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.

Tipping our hat to the good guys (& gals)

A search on Google using the term “stem cell blogs” quickly produces a host of sites offering treatments for everything from ankle, hip and knee problems, to Parkinson’s disease and asthma. Amazingly the therapies for those very different conditions all use the same kind of cells produced in the same way. It’s like magic. Sadly, it’s magic that is less hocus pocus and more bogus bogus.

The good news is there are blogs out there (besides us, of course) that do offer good, accurate, reliable information about stem cells. The people behind them are not in this to make a quick buck selling snake oil. They are in this to educate, inform, engage and enlighten people about what stem cells can, and cannot do.

So, here’s some of our favorites.

The Niche

This blog has just undergone a face lift and is now as colorful and easy to read as it is informative. It bills itself as the longest running stem cell blog around. It’s run by UC Davis stem cell biologist Dr. Paul Knoepfler – full disclosure, we have funded some of Paul’s work – and it’s a constant source of amazement to me how Paul manages to run a busy research lab and post regular updates on his blog.

The power of The Niche is that it’s easy for non-science folk – like me – to read and understand without having to do a deep dive into Google search or Wikipedia. It’s well written, informative and often very witty. If you are looking for a good website to check whether some news about stem cells is real or suspect, this is a great place to start.

Stem Cell Battles

This site is run by another old friend of CIRM’s, Don Reed. Don has written extensively about stem cell research in general, and CIRM in particular. His motivation to do this work is clear. Don says he’s not a doctor or scientist, he’s something much simpler:

“No. I am just a father fighting for his paralyzed son, and the only way to fix him is to advance cures for everyone. Also, my mother died of breast cancer, my sister from leukemia, and I myself am a prostate cancer survivor. So, I have some very personal reasons to support the California Institute for Regenerative Medicine and to want state funding for stem cell and other regenerative medicine research to continue in California!”

The power of Don’s writing is that he always tells human stories, real tales about real people. He makes everything he does accessible, memorable and often very funny. If I’m looking for ways to explain something complex and translate it into everyday English, I’ll often look at Don’s work, he knows how to talk to people about the science without having their eyes cloud over.

A Closer Look at Stem Cells

This is published by the International Society for Stem Cell Research (ISSCR), the leading professional organization for stem cell scientists. You might expect a blog from such a science-focused organization to be heavy going for the ordinary person, but you’d be wrong.

A Closer Look at Stem Cells is specifically designed for people who want to learn more about stem cells but don’t have the time to get a PhD. They have sections explaining what stem cells are, what they can and can’t do, even a glossary explaining different terms used in the field (I used to think the Islets of Langerhans were small islands off the coast of Germany till I went to this site).

One of the best, and most important, parts of the site is the section on clinical trials, helping people understand what’s involved in these trials and the kinds of things you need to consider before signing up for one.

Signals

Of course, the US doesn’t have a monopoly on stem cell research and that’s reflected in the next two choices. One is the Signals Blog from our friends to the north in Canada. This is an easy-to-read site that describes itself as the “Insiders perspective on the world of stem cells and regenerative medicine.” The ‘Categories ‘dropdown menu allows you to choose what you want to read, and it gives you lots of options from the latest news to a special section for patients, even a section on ethical and legal issues. 

EuroStemCell

As you may have guessed from the title this is by our chums across the pond in Europe. They lay out their mission on page one saying they want to help people make sense of stem cells:

“As a network of scientists and academics, we provide independent, expert-reviewed information and road-tested educational resources on stem cells and their impact on society. We also work with people affected by conditions, educators, regulators, media, healthcare professionals and policymakers to foster engagement and develop material that meets their needs.”

True to their word they have great information on the latest research, broken down by different types of disease, different types of stem cell etc. And like CIRM they also have some great educational resources for teachers to use in the classroom.

Everything you wanted to know about COVID vaccines but never got a chance to ask

All this month we are using our blog and social media to highlight a new chapter in CIRM’s life, thanks to the voters approving Proposition 14. We are looking back at what we have done since we were created in 2004, and also looking forward to the future. Today we feature a rare treat, an interview with Moderna’s Dr. Derrick Rossi.

