COVID is a real pain in the ear

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The more you learn about COVID-19 the more there is to dislike about it. The global death toll from the virus is now more than five million and for those who survive there can be long-term health consequences. We know COVID can attack the lungs, heart and brain. Now we are learning it can also mess up your ears causing hearing problems, ringing in the ear (tinnitus) and leave you dizzy.

Viral infections are a known cause of hearing loss and other kinds of infection. That’s why, before the pandemic started, Dr. Konstantina Stantovic at Massachusetts Eye and Ear and Dr. Lee Gherke at MIT had been studying how and why things like measles, mumps and hepatitis affected people’s hearing. After COVID hit they heard reports of patients experiencing sudden hearing loss and other problems, so they decided to take a closer look.

They took cells from ten patients who had all experienced some hearing or ear-related problems after testing positive for COVID and, using the iPSC method, turned those cells into the kind found in the inner ear including hair cells, supporting cells, nerve fibers, and Schwann cells.  

They then compared those to cells from patients who had similar hearing issues but who had not been infected with COVID. They found that the hair and Schwann cells both had proteins the virus can use to infect cells. That’s important because hair cells help with balance and the Schwann cells play a protective role for neuronal axons, which help different nerve cells in the brain communicate with each other.

In contrast, some of the other cells in the inner ear didn’t have those proteins and so were protected from COVID.

In a news release Dr. Stankovic says it’s not known how many people infected with COVID experienced hearing issues. “Initially this was because routine testing was not readily available for patients who were diagnosed with COVID, and also, when patients were having more life-threatening complications, they weren’t paying much attention to whether their hearing was reduced or whether they had tinnitus. We still don’t know what the incidence is, but our findings really call for increased attention to audio vestibular symptoms in people with Covid exposure.”

The doctors are not sure how the virus gets into the inner ear but speculate that it may enter through the Eustachian tube, that’s a small passageway that connects your throat to your middle ear. When you sneeze, swallow, or yawn, your Eustachian tubes open, preventing air pressure and fluid from building up inside your ear. They think that might allow particles from the nose to spread to the ear.

The study is published in the journal Communications Medicine.

CIRM has funded 17 different projects targeting COVID-19, several of which are still active.

A step forward in finding a treatment for a deadly neurological disorder

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MRI section of a brain affected by ALS with the front section of the brain highlighted

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a nasty disease that steadily attacks nerve cells in the brain and spinal cord. It’s pretty much always fatal within a few years. As if that wasn’t bad enough, ALS also can overlap with a condition called frontotemporal dementia (ALS/FTD). Together these conditions cause devastating symptoms of muscle weakness along with changes in memory, behavior and personality.

Now researchers at Cambridge University in the UK have managed to grow groups of cells called “mini-brains” that mimic ALS/FTD and could lead to new approaches to treating this deadly combination.

We have written about these mini-brains before. Basically, they are created, using the iPSC method, that takes skin or blood cells from a patient with a particular condition, in this case ALS/FTD, and turns them into the kind of nerve cells in the brain affected by the disease. Because they came from someone who had ALS/FTD they display many of the characteristics of the disease and this gives researchers a great tool to study the condition.

This kind of approach has been done before and given researchers a glimpse into what is happening in the brains of people with ALS/FTD. But in the past those cells were in a kind of clump, and it wasn’t possible to get enough nutrients to the cells in the middle of the clump for the mini-brain to survive for long.

What is different about the Cambridge team is that they were able to create these mini-brains using thin, slices of cells. That meant all the cells could get enough nutrients to survive a long time, giving the team a better model to understand what is happening in ALS/FTD.

In a news release, Dr András Lakatos, the senior author of the study, said: “Neurodegenerative diseases are very complex disorders that can affect many different cell types and how these cells interact at different times as the diseases progress.

“To come close to capturing this complexity, we need models that are more long-lived and replicate the composition of those human brain cell populations in which disturbances typically occur, and this is what our approach offers. Not only can we see what may happen early on in the disease – long before a patient might experience any symptoms – but we can also begin to see how the disturbances change over time in each cell.”

