As someone with a family history of type 1 diabetes (T1D) I know how devastating the condition can be. I also know how challenging it can be to keep it under control and the consequences of failing to do that. Not maintaining healthy blood sugar levels can have a serious impact on the heart, kidney, eyes, nerves, and blood vessels. It can even be fatal.
Right now, controlling T1D means being careful about what you eat, when you eat and how much you eat. It also means regularly checking your blood throughout the day to see if the glucose level is too high or too low. If it’s too high you need to inject insulin; if it’s too low you need to take a fast-acting carbohydrate such as fruit juice or glucose to try and restore it to a healthy level.
That’s why two new approaches to T1D that CIRM has supported are so exciting. They both use small devices implanted under the skin that contain stem cells. The cells can both monitor blood sugar and, if it’s too high, secrete insulin to bring it down.
We sat down with two key members of the Encellin and ViaCyte teams, Dr. Crystal Nyitray and Dr. Manasi Jaiman, to talk about their research, how it works, and what it could mean for people with T1D. That’s in the latest episode of our podcast ‘Talking ‘Bout (re)Generation’.
It’s always lovely to end the week on a bright note and that’s certainly the case this week, thanks to some encouraging news about CIRM-funded research targeting blood disorders that affect the immune system.
Stanford’s Dr. Rosa Bacchetta and her team learned that their proposed therapy for IPEX Syndrome had been given the go-ahead by the Food and Drug Administration (FDA) to test it in people in a Phase 1 clinical trial.
IPEX Syndrome (it’s more formal and tongue twisting name is Immune dysregulation Polyendocrinopathy Enteropathy X-linked syndrome) is a life-threatening disorder that affects children. It’s caused by a mutation in the FOXP3 gene. Immune cells called regulatory T Cells normally function to protect tissues from damage but in patients with IPEX syndrome, lack of functional Tregs render the body’s own tissues and organs to autoimmune attack that could be fatal in early childhood.
Current treatment options include a bone marrow transplant which is limited by available donors and graft versus host disease and immune suppressive drugs that are only partially effective. Dr. Rosa Bacchetta and her team at Stanford will use gene therapy to insert a normal version of the FOXP3 gene into the patient’s own T Cells to restore the normal function of regulatory T Cells.
This approach has already been accorded an orphan drug and rare pediatric disease designation by the FDA (we blogged about it last year)
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.
Under the FDA’s rare pediatric disease designation program, the FDA may grant priority review to Dr. Bacchetta if this treatment eventually receives FDA approval. The FDA defines a rare pediatric disease as a serious or life-threatening disease in which the serious or life-threatening manifestations primarily affect individuals aged from birth to 18 years and affects fewer than 200,000 people in the U.S.
Congratulations to the team and we wish them luck as they begin the trial.
Someone who needs no introduction to regular readers of this blog is UCLA’s Dr. Don Kohn. A recent study in the New England Journal of Medicine highlighted how his work in developing a treatment for severe combined immune deficiency (SCID) has helped save the lives of dozens of children.
Now a new study in the journal Blood shows that those benefits are long-lasting, with 90% of patients who received the treatment eight to 11 years ago still disease-free.
In a news release Dr. Kohn said: “What we saw in the first few years was that this therapy worked, and now we’re able to say that it not only works, but it works for more than 10 years. We hope someday we’ll be able to say that these results last for 80 years.”
Ten children received the treatment between 2009 and 2012. Nine were babies or very young children, one was 15 years old at the time. That teenager was the only one who didn’t see their immune system restored. Dr. Kohn says this suggests that the therapy is most effective in younger children.
Dr. Kohn has since modified the approach his team uses and has seen even more impressive and, we hope, equally long-lasting results.
Human embryonic stem cells (hESCs) have many remarkable properties, not the least of which is their ability to turn into every other kind of cell in our body. But there are limits to what researchers can do with embryonic stem cells. One issue is that there aren’t always hESCs available – they come from eggs donated by couples who have undergone in vitro fertilization. Another is that researchers can only develop these cells in the laboratory for 14 days (though that rule may be changing).
Now researchers at Caltech have developed a kind of hESC-in-a-dish that could help make it easier to answer questions about human development without the need to wait for a new line of hESCs.
The team, led by Magdalena Zernicka-Goetz, used a line of expanded pluripotent cells (EPSCs), originally derived from a human embryo, to create a kind of 3D model that mimics some of the activities of an embryo.