Moderna co-founder Dr. Derrick Rossi

It’s not often you get a chance to sit down with one of the key figures in the fight against the coronavirus and get to pick his brain about the best ways to beat it. We were fortunate enough to do that on Wednesday, talking to Dr. Derrick Rossi, the co-founder of Moderna, about the vaccine his company has developed.

CIRM’s President and CEO, Dr. Maria Millan, was able to chat to Dr. Rossi for one hour about his background (he got support from CIRM in his early post-doctoral research at Stanford) and how he and his colleagues were able to develop the COVID-19 vaccine, how the vaccine works, how effective it is, how it performs against new variations of the virus.

He also told us what he would have become if this science job hadn’t worked out.

All in all it was a fascinating conversation with someone whose work is offering a sense of hope for millions of people around the world.

If you missed it first time around you can watch it here.

How a CIRM scholar helped create a life-saving COVID vaccine

Dr. Derrick Rossi might be the most famous man whose name you don’t recognize. Dr. Rossi is the co-founder of Moderna. Yes, that Moderna. The COVID-19 vaccine Moderna. The vaccine that in clinical trials proved to be around 95 percent effective against the coronavirus.

Dr. Rossi also has another claim to fame. He is a former CIRM scholar. He did some of his early research, with our support, in the lab of Stanford’s Dr. Irv Weissman.

So how do you go from a lowly post doc doing research in what, at the time, was considered a rather obscure scientific field, to creating a company that has become the focus of the hopes of millions of people around the world?  Well, join us on Wednesday, January 27th at 9am (PST) to find out.

CIRM’s President and CEO, Dr. Maria Millan, will hold a live conversation with Dr. Rossi and we want you to be part of it. You can join us to listen in, and even post questions for Dr. Rossi to answer. Think of the name dropping credentials you’ll get when say to your friends; “Well, I asked Dr. Rossi about that and he told me…..”

Being part of the conversation is as simple as clicking on this link:

After registering, you will receive a confirmation email containing information about joining the webinar.

We look forward to seeing you there.

Month of CIRM – Our Therapeutics Team Goes Hunting

All this month we are using our blog and social media to highlight a new chapter in CIRM’s life, thanks to the voters approving Proposition 14. We are looking back at what we have done since we were created in 2004, and also looking forward to the future. Today we have a guest blog by CIRM Senior Science Officer Lisa Kadyk, outlining how she and her colleagues actively search for the best science to fund.

Lisa Kadyk, Ph.D.

Hi everyone,

This is Lisa Kadyk, a Science Officer from the CIRM Therapeutics team, here to tell you about some of the work our team does to support the CIRM mission of accelerating stem cell treatments to patients with unmet medical needs.  Our job involves seeking out and recruiting great scientists to apply to CIRM and supporting those we fund.

Therapeutics team members manage both the awards that fund the final preclinical studies required before testing a therapeutic in a clinical trial (CLIN1), and the awards that fund the clinical trials themselves (CLIN2). 

I mentioned above that we actively recruit new applicants for our CLIN1 and CLIN2 awards – which is not an activity that is typical of most funding agencies – so why and how do we do this?  

It all comes down to our mission of accelerating the development of therapies to help patients with unmet medical needs.  It turns out that there are many potential applicants developing cutting edge therapies who don’t know much or anything about CIRM, and the ways we can help them with getting those therapies to the clinic and through clinical trials.    So, to bridge this gap, we Science Officers attend scientific conferences, read the scientific literature and meet regularly with each other to stay abreast of new therapeutic approaches being developed in both academia and industry, with the goal of identifying and reaching out to potential applicants about what CIRM has to offer. 

What are some of the things we tell potential applicants about how partnering with CIRM can help accelerate their programs?   First of all, due to the efforts of a very efficient Review team, CIRM is probably the fastest in the business for the time between application and potential funding.  It can be as short as three months for a CLIN1 or CLIN2 application to be reviewed by the external Grants Working Group and approved by the CIRM Board, whereas the NIH (for example) estimates it takes seven to ten months to fund an application.   Second, we have frequent application deadlines (monthly for CLIN1 and CLIN2), so we are always available when the applicant is ready to apply.  Third, we have other accelerating mechanisms in place to help grantees once they’ve received funding, such as the CIRM Alpha Stem Cell Clinics network of six clinical sites throughout California (more efficient clinical trial processes and patient recruitment) and Clinical Advisory Panels (CAPs) – that provide technical, clinical or regulatory expertise as well as patient advocate guidance to the grantee.  Finally, we Science Officers do our best to help every step of the way, from application through grant closeout.