Thanks to these longer-lived cells the team were able to see changes in the mini-brains at a very early stage, including damage to DNA and cell stress, changes that affected other cells which play a role in muscle movements and behavior.

Because the cells developed using the iPSC method are from a patient with ALS/FTD, the researchers were able to use them to screen many different medications to see if any had potential as a therapy. They identified one, GSK2606414, that seemed to help in reducing the build-up of toxic proteins, reduced cell stress and the loss of nerve cells.

The team acknowledge that these results are promising but also preliminary and will require much more research to verify them.

CIRM has funded three clinical trials targeting ALS. You can read about that work here.

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

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.

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.

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.

Identifying the visually impaired patients most likely to benefit from jCyte’s stem cell therapy

We have written about jCyte many times on The Stem Cellar. For one reason, they are showing really encouraging results in their treatment for retinitis pigmentosa (RP). And now they have taken an even deeper dive into those results and identified which patients may be most likely to benefit from the therapy.

RP is a rare genetic disorder that slowly destroys the rods and cones, the light sensing cells in the back of the eye. If you look at the image below the one on the left shows normal vision, the one on the right shows what happens with RP. At first you start to lose night vision, then other parts of your vision are slowly eroded until you are legally blind.

RP starts early, often people are diagnosed in their teens and are legally blind by middle age. There is no treatment, no cure. It’s estimated that as many as 100,000 people in the US have RP, as many as two million worldwide.

That’s where jCyte comes in. They developed jCell, a therapy using adult stem cells that have been changed into human retinal progenitor cells (hRPCs). These are injected into the back of the eye where they secrete small proteins called neurotrophic factors.

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

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

And in patients treated with jCell those islands of vision did expand. The team followed patients for one-year post treatment and found that patients given the highest dose, six million cells, experienced the biggest improvement and were able to read, on average, 16 more letters on a standard eye chart than they had been before treatment. In comparison people given a sham or placebo treatment only had an improvement of less than two letters.

This group also experienced improvements in their peripheral vision, their ability to distinguish objects in the foreground from the background and were better able to get around in low light.

But that’s not all. Dr. Sunil Srivastava, with the Cleveland Clinic Cole Eye Institute, did a detailed analysis of patients treated in the trial and identified central foveal thickness (CFT- the part of the eye located in the center of the retina) as an important marker for who would be most likely to benefit from jCell. People who started out with a higher CFT score were most likely to get the biggest benefits.

In a news release, jCyte CEO Dr. Shannon Blalock said the findings are really encouraging: “We look forward to working closely with our scientific advisory board and principal investigators to apply these key learnings to our upcoming pivotal study of jCell to optimize its probability of success in an effort to advance the clinical development program of our RMAT designated therapy for RP patients who currently have no treatment options.”

Stem cell therapy for diabetic foot ulcers shows promise in new study

For individuals with diabetes, the body’s inability to properly control blood sugar levels can lead to a wide range of other problems as time passes. One major issue is a diabetic foot ulcer (DFU), an open sore or wound that is commonly located on the bottom of the foot and caused by poor blood circulation and nerve damage. It occurs in approximately 15% of individuals with diabetes and in severe cases can lead to foot or leg amputation. Unfortunately, there is usually no effective form of treatment for this condition.

However, results from several studies authorized by the Ministry of Health of Nicaragua showed that using a stem cell therapy to treat patients with DFUs was safe and could be beneficial to patients.

The first results in a pilot study after an 18-month period demonstrated safety of the therapy and complete wound healing by nine months. After the six-year mark, five of the initial 10 subjects still demonstrated persistence of clinical benefits. It should be noted that five had passed away due to cardiac and other non-study-related causes.

In another study, the team wanted to determine the safety and efficacy of the stem cell therapy to treat non-healing DFUs greater than 3 centimeters in diameter.

For this clinical trial, 63 people from 35 to 70 years old with Type 2 diabetes and chronic DFU, all of whom were amputation candidates, were treated with a mixture of various types of stem cells obtained from the patient’s own fat tissue. The stem cell therapy was injected directly into the DFU with the hopes of restoring damaged blood vessels and promoting blood circulation and healing.

