Some good news for people with dodgy knees

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Graphic contrasting a healthy knee with one that has osteoarthritis

About 10% of Americans suffer from knee osteoarthritis, a painful condition that can really impair mobility and quality of life. It’s often caused by an injury to cartilage, say when you were playing sports in high school or college, and over time it continues to degenerate and ultimately results in the  loss of both cartilage and bone in the joint.

Current treatments involve either medication to control the pain or surgery. Medication works up to a point, but as the condition worsens it loses effectiveness.  Knee replacement surgery can be effective, but is a serious, complicated procedure with a long recovery time.  That’s why the governing Board of the California Institute for Regenerative Medicine (CIRM) voted to invest almost $6 million in an innovative stem cell therapy approach to helping restore articular cartilage in the knee.

Dr. Frank Petrigliano, Chief of the Epstein Family Center for Sports Medicine at Keck Medicine of the University of Southern California (USC), is using pluripotent stem cells to create chondrocytes (the cells responsible for cartilage formation) and then seeding those onto a scaffold. The scaffold is then surgically implanted at the site of damage in the knee. Based on scientific data, the seeded scaffold has the potential to regenerate the damaged cartilage, thus decreasing the likelihood of progression to knee osteoarthritis.  In contrast to current methods, this new treatment could be an off-the-shelf approach that would be less costly, easier to administer, and might also reduce the likelihood of progression to osteoarthritis.

This is a late-stage pre-clinical program. The goals are to manufacture clinical grade product, carry out extensive studies to demonstrate safety of the approach, and then file an IND application with the FDA, requesting permission to test the product in a clinical trial in people.

“Damage to the cartilage in our knees can have a big impact on quality of life,” says Dr. Maria T. Millan, MD, President and CEO of CIRM. “It doesn’t just cause pain, it also creates problems carrying out simple, everyday activities such as walking, climbing stairs, bending, squatting and kneeling. Developing a way to repair or replace the damaged cartilage to prevent progression to knee osteoarthritis could make a major difference in the lives of millions of Americans. This program is a continuation of earlier stage work funded by CIRM at the Basic Biology and Translational stages, illustrating how CIRM supports scientific programs from early stages toward the clinic.”

Getting under the skin of people with type 1 diabetes – but in a good way

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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’.

I think you are going to enjoy it.

This is the size of the implant that ViaCyte is using.
This is the size of the implant Encellin is using

Dr. Crystal Nyitray, CEO & Co-founder Encellin

Dr. Manasi Jaiman, Vice President, Clinical Development ViaCyte

Looking back and looking forward: good news for two CIRM-supported studies

Dr. Rosa Bacchetta on the right with Brian Lookofsky (left) and Taylor Lookofsky after CIRM funded Dr. Bacchetta’s work in October 2019. Taylor has IPEX syndrome

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.

Dr. Donald Kohn, Photo courtesy UCLA

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.

Them bones them bones them dry bones – and how to help repair them

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Broken bones

People say that with age comes wisdom, kindness and confidence. What they usually don’t say is that it also comes with aches and pains and problems we didn’t have when we were younger. For example, as we get older our bones get thinner and more likely to break and less likely to heal properly.

That’s a depressing opening paragraph isn’t it. But don’t worry, things get better from here because new research from Germany has found clues as to what causes our bones to become more brittle, and what we can do to try and stop that.

Researchers at the Max Planck Institute for Biology of Ageing and CECAD Cluster of Excellence for Ageing Research at the University of Cologne have identified changes in stem cells from our bone marrow that seem to play a key role in bones getting weaker as we age.

To explain this we’re going to have to go into the science a little, so bear with me. One of the issues the researchers focused on is the role of epigenetics, this is genetic information that doesn’t change the genes themselves but does change their activity. Think of it like a light switch. The switch doesn’t change the bulb, but it does control when it’s on and when it’s off. So this team looked at the epigenome of MSCs, the stem cells found in the bone marrow. These cells play a key role in the creation of cartilage, bone and fat cells.

In a news release, Dr. Andromachi Pouikli, one of the lead researchers in the study, says these MSCs don’t function as well as we get older.