We now feel confident that our recruitment efforts, combined with CIRM’s more efficient funding pipeline and review processes, are accelerating development of new therapies.  Back in 2016, a new CIRM Strategic Plan included the goal of recruiting 50 successful (i.e., funded) clinical trial applicants within five years.  This goal seemed like quite a stretch, since CIRM had funded fewer than 20 clinical trials in the previous ten years.  Fast-forward to the end of 2020, and CIRM had funded 51 new trials in those five years, for a grand total of 68 trials.    

Now, with the passage of Proposition 14 this past November, we are looking forward to bringing more cell and gene therapeutic candidates into clinical trials.   If you are developing one yourself, feel free to let us know… or don’t be surprised if you hear from us!  

You can’t take it if you don’t make it

Biomedical specialist Mamadou Dialio at work in the Cedars-Sinai Biomanufacturing Center. Photo by Cedars-Sinai.

Following the race to develop a vaccine for COVID-19 has been a crash course in learning how complicated creating a new therapy is. It’s not just the science involved, but the logistics. Coming up with a vaccine that is both safe and effective is difficult enough, but then how do you make enough doses of it to treat hundreds of millions of people around the world?

That’s a familiar problem for stem cell researchers. As they develop their products they are often able to make enough cells in their own labs. But as they move into clinical trials where they are testing those cells in more and more people, they need to find a new way to make more cells. And, of course, they need to plan ahead, hoping the therapy is approved by the Food and Drug Administration, so they will need to be able to manufacture enough doses to meet the increased demand.

We saw proof of that planning ahead this week with the news that Cedars-Sinai Medical Center in Los Angeles has opened up a new Biomanufacturing Center.

Dr. Clive Svendsen, executive director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute, said in a news release, the Center will manufacture the next generation of drugs and regenerative medicine therapies.

“The Cedars-Sinai Biomanufacturing Center leverages our world-class stem-cell expertise, which already serves scores of clients, to provide a much-needed biomanufacturing facility in Southern California. It is revolutionary by virtue of elevating regenerative medicine and its therapeutic possibilities to an entirely new level-repairing the human body.”

This is no ordinary manufacturing plant. The Center features nine “clean rooms” that are kept free from dust and other contaminants. Everyone working there has to wear protective suits and masks to ensure they don’t bring anything into the clean rooms.

The Center will specialize in manufacturing induced pluripotent stem cells, or iPSCs. Dhruv Sareen, PhD, executive director of the Biolmanufacturing Center, says iPSCs are cells that can be turned into any other kind of cell in the body.

“IPSCs are powerful tools for understanding human disease and developing therapies. These cells enable us to truly practice precision medicine by developing drug treatments tailored to the individual patient or groups of patients with similar genetic profiles.”

The Biomanufacturing Center is designed to address a critical bottleneck in bringing cell- and gene-based therapies to the clinic. After all, developing a therapy is great, but it’s only half the job. Making enough of it to help the people who need it is the other half.

CIRM is funding Dr. Svendsen’s work in developing therapies for ALS and other diseases and disorders.  

CIRM-funded therapy to ease the impact of chemotherapy

Treatments for cancer have advanced a lot in recent years, but many still rely on the use of chemotherapy to either shrink tumors before surgery or help remove cancerous cells the surgery missed. The chemo can be very effective, but it’s also very toxic. Angiocrine Bioscience Inc. is developing a way to reduce those toxic side effects, and they just got a nice vote of confidence for that approach.

The US Food and Drug Administration (FDA) has granted Angiocrine Regenerative Medicine Advanced Therapy (RMAT) designation for their product AB-205.

RMAT is a big deal. It means the therapy, in this case AB-205, has already shown it is safe and potentially beneficial to patients, so the designation means that if it continues to be safe and effective it may be eligible for a faster, more streamlined approval process. And that means it can get to the patients who need it, outside of a clinical trial, faster.

What is AB-205? Well it’s made from genetically engineered cells, derived from cord blood, designed to help alleviate or accelerate recovery from the toxic side effects of chemotherapy for people undergoing treatment for lymphoma and other aggressive cancers of the blood or lymph system.