Patients were seen six months post treatment to evaluate ulcer closure, with 51 patients achieving 100 percent DFU closure and eight having greater than 75 percent. Only three required early amputations and one patient died. At 12 months post treatment, 50 patients had 100 percent DFU healing, while four had greater than 85 percent healing.

In a news release, Dr. Anthony Atala, Director of the Wake Forest Institute for Regenerative Medicine, expressed interest in evaluating this stem cell therapy and results further.

“This work should be reviewed as it demonstrates the possibility of a novel cell injection therapy that can alleviate pain and infection, accelerate wound healing, and possibly avoid amputation.”

The full results of the recent study were published in Stem Cells Translational Medicine.

A word from our Chair, several in fact

In 2005, the New Oxford American Dictionary named “podcast” its word of the year. At the time a podcast was something many had heard of but not that many actually tuned in to. My how times have changed. Now there are some two million podcasts to chose from, at least according to the New York Times, and who am I to question them.

Yesterday, in the same New York Times, TV writer Margaret Lyons, wrote about how the pandemic helped turn her from TV to podcasts: “Much in the way I grew to prefer an old-fashioned phone call to a video chat, podcasts, not television, became my go-to medium in quarantine. With their shorter lead times and intimate production values, they felt more immediate and more relevant than ever before.”

I mention this because an old colleague of ours at CIRM, Neil Littman, has just launched his own podcast and the first guest on it was Jonathan Thomas, Chair of the CIRM Board. Their conversation ranged from CIRM’s past to the future of the regenerative field as a whole, with a few interesting diversions along the way. It’s fun listening. And as Margaret Lyons said it might be more immediate and more relevant than ever before.

Inspiring new documentary about stem cell research

Poster for the documentary “Ending Disease”

2020 has been, to say the very least, a difficult and challenging year for all of us. But while the focus of the world has, understandably, been on the coronavirus there was also some really promising advances in stem cell research. Those advances are captured in a great new documentary called Ending Disease.

The documentary is by Emmy award-winning filmmaker Joe Gantz. In it he follows ten people who are facing life-threatening or life-changing diseases and injuries and who turn to pioneering stem cell therapies for help.

It’s an inspiring documentary, one that reminds you of the real need for new treatments and the tremendous hope and promise of stem cell therapies. Here’s a look at a trailer for Ending Disease.

You can see an exclusive screening of Ending Disease on Friday, January 8th, 2021 at 5:00pm PST.

After the livestream, there will be a live Q&A session where former members of the successful Proposition 14 campaign team – which refunded CIRM with an additional $5.5 billion – will be joined by CIRM’s President and CEO Dr. Maria Millan, talking about what lies ahead for CIRM and the future of stem cell research.

To purchase a ticket, click here. It only costs $12 and 50% of the ticket sales proceeds will go to Americans for Cures to help them continue to advocate for the advancement of stem cell research, and more importantly, for the patients and families to whom stem cell research provides so much hope.

If you need any extra persuading that it’s something you should definitely put on our calendar, here’s a letter from the film maker Joe Gantz.

I am the director of the documentary Ending Disease: The Stem Cell, Anti-Cancer T-Cell, & Antibody Revolution In Medicine, a film that will help inform people about the progress that’s been made in this field and how people with their lives on the line are now able to benefit from these new regenerative therapies. 

I was granted unprecedented access to ten of the first generation of clinical trials using stem cell and regenerative medicine to treat and cure many of the most devastating diseases and conditions including: brain cancer, breast cancer, leukemia and lymphoma, HIV, repairing a broken spinal cord, retinitis pigmentosa and SCID. The results are truly inspiring.

This is personal for me.  After spending four years making this documentary, I was diagnosed with bladder cancer. Upon diagnosis, I immediately felt the same desperation as millions of families who are in search of a medical breakthrough. I understood, on a personal level, what the patients we followed in the film all knew: when you are diagnosed with a disease, there is a narrow window of time in which you can effectively seek a life-saving treatment or cure. If treatment becomes available outside of that window, then it is too late. However, Ending Disease shows that with continued support for regenerative medicine, we can create a near future in which one-time cures and highly mitigating therapies are available to patients for a whole host of diseases.

Best regards,

Joe