“We wanted to know why these stem cells produce less material for the development and maintenance of bones as we age, causing more and more fat to accumulate in the bone marrow. To do this, we compared the epigenome of stem cells from young and old mice. We could see that the epigenome changes significantly with age. Genes that are important for bone production are particularly affected.”

So, they took some stem cells from the bone marrow of mice and tested them with a solution of sodium acetate. Now sodium acetate has a lot of uses, including being used in heating pads, hand warmers and as a food seasoning, but in this case the solution was able to make it easier for enzymes to get access to genes and boost their activity.

“This treatment impressively caused the epigenome to rejuvenate, improving stem cell activity and leading to higher production of bone cells,” Pouikli said.

So far so good. But does this work the same way in people? Maybe so. The team analyzed MSCs from people who had undergone hip surgery and found that they showed the same kind of age-related changes as the cells from mice.

Clearly there’s a lot more work to do before we can even think about using this finding as a solution to aging bones. But it’s an encouraging start.

The study is published in the journal Nature Aging.

Mother and daughter team up to fight bias and discrimination in treatment for people with sickle cell disease

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Adrienne Shapiro and Marissa Cors are a remarkable pair by any definition. The mother and daughter duo share a common bond, and a common goal. And they are determined not to let anyone stop them achieving that goal.

Marissa was born with sickle cell disease (SCD) a life-threatening genetic condition where normally round, smooth red blood cells are instead shaped like sickles. These sickle cells are brittle and can clog up veins and arteries, blocking blood flow, damaging organs, and increasing the risk of strokes. It’s a condition that affects approximately 100,000 Americans, most of them Black.

Adrienne became a patient advocate, founding Axis Advocacy, after watching Marissa get poor treatment in hospital Emergency Rooms.  Marissa often talks about the way she is treated like a drug-seeker simply because she knows what medications she needs to help control excruciating pain on her Sickle Cell Experience Live events on Facebook.

Now the two are determined to ensure that no one else has to endure that kind of treatment. They are both fierce patient advocates, vocal both online and in public. And we recently got a chance to sit down with them for our podcast, Talking ‘Bout (re) Generation. These ladies don’t pull any punches.

Enjoy the podcast.

CIRM is funding four clinical trials aimed at finding new treatments and even a cure for sickle cell disease.

Creating a better way to treat type 1 diabetes

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The cell encapsulation device (right) that is being developed by Encellin, a San Francisco–based biotechnology company. Photo courtesy of Encellin

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.

Dr. Grace Wei

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.

Stem cell therapy may help mend a broken heart

Blausen.com staff (2014). “Medical gallery of Blausen Medical 2014

Dilated cardiomyopathy (DCM), a condition where the muscles of the heart are weak and can lead to heart failure, is considered rare in children. However, because the symptoms are not always easy to recognize the condition can go unnoticed for many years, and in severe cases can damage the heart irreparably. In that case the child’s only option is a heart transplant, and a lack of organ donors means that is not always available.

Now, new research out of Japan – published in the journal Science Translation Medicine – could lead the way to new treatments to help children avoid the need for a transplant.

In the study, researchers at Okayama University used heart stem cells called cardiosphere-derived cells (CDCs) to try and repair the damage caused by DCM.  

In a news release, lead researcher Professor Hidemasa Oh, says previous work has shown that because CDCs have the ability to turn into heart tissue they have the potential of reversing damage, but it’s not clear if this would work in children.

“I have been working on cardiac regeneration therapy since 2001. In this study, my team and I assessed the safety and efficacy of using CDCs to treat DCM in children.”

Tests in animal models with DCM showed that the CDCs resulted in a thickening of the heart muscle leading to increased blood flow around the body. This increased blood supply helped repair damaged tissue. Based on this trial the researcher determined what might be a suitable dose of CDCs for children with DCM and were granted permission to carry out a Phase 1 clinical trial.

Five young patients were treated and the results were cautiously encouraging. After a year none of the patients had experienced any severe side effects, but all had indications of improved heart function.

The study also gave the researchers some strong clues as to how the therapy seem to work. They found that when the CDCs were transplanted into the patient they secreted exosomes, which play an important role in cells communicating with one another. These exosomes then helped create a series of actions within the body; they blocked further damage to the heart tissue and they also helped kickstart the repair process.

