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.

Feds hit predatory stem cell clinics with a one-two punch

Federal Trade Commission

Stem cells have a number of amazing properties and tremendous potential to heal previously untreatable conditions. But they also have the potential to create a financial windfall for clinics that are more focused on lining their wallets than helping patients. Now the federal government is cracking down on some of these clinics in a couple of different ways.

The Food and Drug Administration (FDA) sent a warning letter to the Utah Cord Bank LLC and associated companies warning them that the products it sold – specifically “human umbilical cord blood, umbilical cord, and amniotic membrane derived cellular products” – were violating the law.

At the same time the Federal Trade Commission and the Georgia Office of the Attorney General began legal proceedings against Regenerative Medicine Institute of America. The lawsuit says the company claims its products can rebuild cartilage and help treat joint and arthritis pain, and is charging patients thousands of dollars for “treatments” that haven’t been shown to be either safe or effective.

Bloomberg Law reporter Jeannie Baumann recently wrote a fine, in-depth article on these latest steps against predatory stem cell clinics.

CIRM has been a fierce opponents of bogus stem cell clinics for years and has worked with California lawmakers to try and crack down on them. We’re delighted to see that the federal government is stepping up its efforts to stop them marketing their snake oil to unsuspecting patients and will support them every step along the way.

CIRM has produced a short video and other easy to digest information on questions people should ask before signing up for any clinical trial. You can find those resources here.

CIRM has also published findings in Stem Cells Translational Medicine that discuss the three R’s–regulated, reliable, and reputable–and how these can help protect patients with uniform standards for stem cell treatments .

Paving the way for a treatment for dementia

What happens in a stroke

When someone has a stroke, the blood flow to the brain is blocked. This kills some nerve cells and injures others. The damaged nerve cells are unable to communicate with other cells, which often results in people having impaired speech or movement.

While ischemic and hemorrhagic strokes affect large blood vessels and usually produce recognizable symptoms there’s another kind of stroke that is virtually silent. A ‘white’ stroke occurs in blood vessels so tiny that the impact may not be noticed. But over time that damage can accumulate and lead to a form of dementia and even speed up the progression of Alzheimer’s disease.

Now Dr. Tom Carmichael and his team at the David Geffen School of Medicine at UCLA have developed a potential treatment for this, using stem cells that may help repair the damage caused by a white stroke. This was part of a CIRM-funded study (DISC2-12169 – $250,000).

Instead of trying to directly repair the damaged neurons, the brain nerve cells affected by a stroke, they are creating support cells called astrocytes, to help stimulate the body’s own repair mechanisms.

In a news release, Dr. Irene Llorente, the study’s first author, says these astrocytes play an important role in the brain.

“These cells accomplish many tasks in repairing the brain. We wanted to replace the cells that we knew were lost, but along the way, we learned that these astrocytes also help in other ways.”

The researchers took skin tissue and, using the iPSC method (which enables researchers to turn cells into any other kind of cell in the body) turned it into astrocytes. They then boosted the ability of these astrocytes to produce chemical signals that can stimulate healing among the cells damaged by the stroke.

These astrocytes were then not only able to help repair some of the damaged neurons, enabling them to once again communicate with other neurons, but they also helped another kind of brain cell called oligodendrocyte progenitor cells or OPCs. These cells help make a protective sheath around axons, which transmit electrical signals between brain cells. The new astrocytes stimulated the OPCs into repairing the protective sheath around the axons.

Mice who had these astrocytes implanted in them showed improved memory and motor skills within four months of the treatment.  

And now the team have taken this approach one step further. They have developed a method of growing these astrocytes in large amounts, at very high quality, in a relatively short time. The importance of that is it means they can produce the number of cells needed to treat a person.

“We can produce the astrocytes in 35 days,” Llorente says. “This process allows rapid, efficient, reliable and clinically viable production of our therapeutic product.”

The next step is to chat with the Food and Drug Administration (FDA) to see what else they’ll need to do to show they are ready for a clinical trial.

The study is published in the journal Stem Cell Research.