The cool thing about these cells is that, because they were originally derived from an embryo, they retain some “memory” of how they are supposed to work. In a news release Zernicka-Goetz says this enables them to display elements of both polarization and cavitation, early crucial phases in the development of a human embryo.
“The ability to assemble the basic structure of the embryo seems to be a built-in property of these earliest embryonic cells that they are simply unable to ‘forget.’ Nevertheless, either their memory is not absolutely precise or we don’t yet have the best method of helping the cells recover their memories. We still have further work to do before we can get human stem cells to achieve the developmental accuracy that is possible with their equivalent mouse stem cell counterparts.”
Being able to create these embryo-like elements means researchers can generate cells in large numbers and won’t be so dependent on donated embryos.
In the study, published in the journal Nature Communications, the researchers say this could help them develop a deeper understanding of embryonic development.
“Understanding human development is of fundamental biological and clinical importance. Despite its significance, mechanisms behind human embryogenesis remain largely unknown…. this stem cell platform provides insights into the design of stem cell models of embryogenesis.
For Sharif Tabebordbar, finding a gene therapy for genetic muscle wasting diseases was personal. When he was a teenager, his father was diagnosed with a rare genetic muscle disease that eventually left him unable to walk.
In an interview with the Broad Institute at MIT he said: “I watched my dad get worse and worse each day. It was a huge challenge to do things together as a family – genetic disease is a burden on not only patients but families. I thought: This is very unfair to patients and there’s got to be a way to fix this. That’s been my motivation during the 10 years that I’ve been working in the field of gene therapy.”
That commitment now seems to be paying off. In a study published in the journal Cell, Tabebordar and his team at MIT and Harvard showed how they have developed a new, safer and easier way to deliver genes to help repair wasting muscles.
In earlier treatments targeting genetic muscle diseases, researchers used a virus to help deliver the gene that would correct the problem. However, to be effective they had to use high doses of the gene-carrying virus to ensure it reached as many muscles throughout the body as possible. But this meant that more of the payload often ended up in the liver and that led to severe side effects in some patients, even a few deaths.
The usual delivery method of these gene-correcting therapies is something called an adeno-associated virus (AAV), so Dr. Tabebordar set out to develop a new kind of AAV, one that would be safer for patients and more effective at tackling the muscle wasting.
They started by taking an adeno-associated virus called AAV9 and then set out about tweaking its capsid – that’s the outer shell that helps protect the virus and allows it to attach to another cell and penetrate it to deliver the corrected gene. They called this new viral vector MyoAAV and in tests it quickly showed it had an enhanced ability to deliver genes into cells.
The team showed that it not only was around 10 times more efficient at reaching muscle than other AAVs, but that it also reduces the amount that reaches the liver. This meant that MyoAAV could achieve impressive results in doses up to 250 times lower than those previously used.
“All of these results demonstrate the broad applicability of the MyoAAV vectors for delivery to muscle. These vectors work in different disease models and across different ages, strains and species, which demonstrates the robustness of this family of AAVs. We have an enormous amount of information about this class of vectors from which the field can launch many exciting new studies.”
Having the right tools to do a job is important. Try using a large screwdriver to tighten the screws on your glasses and you quickly appreciate that it’s not just the type of tool that’s important, it’s also the size. The same theory applies to gene editing. And now researchers at Stanford have developed a tool that can take on even the tiniest of jobs.
The tool involves the use of CRISPR. You may well have heard about CRISPR. The magazine New Scientist described it this way: “CRISPR is a technology that can be used to edit genes and, as such, will likely change the world.” For example, CIRM is funding research using CRISPR to help children born with severe combined immunodeficiency, a rare, fatal immune disorder.
There’s just one problem. Right now, CRISPR is usually twinned with a protein called Cas9. Together they are used to remove unwanted genes and insert a corrected copy of the bad gene. However, that CRISPR-Cas9 combination is often too big to fit into all our cells. That may seem hard to understand for folks like me with a limited science background, but trust the scientists, they aren’t making this stuff up.
To address that problem, Dr. Stanley Qi and his team at Stanford created an even smaller version, one they call CasMINI, to enable them to go where Cas9 can’t go. In an article on Fierce Biotech, Dr. Qi said this mini version has some big benefits: “If people sometimes think of Cas9 as molecular scissors, here we created a Swiss knife containing multiple functions. It is not a big one, but a miniature one that is highly portable for easy use.”