CIRM awarded Angiocrine Bioscience $6.2 million in 2018 to help carry out the Phase 2 clinical trial testing the therapy. In a news release ,CIRM President & CEO, Dr. Maria Millan, said there is a real need for this kind of therapy.

“This is a project that CIRM has supported from an earlier stage of research, highlighting our commitment to moving the most promising research out of the lab and into people. Lymphoma is the most common blood cancer and the 6th most commonly diagnosed cancer in California. Despite advances in therapy many patients still suffer severe complications from the chemotherapy, so any treatment that can reduce those complications can not only improve quality of life but also, we hope, improve long term health outcomes for patients.”

In a news release Dr. Paul Finnegan, Angiocrine’s CEO, welcomed the news.

“The RMAT designation speaks to the clinical meaningfulness and the promising efficacy data and safety profile of AB-205 based on our Phase 1b/2 study. This is an important step in accelerating the development of AB-205 towards its first market approval. We appreciate the thorough assessment provided by the FDA reviewers and the support from our partner, the California Institute for Regenerative Medicine.” 

The investment in Angiocrine marked a milestone for CIRM. It was the 50th clinical trial we had funded. It was a cause for celebration then. We’re hoping it will be a cause for an even bigger celebration in the not too distant future.

The company hopes to start a Phase 3 clinical trial in the US and Europe next year.

Thank you

Bob Klein

These last few days have been interesting on so many levels. First the presidential race has kept the nation on tenterhooks. Closer to home the vote count for Proposition 14, to refunded CIRM, has been painstakingly slow (by the way, painstakingly means “with great care and thoroughness” for which we thank all the vote counters). But now, finally, happily, we have a verdict.

WE WON.

 It was close, desperately so. In the end the Associated Press called the race with the count at 51% yes, to 49% no. You can understand why so many of us were so nervous for so long. But now we have something to celebrate.

As Jonathan Thomas, JD, PhD, the Chair of our Board said: “We are thrilled to see Proposition 14 approved by the voters of California. We are proud of what we have achieved so far – the cures and therapies we helped develop, the billions we brought into the state in additional investments, and the tens of thousands of jobs we created – and we look forward to continuing that work.

“We are honored by the trust the people of California have placed in us, and by the support of our extraordinary patient advocate community and by the many Chambers of Commerce around California who have all recognized our historic achievements.

“We are already working on ways to repay that trust and bring stem cell and regenerative therapies to all the people of this great state, particularly for communities that have traditionally been overlooked or underserved.” 

In a news release on the Californians for Cures website, Bob and Danielle Klein, who led the Yes on 14 campaign, were understandably delighted:  

“The success of Prop. 14 sends a clear message from California voters that one of the most important investments our state can make is in the future health of our families. Over the past decade, California has made incredibly thoughtful and impactful investments in developing stem cell therapies and cures for diseases and conditions like diabetes, cancer, blindness, Parkinson’s, paralysis and many more; now we know this progress and work to mitigate human suffering, restore health and improve the human condition will continue. A special thank you to California’s voters and our supporters in passing this critical measure. Today would not have been possible without our historically unprecedented coalition of patient advocate organizations and individuals – the heart and soul of this campaign – who worked tirelessly to overcome all obstacles and help secure a victory for patients and their families, and deliver hope to those searching for a cure for generations to come.”

To all of you who voted for us, thank you from the bottom of our hearts.

To all the people who worked so hard to get Prop 14 passed, thank you. We are indebted to you.

OK, gotta go. We have work to do.

Stem cell therapy for deadly childhood immune disorder goes four for four

The gold standard for any new therapy in the U.S. is approval by the Food and Drug Administration (FDA). This approval clears the therapy for sale and often also means it will be covered by insurance. But along the way there are other designations that can mean a lot to a company developing a new approach to a deadly disease.

That’s what recently happened with Mustang Bio’s MB-107. The therapy was given Orphan Drug Designation for the treatment of X-linked Severe Combined Immunodeficiency (SCID) also known as “bubble baby disease”, a rare but deadly immune disorder affecting children. This is the same therapy that CIRM is funding in a clinical trial we’ve blogged about in the past.  