City of Hope scientists use stem cells to develop ‘mini-brains’ to study Alzheimer’s and to test drugs in development

Alzheimer’s is a progressive disease that destroys memory and other important mental functions. According to the non-profit HFC, co-founded by CIRM Board member Lauren Miller Rogen and her husband Seth Rogen, more than 5 million Americans are living with Alzheimer’s. It is the 6th leading cause of death in the U.S and it is estimated that by 2050 as many as 16 million Americans will have the disease. Alzheimer’s is the only cause of death among the top 10 in the U.S. without a way to prevent, cure, or even slow its progression, which is it is crucial to better understand the disease and to develop and test potential treatments.

It is precisely for this reason that researchers led by Yanhong Shi, Ph.D. at City of Hope have developed a ‘mini-brain’ model using stem cells in order to study Alzheimer’s and to test drugs in development.

The team was able to model sporadic Alzheimer’s, the most common form of the disease, by using human induced pluripotent stem cells (iPSCs), a kind of stem cell that can be created from skin or blood cells of people through reprogramming and has the ability to turn into virtually any other kind of cell. The researchers used these iPSCs to create ‘mini-brains’, also known as brain organoids, which are 3D models that can be used to analyze certain features of the human brain. Although they are far from perfect replicas, they can be used to study physical structure and other characteristics. 

The scientists exposed the ‘mini-brains’ to serum that mimics age-associated blood-brain barrier (BBB) breakdown. The BBB is a protective barrier that surrounds the brain and its breakdown has been associated with Alzheimer’s and other age-related neurodegenerative diseases . After exposure, the team tested the ‘mini-brains’ for various Alzheimer’s biomarkers. These markers included elevated levels of proteins known as amyloid and tau that are associated with the disease and synaptic breaks linked to cognitive decline.

Research using brain organoids has shown that exposure to serum from blood could induce multiple Alzheimer’s symptoms. This suggests that combination therapies targeting multiple areas would be more effective than single-target therapies currently in development.

The team found that attempting a single therapy, such as inhibiting only amyloid or tau proteins, did not reduce the levels of tau or amyloid, respectively. These findings suggest that amyloid and tau likely cause disease progression independently. Furthermore, exposure to serum from blood, which mimics BBB breakdown, could cause breaks in synaptic connections that help brains remember things and function properly.

Image Description: Yanhong Shi, Ph.D.

In a press release from the Associated Press, Dr. Shi elaborated on the importance of their model for studying Alzheimer’s.

“Drug development for Alzheimer’s disease has run into challenges due to incomplete understanding of the disease’s pathological mechanisms. Preclinical research in this arena predominantly uses animal models, but there is a huge difference between humans and animals such as rodents, especially when it comes to brain architecture. We, at City of Hope, have created a miniature brain model that uses human stem cell technology to study Alzheimer’s disease and, hopefully, to help find treatments for this devastating illness.”

The full results of this study were published in Advance Science.

Dr. Shi has previously worked on several CIRM-funded research projects, such as looking at a potential link between COVID-19 and a gene for Alzheimer’s as well as the development of a therapy for Canavan disease.

Scientists use stem cell ‘mini-brains’ to better understand signs of frontotemporal dementia

Dementia is a general term that describes a set of diseases that impair the ability to remember, think, or make decisions that interfere with doing everyday activities. According to the World Health Organization (WHO), around 50 million people worldwide have dementia with nearly 10 million new cases every year. Although it primarily affects older people it is not a normal part of aging. As our population ages its critical to better understand why this occurs.

Frontotemporal dementia is a rare form of dementia where people start to show signs between the ages of 40 and 60. It affects the front and side (temporal) areas of the brain, hence the name. It leads to behavior changes and difficulty with speaking and thinking. This form of the disease is caused by a genetic mutation called tau, which is known to be associated with Alzheimer’s disease and other dementias.

A CIRM supported study using induced pluripotent stem cells (iPSCs) led by Kathryn Bowles, Ph.D. and conducted by a team of researchers at Mount Sinai were able to recreate much of the damage seen in a widely studied form of the frontotemporal dementia by growing special types of ‘mini-brains’, also known as cerebral organoids.

iPSCs are a kind of stem cell that can be created from skin or blood cells through reprogramming and have the ability to turn into virtually any other kind of cell. The team used iPSCs to create thousands of tiny, 3D ‘mini-brains’, which mimic the early growth and development of the brain.

