findings.

“…we found Zika uses αvβ5, which is unique. When we further examined αvβ5 expression in brain, it made perfect sense because αvβ5 is the only integrin member enriched in neural stem cells, which Zika preferentially infects. Therefore, we believe that αvβ5 is the key contributor to Zika’s ability to infect brain cells.”

In the second study, Dr. Rich and his team use an antibody to block αvβ5 integrin and found that it prevented the virus from infecting brain cancer stem cells and normal brain stem cells. The team then went on to block αvβ5 integrin in a mouse model for glioblastoma, an aggressive type of brain tumor, by using an antibody or deactivating the gene responsible for the molecule. Both approaches blocked Zika virus infection and allowed the treated mice to live longer than untreated mice. 

Dr. Rich then partnered with Dr. Alysson Muotri at UC San Diego to transplant glioblastoma tumors into laboratory “mini-brains” that can be used for drug discovery. The researchers discovered that Zika virus selectively eliminates glioblastoma stem cells from the mini-brains. Additionally, blocking αvβ5 integrin reversed that anti-cancer activity, further demonstrating the molecule’s crucial role in Zika virus’ ability to destroy cells.

In the same UC San Diego press release, Dr. Rich talks about how understanding Zika virus could help in treating glioblastoma.

“While we would likely need to modify the normal Zika virus to make it safer to treat brain tumors, we may also be able to take advantage of the mechanisms the virus uses to destroy cells to improve the way we treat glioblastoma.”

Dr. Rana’s full study was published in Cell Reports and Dr. Rich’s full study was published in Cell Stem Cell.

CIRM supported study of gene silencer blocks ALS degeneration, saves motor function

Dr. Martin Marsala, UC San Diego

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a neurodegenerative disease that destroys the nerve cells in the brain and spinal cord. As a result of ALS, the motor neurons that enable bodily movement and muscle control are harmed, which can make it difficult to move, speak, eat, and breathe. This condition usually affects people from age 40 to 70, but individuals in their 20s and 30s have also been known to develop ALS. Unfortunately there is no cure for this condition.

However, a study supported by CIRM and conducted by Dr. Martin Marsala at UC San Diego is using a mouse model to look at an approach that uses a gene silencer to protect motor neurons before or shortly after ALS symptoms start to develop.

The gene silencer works by turning off a targeted gene and is delivered via injection. In the case of ALS, previous research suggests that mutations in a gene called SOD1 may cause motor neuronal cell death, resulting in ALS. For this study, Dr. Marsala and his team injected the gene silencer at two sites in the spinal cord in adult mice expressing an ALS-causing mutation of the SOD1 gene. The mice injected did not yet display symptoms of ALS or had only begun showing symptoms.

In mice not yet showing ALS symptoms, they displayed normal neurological function with no onset ALS symptoms after treatment. Additionally, near complete protection of motor neurons and other cells was observed. In mice that had just began showing ALS symptoms, the injection blocked further disease progression as well as further harm to remaining motor neurons. Both of these groups of mice lived without negative side effects for the duration of the study.

In a news release, Dr. Marsala talks about what these results mean for the study of ALS.

“At present, this therapeutic approach provides the most potent therapy ever demonstrated in mouse models of mutated SOD1 gene-linked ALS.”

The next steps for this research would be to conduct additional safety studies with a larger animal model in order to determine an optimal, safe dose for the treatment.

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

In addition to supporting this research for ALS, CIRM has funded two clinical trials in the field as well. One of these trials is being conducted by BrainStorm Cell Therapeutics and the other trial is being by Cedars-Sinai Medical Center.

The Top CIRM Blogs of 2019

This year the most widely read blog was actually one we wrote back in 2018. It’s the transcript of a Facebook Live: “Ask the Stem Cell Team” event about strokes and stroke recovery. Because stroke is the third leading cause of death and disability in the US it’s probably no surprise this blog has lasting power. So many people are hoping that stem cells will help them recover from a stroke.

But of the blogs that we wrote and posted this year there’s a really interesting mix of topics.

The most read 2019 blog was about a potential breakthrough in the search for a treatment for type 1 diabetes (T1D).  Two researchers at UC San Francisco, Dr. Matthias Hebrok and Dr. Gopika Nair developed a new method of replacing the insulin-producing cells in the pancreas that are destroyed by type 1 diabetes. 

Dr. Matthias Hebrok
Dr. Gopika Nair

Dr. Hebrok described it as a big advance saying: “We can now generate insulin-producing cells that look and act a lot like the pancreatic beta cells you and I have in our bodies. This is a critical step towards our goal of creating cells that could be transplanted into patients with diabetes.”

It’s not too surprising a blog about type 1 diabetes was at the top. This condition affects around 1.25 million Americans, a huge audience for any potential breakthrough. However, the blog that was the second most read is the exact opposite. It is about a rare disease called cystinosis. How rare? Well, there are only around 500 children and young adults in the US, and just 2,000 worldwide diagnosed with this condition.  

It might be rare but its impact is devastating. A genetic mutation means children with this condition lack the ability to clear an amino acid – cysteine – from their body. The buildup of cysteine leads to damage to the kidneys, eyes, liver, muscles, pancreas and brain.

Dr. Stephanie Cherqui

UC San Diego researcher Dr. Stephanie Cherqui and her team are taking the patient’s own blood stem cells and, in the lab, genetically re-engineering them to correct the mutation, then returning the cells to the patient. It’s hoped this will create a new, healthy blood system free of the disease.

Dr. Cherqui says if it works, this could help not just people with cystinosis but a wide array of other disorders: “We were thrilled that the stem cells and gene therapy worked so well to prevent tissue degeneration in the mouse model of cystinosis. This discovery opened new perspectives in regenerative medicine and in the application to other genetic disorders. Our findings may deliver a completely new paradigm for the treatment of a wide assortment of diseases including kidney and other genetic disorders.”

Sickled cells

The third most read blog was about another rare disease, but one that has been getting a lot of media attention this past year. Sickle cell disease affects around 100,000 Americans, mostly African Americans. In November the Food and Drug Administration (FDA) approved Oxbryta, a new therapy that reduces the likelihood of blood cells becoming sickle shaped and clumping together – causing blockages in blood vessels.

But our blog focused on a stem cell approach that aims to cure the disease altogether. In many ways the researchers in this story are using a very similar approach to the one Dr. Cherqui is using for cystinosis. Genetically correcting the mutation that causes the problem, creating a new, healthy blood system free of the sickle shaped blood cells.

Two other blogs deserve honorable mentions here as well. The first is the story of James O’Brien who lost the sight in his right eye when he was 18 years old and now, 25 years later, has had it restored thanks to stem cells.

The fifth most popular blog of the year was another one about type 1 diabetes. This piece focused on the news that the CIRM Board had awarded more than $11 million to Dr. Peter Stock at UC San Francisco for a clinical trial for T1D. His approach is transplanting donor pancreatic islets and parathyroid glands into patients, hoping this will restore the person’s ability to create their own insulin and control the disease.

2019 was certainly a busy year for CIRM. We are hoping that 2020 will prove equally busy and give us many new advances to write about. You will find them all here, on The Stem Cellar.