Getting Orphan Drug Designation can be a big deal. It is given to therapies intended for the treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the U.S. It comes with some sweet incentives, such as tax credits toward the cost of clinical trials and prescription drug user fee waivers. And, if the product becomes the first in its class to get FDA approval for a particular disease, it is entitled to seven years of market exclusivity, which is independent from intellectual property protection.

This is not the first time Mustang Bio’s MB-107 has been acknowledged as a potential gamechanger. It’s also been given three other classifications both here in the US and in Europe.

  • Rare Pediatric Disease Designation: this also applies to treatments for diseases affecting fewer than 200,000 people in the US that have the potential to provide clinically meaningful benefits to patients. It provides the company with a “voucher” that they can use to apply for priority review for another therapy they are developing. The hope is that this will encourage companies to develop treatments for rare childhood diseases that might not otherwise be profitable.
  • Regenerative Medicine Advanced Therapy (RMAT) designation: this allows for faster, more streamlined approvals of regenerative medicine products
  • Advanced Therapy Medicinal Product classification: this is granted by the European Medicines Agency (EMA) to medicines that are based on genes, tissues or cells and can offer groundbreaking opportunities for the treatment of disease.

Of course, none of these designations are a guarantee that Mustang Bio’s MB-107 will ultimately get FDA approval, but they’re a pretty good indication that a lot of people have confidence they’ll get there.

One shot, two benefits!

Doctor preparing an influenza vaccine for a patient.

To try and boost sales during the pandemic many businesses are offering two-for-one deals; buy one product get another free. Well, that might also be the case with a flu shot; get one jab and get protection from two viruses.

A new study offers an intriguing – though not yet certain – suggestion that getting a flu shot could not only reduce your risk of getting the flu, but also help reduce your risk of contracting the coronavirus. If it’s true it would be a wonderful tool for health professionals hoping to head of a twindemic of flu and COVID-19 this winter. It would also be a pretty sweet deal for the rest of us.

Researchers at Radboud University Medical Center in the Netherlands looked through their hospital’s database and compared people who got a flu shot during the previous year with people who didn’t. They found that people who got the vaccine were 39 percent less likely to have tested positive for the coronavirus than people who didn’t get the vaccine.

Now, there are a bunch of caveats about this study (published in the preprint journal MedRxiv) one of which is that it wasn’t peer reviewed. Another is that people who get flu shots might just be more health conscious than people who don’t, which means they might also be more aware of the need to wear a mask, social distance, wash their hands etc.

But that doesn’t mean this study is wrong. Two recent studies (in the journal Vaccines and the Journal of Medical Virology) also found similar findings, that people over the age of 65 who got a flu shot had a lower risk of getting COVID-19. That’s particularly important for that age group as they are the ones most likely to experience life-threatening complications from COVID-19.

But what could explain getting a two-fer from one vaccine? Well, there’s a growing body of research that points to something called “trained innate immunity”. Our bodies have two different kinds of immune system, adaptive and innate. Vaccines activate the adaptive system, causing it to develop antibodies to attack and kill a virus. But there’s also evidence these same vaccines could trigger our innate immune system to help fight off infections. So, a flu vaccine could boost your adaptive immunity against the flu, but also kick in the innate immunity against the coronavirus.

In an article in Scientific American, Ellen Foxman, an immunobiologist and clinical pathologist at the Yale School of Medicine, says that might be the case here: “There is evidence from the literature that trained immunity does exist and can offer broad protection, in unexpected ways, against other pathogens besides what the vaccine was designed against.”

The researchers in the Netherlands wanted to see if there was any evidence that what they saw in their hospital had any basis in fact. So, they devised a simple experiment. They took blood cells from healthy individuals and exposed some of the cells to the flu vaccine. After six days they exposed all the cells to the SARS-CoV-2, the virus that causes COVID-19.

Compared to the untreated cells, the cells that had been exposed to the flu vaccine produced more virus-fighting immune molecules called cytokines. These can attack the virus and help protect people early on, resulting in a milder, less dangerous infection.

All in all it’s encouraging evidence that a flu shot might help protect you against the coronavirus. And at the very least it will reduce your risk of the flu, and if there’s one thing you definitely don’t want this year it’s having to battle two life-threatening viruses at the same time.