Muscle stem cells provide insight into treatment of muscular dystrophies and aging muscles

Dr. Alessandra Sacco, associate professor in the Development, Aging and Regeneration Program at Sanford Burnham Prebys.

Muscles are a vital part of the body that enable us to walk, run, lift, and do everyday activities. When muscles start to deteriorate, we start to have difficulty performing these activities, which severely limits quality of life and autonomy. Typically, this becomes more commonplace as we age and is known as sarcopenia, which affects nearly ten percent of adults over the age of 50 and nearly half of individuals in their 80s.

However, there are other instances where this happens much more rapidly and early on due to genetic disease. These are commonly known as muscular dystrophies, which consist of more than 30 genetic diseases characterized by progressive muscle weakness and degeneration. A cure does not currently exist.

Regardless of the cause of the muscle deterioration, scientists at Sanford Burnham Prebys have uncovered how to potentially promote growth inside stem cells found within the muscle, thereby promoting muscle growth. In a mouse model study funded in part by CIRM and published in Nature Communications, Dr. Alessandra Sacco, senior author of the paper, and her team describe how a signaling pathway, along with a specific protein, can help regulate what muscle stem cells do.

Muscle stem cells can do two things, they either become adult muscle cells or self-renew to replenish the stem cell population. The paper discusses how the signaling pathway and specific protein are crucial for muscle stem cell differentiation and muscle growth, both of which are needed to prevent deterioration. Their aim is to use this knowledge to develop therapeutic targets that can aid with muscle growth.

Dr. Alessandra Sacco is quoted in an article as saying,

“Muscle stem cells can ‘burn out’ trying to regenerate tissue during the natural aging process or due to chronic muscle disease. We believe we have found promising drug targets that direct muscle stem cells to ‘make the right decision’ and stimulate muscle repair, potentially helping muscle tissue regeneration and maintaining tissue function in chronic conditions such as muscular dystrophy and aging.”

Stem Cell Roundup: Improving muscle function in muscular dystrophy; Building a better brain; Boosting efficiency in making iPSC’s

Here are the stem cell stories that caught our eye this week.

Photos of the week

TGIF! We’re so excited that the weekend is here that we are sharing not one but TWO amazing stem cell photos of the week.

RMI IntestinalChip

Image caption: Cells of a human intestinal lining, after being placed in an Intestine-Chip, form intestinal folds as they do in the human body. (Photo credit: Cedars-Sinai Board of Governors Regenerative Medicine Institute)

Photo #1 is borrowed from a blog we wrote earlier this week about a new stem cell-based path to personalized medicine. Scientists at Cedars-Sinai are collaborating with a company called Emulate to create intestines-on-a-chip using human stem cells. Their goal is to create 3D-organoids that represent the human gut, grow them on chips, and use these gut-chips to screen for precision medicines that could help patients with intestinal diseases. You can read more about this gut-tastic research here.

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Image caption: UCLA scientists used four different fluorescent-colored proteins to determine the origin of cardiomyocytes in mice. (Image credit: UCLA Broad Stem Cell Research Center/Nature Communications)

Photo #2 is another beautiful fluorescent image, this time of a cross-section of a mouse heart. CIRM-funded scientists from UCLA Broad Stem Cell Research Center are tracking the fate of stem cells in the developing mouse heart in hopes of finding new insights that could lead to stem cell-based therapies for heart attack victims. Their research was published this week in the journal Nature Communications and you can read more about it in a UCLA news release.

Stem cell injection improves muscle function in muscular dystrophy mice

Another study by CIRM-funded Cedars-Sinai scientists came out this week in Stem Cell Reports. They discovered that they could improve muscle function in mice with muscular dystrophy by injecting cardiac progenitor cells into their hearts. The injected cells not only improved heart function in these mice, but also improved muscle function throughout their bodies. The effects were due to the release of microscopic vesicles called exosomes by the injected cells. These cells are currently being used in a CIRM-funded clinical trial by Capricor therapeutics for patients with Duchenne muscular dystrophy.

How to build a better brain (blob)

For years stem cell researchers have been looking for ways to create “mini brains”, to better understand how our own brains work and develop new ways to repair damage. So far, the best they have done is to create blobs, clusters of cells that resemble some parts of the brain. But now researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have come up with a new method they think can advance the field.

Their approach is explained in a fascinating article in the journal Science News, where lead researcher Bennet Novitch says finding the right method is like being a chef:

“It’s like making a cake: You have many different ways in which you can do it. There are all sorts of little tricks that people have come up with to overcome some of the common challenges.”

Brain cake. Yum.

A more efficient way to make iPS cells

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Shinya Yamanaka. (Image source: Ko Sasaki, New York Times)

In 2006 Shinya Yamanaka discovered a way to take ordinary adult cells and reprogram them into embryonic-like stem cells that have the ability to turn into any other cell in the body. He called these cells induced pluripotent stem cells or iPSC’s. Since then researchers have been using these iPSC’s to try and develop new treatments for deadly diseases.