How much smaller is the miniature version compared to the standard Cas9? About half the size, 529 amino acids, compared to Cas9’s 1,368 amino acids.”
The team conclude their study in the journal Molecular Cellsaying this could have widespread implications for the field: “This provides a new method to engineer compact and efficient CRISPR-Cas effectors that can be useful for broad genome engineering applications, including gene regulation, gene editing, base editing, epigenome editing, and chromatin imaging.”
As someone who is not always as diligent as he would like to be about sending birthday cards on time, I’m used to sending belated greetings to people. So, I have no shame in sending belated greetings to four CIRM grantees who were inducted into the National Academy of Medicine in 2020.
I say four, but it’s really three and a half. I’ll explain that later.
Being elected to the National Academy of Medicine is, in the NAM’s own modest opinion, “considered one of the highest honors in the fields of health and medicine and recognizes individuals who have demonstrated outstanding professional achievement and commitment to service.”
To be fair, NAM is right. The people elected are among the best and brightest in their field and membership is by election from the other members of NAM, so they are not going to allow any old schmuck into the Academy (which could explain why I am still waiting for my membership).
The CIRM grantees elected last year are:
Antoni Ribas, MD, PhD, professor of medicine, surgery, and molecular and medical pharmacology, U. C. Los Angeles.
Dr. Ribas is a pioneer in cancer immunology and has devoted his career to developing new treatments for malignant melanoma. When Dr. Ribas first started malignant melanoma was an almost always fatal skin cancer. Today it is one that can be cured.
In a news release Dr. Ribas said it was a privilege to be honored by the Academy: “It speaks to the impact immunotherapy has played in cancer research. When I started treating cases of melanoma that had metastasized to other organs, maybe 1 in 20 responded to treatment. Nobody in their right mind wanted to be a specialist in this field. It was the worst of the worst cancers.”
Dr. Goldberg was honored for his contribution to the understanding of vision loss and ways to reverse it. His lab has developed artificial retinas that transmit images down the optic nerve to the brain through tiny silicon chips implanted in the eye. He has also helped use imaging technology to better improve our ability to detect damage in photoreceptor cells (these are cells in the retina that are responsible for converting light into signals that are sent to the brain and that give us our color vision and night vision)
In a news release he expressed his gratitude saying: “I look forward to serving the goals of the National Academies, and to continuing my collaborative research efforts with my colleagues at the Byers Eye Institute at Stanford and around the world as we further our efforts to combat needless blindness.”
Dr. Anderson was honored for being a leader in the study of autoimmune diseases such as type 1 diabetes. This focus extends into the lab, where his research examines the genetic control of autoimmune diseases to better understand the mechanisms by which immune tolerance is broken.
Understanding what is happening with the immune system, figuring out why it essentially turns on the body, could one day lead to treatments that can stop that, or even reverse it by boosting immune activity.
Remember at the beginning I said that three and a half CIRM grantees were elected to the Academy, well, Canadian researcher, Dr. John Dick is the half. Why? Well, because the award we funded actually went to UC San Diego’s Dennis Carson but it was part of a Collaborative Funding Partnership Program with Dr. Dick at the University of Toronto. So, we are going to claim him as one of our own.
And he’s a pretty impressive individual to partner with. Dr. Dick is best known for developing a test that led to the discovery of leukemia stem cells. These are cells that can evade surgery, chemotherapy and radiation and which can lead to patients relapsing after treatment. His work helped shape our understanding of cancer and revealed a new strategy for curing it.
Type 1 diabetes (t1d) affects every aspect of a person’s life, from what they eat and when they eat, to when they exercise and how they feel physically and emotionally. Because the peak age for being diagnosed with t1d is around 13 or 14 years of age it often hits at a time when a child is already trying to cope with big physical and emotional changes. Add in t1d and you have a difficult time made a lot more challenging.
There are ways to control the disease. Regular blood sugar monitoring and insulin injections can help people manage their condition but those come with their own challenges. Now researchers are taking a variety of different approaches to developing new, innovative ways of helping people with t1d.
One of those companies is Encellin. They are developing a pouch-like device that can be loaded with stem cells and then implanted in the body. The pouch acts like a mini factory, releasing therapies when they are needed.