The researchers examined the growth and development of these ‘mini-brains’ using stem cells derived from three patients, all of whom carried a mutation in tau. They then compared their results with those observed in “normal” mini-brains which were derived from patient stem cells in which the disease-causing mutation was genetically corrected.

After six months, signs of neurodegeneration were seen in the patient ‘mini-brains’. The patient-derived ‘mini-brains’ had fewer excitatory neurons compared to the “normal” ones which demonstrates that the tau mutation was sufficient to cause higher levels of cell death of this specific class of neurons. Additionally, the patient-derived ‘mini-brains’ also had higher levels of harmful versions of tau protein and elevated levels of inflammation.

In a news release from Mount Sinai, Dr. Bowles elaborated on the results of this study.

“Our results suggest that the V337M mutant tau sets off a vicious cycle in the brain that puts excitatory neurons under great stress. It hastens the production of new proteins needed for maturation but prevents disposal of the proteins that are being replaced.”

The full results of this study were published in Cell.

Stem cell treatment improves motor function in monkeys modeling Parkinson’s Disease

Neurodegenerative diseases impact millions of people worldwide with the risk of being affected by one of these diseases increasing as you get older. For many of these diseases, there are very few treatments available to patients. As life expectancy increases and the population continues to age, it is crucial to try and find treatments that can potentially slow the progression of these diseases or cure them entirely. This is one of the reasons why CIRM has committed directing around $1.5 billion in funding over the next few years to research related to neurological disorders.

One of the most common neurodegenerative diseases is Parkinson’s Disease (PD), a movement disorder that affects one million people in the U.S alone and leads to shaking, stiffness, insomnia, fatigue, and problems with walking, balance, and coordination.  It is caused by the breakdown and death of dopaminergic neurons, special nerve cells in the brain responsible for the production of dopamine, a chemical messenger that is crucial for normal brain activity.

A recent study published in Nature Medicine has shown improved motor function and growth of neurons over a two year period in monkeys modeling PD. The study was conducted by Su-Chun Zhang, M.D., Ph.D. and his team at the University of Wisconsin using induced pluripotent stem cells (iPSCs), a kind of stem cell that can become virtually any type of cell that can be made from skin cells. The hope is that these results can pave the way for starting human clinical trials.

In order to replicate PD in humans, the team injected 10 adult monkeys with a neurotoxin that produces PD like symptoms. As a result of this, all 10 monkeys developed slow movements, imbalances, tremors, and impaired coordination in the hand on the opposite side of the injection. Additionally, scans revealed that on the injected side, monkeys lost most brain activity involving dopamine in two key brain areas. The team then waited three years after injecting the neurotoxin before administering the therapy, during which time the monkeys’ symptoms persisted.

To generate iPSC lines, the team obtained skin cells from five of the monkeys. The iPSCs were then turned into dopamine neural progenitor cells, which have the ability to create dopamine. These newly created cells were then administered into the brains of the five monkeys, with each monkey receiving a treatment derived from their own skin cells. A sixth iPSC line from a donor monkey was used for the remaining five monkeys to see how the treatment would work if it was not derived from their own skin cells.

The results showed that the monkeys that received the treatment derived from their own skin cells recovered. These animals moved more, moved faster, and were nimbler than before the treatment. They gained the ability to grasp treats, use all four limbs for walking, and climb their cages with ease and increased agility. However, the monkeys that received iPSCs derived from a donor did not recover. Their symptoms remained unchanged or worsened compared to before the treatment.

In a news article, Zhang emphasizes how he and his team are proceeding with a treatment derived from one’s own cells (autologous) vs. one from a donor (allogeneic).

“I initially wanted to do allogeneic transplants in patients because the autologous approach is too expensive. However, after seeing [our] data, I changed my mind. I want to go with the autologous first… because I feel the chance of success is really, really high.”

CIRM is currently funding a human clinical trial ($5.5 million) that is using a gene therapy approach for PD.

Sometimes a cold stare is a good thing

A retina of a patient with macular degeneration. (Photo credit: Paul Parker/SPL)

Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness in the elderly in the U.S. It’s estimated that some 11 million Americans could have some form of the disease, a number that is growing every year. So if you are going to develop a treatment for this condition, you need to make sure it can reach a lot of people easily. And that’s exactly what some CIRM-supported researchers are doing.