The Okayama team are now hoping to carry out a Phase 2 clinical trial with more patients. Ultimately, they hope to be able to see if this approach could help prevent the need for a heart transplant in children, and even adults.

Celebrating a young life that almost wasn’t

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.

Ja’Ceon on his first day at pre-K. He loved it.

Learning life lessons in the lab

Rohan Upadhyay, CIRM SPARK student 2021

One of the most amazing parts of an amazing job is getting to know the students who take part in CIRM’s SPARK (Summer Program to Accelerate Regenerative Medicine Knowledge) program. It’s an internship giving high school students, that reflect the diversity of California, a chance to work in a world-class stem cell research facility.

This year because of the pandemic I didn’t get a chance to meet them in person but reading the blogs they wrote about their experiences I feel as if I know them anyway.

The blogs were fun, creative, engaging and dealt with many issues, as well as stem cell and gene therapy research.

A common theme was how hard the students, many of whom knew little about stem cells before they started, had to work just to understand all the scientific jargon.

Areana Ramirez, who did her internship at UC Davis summed it up nicely when she wrote:

“Despite the struggles of taking over an hour to read a scientific article and researching what every other word meant, it was rewarding to know that all of the strain I had put on my brain was going toward a larger understanding of what it means to help others. I may not know everything about osteogenic differentiation or the polyamine pathway, but I do know the adversities that patients with Snyder-Robinson are facing and the work that is being done to help them. I do know how hard each one of our mentors are working to find new cures and are coming up with innovating ideas that will only help humankind.”

Lauren Ginn at City of Hope had the same experience, but said it taught her a valuable lesson:

“Make no mistake, searching for answers through research can sometimes feel like shooting arrows at a bulls-eye out of sight. Nonetheless, what CIRM SPARK has taught me is the potential for exploration that lies in the unknown. This internship showed me that there is so much more to science than the facts printed in textbooks.”

Rohan Upadhyay at UC Davis discovered that even when something doesn’t work out, you can still learn a lot:

“I asked my mentor (Gerhard Bauer) about what he thought had occurred. But unlike the textbooks there was no obvious answer. My mentor and I could only speculate what had occurred. It was at this point that I realized the true nature of research: every research project leads to more questions that need to be answered. As a result there is no endpoint to research. Instead there are only new beginnings.”

Melanie Nguyen, also at UC Davis, wrote her blog as a poem. But she saved the best part for the prose at the end:

“Like a hematopoietic stem cell, I have learned that I am able to pursue my different interests, to be multi-potential. One can indulge in the joys of biology while simultaneously live out their dreams of being an amateur poet. I choose it all. Similarly, a bone marrow stem cell can become whatever it may please—red, white, platelet. It’s ability to divide and differentiate is the source of its ingenuity. I view myself in the same light. Whether I can influence others with research, words, or stories, I know that with each route I will be able to make change in personalized ways.”

For Lizbeth Bonilla, at Stanford, her experiences transcended the personal and took on an even bigger significance:

“As a first-generation Mexican American, my family was thrilled about this internship and opportunity especially knowing it came from a prestigious institution. Unfortunately there is very little to no representation in our community in regards to the S.T.E.M. field. Our dreams of education and prosperity for the future have to be compromised because of the lack of support and resources. To maintain pride in our culture, we focus on work ethics and family, hoping it will be the next generations’ time to bring successful opportunities home. However, while this is a hope widely shared the effort to have it realized is often limited to men. A Latina woman’s success and interest in education are still celebrated, but not expected. As a first-generation Latina, I want to prove that I can have a career and hopefully contribute to raising the next leading generation, not with the hope that dreams are possible but to be living proof that they are.”

Reading the blogs it was sometimes easy to forget these are 16 and 17 year old students. They write with creativity, humor, thoughtfulness and maturity. They learned a lot about stem cell research over the summer. But I think they also learned a lot more about who they are as individuals and what they can achieve.

Retooling a COVID drug to boost its effectiveness

Coronavirus particles, illustration.

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.

The study is published in the journal Antimicrobial Agents and Chemotherapy.