This work began at UC San Francisco in the lab of Dr. Tejal Desai – with help from CIRM funding – that led to the creation of Encellin. We recently sat down – virtually of course – with Dr. Grace Wei, the co-founder of the company to chat about their work, and their hopes for the future.
She said the decision to target t1d was an easy one:
“Type 1 diabetes is an area of great need. It’s very difficult to manage at any age but particularly in children. It affects what they can eat, what they can do, it’s a big burden on the family and can become challenging to manage when people get older.
“It’s an autoimmune disease so everyone’s disease progression is a bit different. People think it’s just a matter of you having too much blood sugar and not enough insulin, but the problem with medicines like insulin is that they are not dynamic, they don’t respond to the needs of your body as they occur. That means people can over-regulate and give themselves too much insulin for what their body needs and if it happens at night, it can be deadly.
Dr. Wei says stem cell research opens up the possibility of developing dynamic therapies, living medicines that are delivered to you by cells that respond to your dynamic needs. That’s where their pouch, called a cell encapsulation device (CED) comes in.
The pouch is tiny, only about the size of a quarter, and it can be placed just under the skin. Encellin is filling the pouch with glucose-sensitive, insulin producing islet cells, the kind of cells destroyed by t1d. The idea is that the cells can monitor blood flow and, when blood sugar is low, secrete insulin to restore it to a healthy level.
Another advantage of the pouch is that it may eliminate the need for the patient to take immunosuppressive medications.
“The pouch is really a means to protect both the patient receiving the cells and the cells themselves. Your body tends to not like foreign objects shoved into it and the pouch in one respect protects the cells you are trying to put into the person. But you also want to be able to protect the person, and that means knowing where the cells are and having a means to remove them if you need to. That’s why it’s good to have a pouch that you can put in the body, take it out if you need, and replace if needed.”
Dr. Wei says it’s a little like making tea with a tea bag. When the need arises the pouch can secrete insulin but it does so in a carefully controlled manner.
“These are living cells and they are responsive, it’s not medicine where you can overdose, these cells are by nature self-regulating.”
They have already tested their approach with a variety of different kinds of islets, in a variety of different kinds of model.
“We’ve tested for insulin production, glucose stimulation and insulin response. We have tested them in a number of animal models and those studies are supporting our submission for a first-in-human safety clinical trial.”
Dr. Wei says if this approach works it could be used for other metabolic conditions such as parathyroid disorders. And she says a lot of this might not be possible without the early funding and support from CIRM.
“CIRM had the foresight to invest in groups that are looking ahead and said it would be great to have renewable cells to transplant into the body (that function properly. We are grateful that groundwork that has been laid and are looking forward to advancing this work.”
And we are looking forward to working with them to help advance that work too.
Often on the Stem Cellar we feature CIRM-funded work that is helping advance the field, unlocking some of the secrets of stem cells and how best to use them to develop promising therapies. But every once in a while it’s good to remind ourselves that this work, while it may often seem slow, is already saving lives.
Meet Ja’Ceon Golden. He was one of the first patients treated at U.C. San Francisco, in partnership with St. Jude Children’s Hospital in Memphis, as part of a CIRM-funded study to treat a rare but fatal disorder called Severe Combined Immunodeficiency (SCID). Ja’Ceon was born without a functioning immune system, so even a simple cold could have been fatal.
At UCSF a team led by Dr. Mort Cowan, took blood stem cells from Ja’Ceon and sent them to St. Jude where another team corrected the genetic mutation that causes SCID. The cells were then returned to UCSF and re-infused into Ja’Ceon.
Over the next few months those blood stem cells grew in number and eventually helped heal his immune system.
He recently came back to UCSF for more tests, just to make sure everything is OK. With him, as she has been since his birth, was his aunt and guardian Dannie Hawkins. She says Ja’Ceon is doing just fine, that he has just started pre-K, is about to turn five years old and in January will be five years post-therapy. Effectively, Ja’Ceon is cured.
SCID is a rare disease, there are only around 70 cases in the US every year, but CIRM funding has helped produce cures for around 60 kids so far. A recent study in the New England Journal of Medicine showed that a UCLA approach cured 95 percent of the children treated.
The numbers are impressive. But not nearly as impressive, or as persuasive of the power of regenerative medicine, as Ja’Ceon and Dannie’s smiles.