Let’s back up a little first. AMD is a degenerative condition where the macular, the small central portion of your retina, is slowly worn away. That’s crucial because the retina is the light-sensing nerve tissue at the back of your eye. At first you notice that your vision is getting blurry and it’s hard to read fine print or drive a car. As it progresses you develop dark, blurry areas in the center of your vision.

There are two kinds of AMD, a wet form and a dry form. The dry form is the most common, affecting 90% of patients. There is no cure and no effective treatment. But researchers at the University of Southern California (USC), the University of California Santa Barbara (UCSB) and a company called Regenerative Patch Technologies are developing a method that is looking promising.

They are using stem cells to grow retinal pigment epithelium (RPE) cells, the kind attacked by the disease, and putting them on a tiny synthetic scaffold which is then placed at the back of the eye. The hope is these RPE cells will help slow down the progression of the disease or even restore vision.

Early results from a CIRM-funded clinical trial are encouraging. Of the five patients enrolled in the Phase 1/2a trial, four maintained their vision in the treated eye, two showed improvement in the stability of their vision, and one patient had a 17-letter improvement in their vision on a reading chart. In addition, there were no serious side effects or unanticipated problems.

So now the team are taking this approach one step further. In a study published in Scientific Reports, they say they have developed a way to cryopreserve or freeze this cell and scaffold structure.

In a news release, Dr. Dennis Clegg of UCSB, says the frozen implants are comparable to the non-frozen ones and this technique will extend shelf life and enable on-demand distribution to distant clinical sites, increasing the number of patients able to benefit from such treatments.

“It’s a major advance in the development of cell therapies using a sheet of cells, or a monolayer of cells, because you can freeze them as the final product and ship them all over the world.”

Cool.

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.

Unlocking a key behind why our bones get weaker as we age

Magnified image of a bone with osteoporosis. Photo Courtesy Sciencephoto.com

Getting older brings with it a mixed bag of items. If you are lucky you can get wiser. If you are not so lucky you can get osteoporosis. But while scientists don’t know how to make you wiser, they have gained some new insights into what makes bones weak and so they might be able to help with the osteoporosis.

Around 200 million people worldwide suffer from osteoporosis, a disease that causes bones to become so brittle that in extreme cases even coughing can lead to a fracture.

Scientists have known for some time that the cells that form the building blocks of our skeletons are found in the bone marrow. They are called mesenchymal stem cells (MSCs) and they have the ability to turn into a number of different kinds of cells, including bone or fat. The keys to deciding which direction the MSCs take are things called epigenetic factors, these basically control which genes are switched on or off and in what order. Now researchers from the UCLA School of Dentistry have identified an enzyme that plays a critical role in that process.

The team found that when the enzyme KDM4B is missing in MSCs those cells are more likely to become fat cells rather than bone cells. Over time that leads to weaker bones and more fractures.

In a news release Dr. Cun-Yu Wang, the lead researcher, said: “We know that bone loss comes with age, but the mechanisms behind extreme cases such as osteoporosis have, up until recently, been very vague.”

To see if they were on the right track the team created a mouse model that lacked KDM4B. Just as they predicted the MSCs in the mouse created more fat than bone, leading to weaker skeletons.

They also looked at mice who were placed on a high fat diet – something known to increase bone loss and weaker bones in people – and found that the diet seemed to reduce KDM4B which in turn produced weaker bones.

In the news release Dr. Paul Krebsbach, Dean of the UCLA School of Dentistry, said the implications for the research are enormous. “The work of Dr. Wang, his lab members and collaborators provides new molecular insight into the changes associated with skeletal aging. These findings are an important step towards what may lead to more effective treatment for the millions of people who suffer from bone loss and osteoporosis.”

The study is published in the journal Cell Stem Cell.

Cures, clinical trials and unmet medical needs

When you have a great story to tell there’s no shame in repeating it as often as you can. After all, not everyone gets to hear first time around. Or second or third time. So that’s why we wanted to give you another opportunity to tune into some of the great presentations and discussions at our recent CIRM Alpha Stem Cell Clinic Network Symposium.

It was a day of fascinating science, heart-warming, and heart-breaking, stories. A day to celebrate the progress being made and to discuss the challenges that still lie ahead.

There is a wide selection of topics from “Driving Towards a Cure” – which looks at some pioneering work being done in research targeting type 1 diabetes and HIV/AIDS – to Cancer Clinical Trials, that looks at therapies for multiple myeloma, brain cancer and leukemia.

The COVID-19 pandemic also proved the background for two detailed discussions on our funding for projects targeting the coronavirus, and for how the lessons learned from the pandemic can help us be more responsive to the needs of underserved communities.

Here’s the agenda for the day and with each topic there’s a link to the video of the presentation and conversation.

Thursday October 8, 2020

View Recording: CIRM Fellows Trainees

9:00am Welcome Mehrdad Abedi, MD, UC Davis Health, ASCC Program Director  

Catriona Jamieson, MD,  View Recording: ASCC Network Value Proposition

9:10am Session I:  Cures for Rare Diseases Innovation in Action 

Moderator: Mark Walters, MD, UCSF, ASCC Program Director 

Don Kohn, MD, UCLA – View Recording: Severe combined immunodeficiency (SCID) 

Mark Walters, MD, UCSF, ASCC Program Director – View Recording: Thalassemia 

Pawash Priyank, View Recording: Patient Experience – SCID

Olivia and Stacy Stahl, View Recording: Patient Experience – Thalassemia

10 minute panel discussion/Q&A 

BREAK

9:55am Session II: Addressing Unmet Medical Needs: Driving Towards a Cure 

Moderator: John Zaia, MD, City of Hope, ASCC Program Direction 

Mehrdad Abedi, MD, UC Davis Health, ASCC Program Director – View Recording: HIV

Manasi Jaiman, MD, MPH, ViaCyte, Vice President, Clinical Development – View Recording: Diabetes

Jeff Taylor, Patient Experience – HIV

10 minute panel discussion/Q&A 

BREAK

10:40am Session III: Cancer Clinical Trials: Networking for Impact 

Moderator: Catriona Jamieson, MD, UC San Diego, ASCC Program Director 

Daniela Bota, MD, PhD, UC Irvine, ASCC Program Director – View Recording:  Glioblastoma 

Michael Choi, MD, UC San Diego – View Recording: Cirmtuzimab

Matthew Spear, MD, Poseida Therapeutics, Chief Medical Officer – View Recording: Multiple Myeloma  

John Lapham, Patient Experience –  View Recording: Chronic lymphocytic leukemia (CLL) 

10 minute panel discussion/Q&A 

BREAK

11:30am Session IV: Responding to COVID-19 and Engaging Communities

Two live “roundtable conversation” sessions, 1 hour each.

Roundtable 1: Moderator Maria Millan, MD, CIRM 

CIRM’s / ASCC Network’s response to COVID-19 Convalescent Plasma, Cell Therapy and Novel Vaccine Approaches

Panelists

Michael Matthay, MD, UC San Francisco: ARDS Program

Rachael Callcut, MD, MSPH, FACS, UC Davis: ARDS Program 

John Zaia, MD, City of Hope: Convalescent Plasma Program 

Daniela Bota, MD, PhD, UC Irvine: Natural Killer Cells as a Treatment Strategy 

Key questions for panelists: 

  • Describe your trial or clinical program?
  • What steps did you take to provide access to disproportionately impacted communities?
  • How is it part of the overall scientific response to COVID-19? 
  • How has the ASCC Network infrastructure accelerated this response? 

Brief Break

Roundtable 2: Moderator Ysabel Duron, The Latino Cancer Institute and Latinas Contra Cancer

View Recording: Roundtable 2

Community Engagement and Lessons Learned from the COVID Programs.  

Panelists

Marsha Treadwell, PhD, UC San Francisco: Community Engagement  

Sheila Young, MD, Charles R. Drew University of Medicine and Science: Convalescent Plasma Program in the community

David Lo, MD, PhD,  UC Riverside: Bringing a public health perspective to clinical interventions

Key questions for panelists: 

  • What were important lessons learned from the COVID programs? 
  • How can CIRM and the ASCC Network achieve equipoise among communities and engender trust in clinical research? 
  • How can CIRM and the ASCC Network address structural barriers (e.g. job constrains, geographic access) that limit opportunities to participate in clinical trials?