When the COVID-19 pandemic broke out scientists scrambled to find existing medications that might help counter the life-threatening elements of the virus. One of the first medications that showed real promise was remdesivir. It’s an anti-viral drug that was originally developed to target novel, emerging viruses, viruses like COVID19. It was approved for use by the Food and Drug Administration (FDA) in October 2020.
Remdesivir showed real benefits for some patients, reducing recovery time for those in the hospital, but it also had problems. It had to be delivered intravenously, meaning it could only be used in a hospital setting. And it was toxic if given in too high a dose.
In a new study – partially funded by CIRM (DISC2 COVID19-12022 $228,229) – researchers at the University of California San Diego (UCSD) found that by modifying some aspects of remdesivir they were able to make it easier to take and less toxic.
In a news release about the work Dr. Robert Schooley, a first author on the study, says we still need medications like this.
“Although vaccine development has had a major impact on the epidemic, COVID-19 has continued to spread and cause disease — especially among the unvaccinated. With the evolution of more transmissible viral variants, breakthrough cases of COVID are being seen, some of which can be severe in those with underlying conditions. The need for effective, well-tolerated antiviral drugs that can be given to patents at high risk for severe disease at early stages of the illness remains high.”
To be effective remdesivir must be activated by several enzymes in the body. It’s a complex process and explains why the drug is beneficial for some areas, such as the lung, but can be toxic to other areas, such as the liver. So, the researchers set out to overcome those problems.
The team created what are called lipid prodrugs, these are compounds that do not dissolve in water and are used to improve how a drug interacts with cells or other elements; they are often used to reduce the bad side effects of a medication. By inserting a modified form of remdesivir into this lipid prodrug, and then attaching it to an enzyme called a lipid-phosphate (which acts as a delivery system, bringing along the remdesivir prodrug combo), they were able to create an oral form of remdesivir.
Dr. Aaron Carlin, a co-first author of the study, says they were trying to create a hybrid version of the medication that would work equally well regardless of the tissue it interacted with.
“The metabolism of remdesivir is complex, which may lead to variable antiviral activity in different cell types. In contrast, these lipid-modified compounds are designed to be activated in a simple uniform manner leading to consistent antiviral activity across many cell types.”
When they tested the lipid prodrugs in animal models and human cells they found they were effective against COVID-19 in different cell types, including the liver. They are now working on further developing and testing the lipid prodrug to make sure it’s safe for people and that it can live up to their hopes of reducing the severity of COVID-19 infections and speed up recovery.
Hearing loss is something that affect tens of millions of Americans. Usually people notice those changes as they get older but the damage can be done years before that through the use of some prescription drugs or exposure to loud noise (I knew I shouldn’t have sat in the 6th row of that Led Zeppelin concert!)
Now researchers at the University of Southern California (USC) have identified the mechanism that appears to stop cells that are crucial to hearing from regenerating.
In a news release Dr. Neil Segil says this could, in theory, help reverse some hearing loss. “Permanent hearing loss affects more than 60 percent of the population that reaches retirement age. Our study suggests new gene engineering approaches that could be used to channel some of the same regenerative capability present in embryonic inner ear cells.”
The inner ear has two types of cells that are crucial for hearing; “hair cells” are sensory receptors and these help the brain detect sounds, and support cells that play, as the name implies, an important structural and supporting role for the hair cells.
In people, once the hair cells are damaged that’s it, you can’t repair or replace them and the resulting hearing loss is permanent. But mice, in the first few days of life, have ability to turn some of their support cells into hair cells, thus repairing any damage. So Segil and the team set out to identify how mice were able to do that and see if those lessons could be applied to people.
They identified specific proteins that played a key role in turning genes on and off, regulating if and when the support cells could turn into hair cells. They found that one molecule, H3K4mel, was particularly important in activating the correct genetic changes need to turn the support cells into hair cells. But in mice, levels of H3K4mel disappeared quickly after birth, so the team found a drug that helped preserve the molecule, meaning the support cells retained the ability to turn into hair cells.
Now, obviously because this was just done in mice there’s a lot more work that needs to be done to see if it can also work in people, but Segil says it’s certainly an encouraging and intriguing start.
“Our study raises the possibility of using therapeutic drugs, gene editing, or other strategies to make epigenetic modifications that tap into the latent regenerative capacity of inner ear cells as a way to restore hearing. Similar epigenetic modifications may also prove useful in other non-regenerating tissues, such as the retina, kidney, lung, and heart.”