There’s been a big problem, however. Making these cells is really tricky and current methods are really inefficient. Out of a batch of, say, 1,000 cells sometimes only one or two are turned into iPSCs. Obviously, this slows down the pace of research.

Now researchers in Colorado have found a way they say dramatically improves on that. The team says it has to do with controlling the precise levels of reprogramming factors and microRNA and…. Well, you can read how they did it in a news release on Eurekalert.

 

 

 

Stem Cell Stories That Caught Our Eye: Free Patient Advocate Event in San Diego, and new clues on how to fix muscular dystrophy and Huntington’s disease

UCSD Patient Advocate mtg instagram

Stem cell research is advancing so fast that it’s sometimes hard to keep up. That’s one of the reasons we have our Friday roundup, to let you know about some fascinating research that came across our desk during the week that you might otherwise have missed.

Of course, another way to keep up with the latest in stem cell research is to join us for our free Patient Advocate Event at UC San Diego next Thursday, April 20th from 12-1pm.  We are going to talk about the progress being made in stem cell research, the problems we still face and need help in overcoming, and the prospects for the future.

We have four great speakers:

  • Catriona Jamieson, Director of the CIRM UC San Diego Alpha Stem Cell Clinic and an expert on cancers of the blood
  • Jonathan Thomas, PhD, JD, Chair of CIRM’s Board
  • Jennifer Briggs Braswell, Executive Director of the Sanford Stem Cell Clinical Center
  • David Higgins, Patient Advocate for Parkinson’s on the CIRM Board

We will give updates on the exciting work taking place at UCSD and the work that CIRM is funding. We have also set aside some time to get your thoughts on how we can improve the way we work and, of course, answer your questions.

What: Stem Cell Therapies and You: A Special Patient Advocate Event

When: Thursday, April 20th 12-1pm

Where: The Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037

Why: Because the people of California have a right to know how their money is helping change the face of regenerative medicine

Who: This event is FREE and open to everyone.

We have set up an EventBrite page for you to RSVP and let us know if you are coming. And, of course, feel free to share this with anyone you think might be interested.

This is the first of a series of similar Patient Advocate Update meetings we plan on holding around California this year. We’ll have news on other locations and dates shortly.

 

Fixing a mutation that causes muscular dystrophy (Karen Ring)

It’s easy to take things for granted. Take your muscles for instance. How often do you think about them? (Don’t answer this if you’re a body builder). Daily? Monthly? I honestly don’t think much about my muscles unless I’ve injured them or if they’re sore from working out.

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Heart muscle cells (green) that don’t have dystrophin protein (Photo; UT Southwestern)

But there are people in this world who think about their muscles or their lack of them every day. They are patients with a muscle wasting disease called Duchenne muscular dystrophy (DMD). It’s the most common type of muscular dystrophy, and it affects mainly young boys – causing their muscles to progressively weaken to the point where they cannot walk or breathe on their own.

DMD is caused by mutations in the dystrophin gene. These mutations prevent muscle cells from making dystrophin protein, which is essential for maintaining muscle structure. Scientists are using gene editing technologies to find and fix these mutations in hopes of curing patients of DMD.

Last year, we blogged about a few of these studies where different teams of scientists corrected dystrophin mutations using CRISPR/Cas9 gene editing technology in human cells and in mice with DMD. One of these teams has recently followed up with a new study that builds upon these earlier findings.

Scientists from UT Southwestern are using an alternative form of the CRISPR gene editing complex to fix dystrophin mutations in both human cells and mice. This alternative CRISPR complex makes use of a different cutting enzyme, Cpf1, in place of the more traditionally used Cas9 protein. It’s a smaller protein that the scientists say can get into muscle cells more easily. Cpf1 also differs from Cas9 in what DNA nucleotide sequences it recognizes and latches onto, making it a new tool in the gene editing toolbox for scientists targeting DMD mutations.

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Gene-edited heart muscle cells (green) that now express dystrophin protein (Photo: UT Southwestern)

Using CRISPR/Cpf1, the scientists corrected the most commonly found dystrophin mutation in human induced pluripotent stem cells derived from DMD patients. They matured these corrected stem cells into heart muscle cells in the lab and found that they expressed the dystrophin protein and functioned like normal heart cells in a dish. CRISPR/Cpf1 also corrected mutations in DMD mice, which rescued dystrophin expression in their muscle tissues and some of the muscle wasting symptoms caused by the disease.

Because the dystrophin gene is one of the longest genes in our genome, it has more locations where DMD-causing mutations could occur. The scientists behind this study believe that CRISPR/Cpf1 offers a more flexible tool for targeting different dystrophin mutations and could potentially be used to develop an effective gene therapy for DMD.

Senior author on the study, Dr. Eric Olson, provided this conclusion about their research in a news release by EurekAlert:

“CRISPR-Cpf1 gene-editing can be applied to a vast number of mutations in the dystrophin gene. Our goal is to permanently correct the underlying genetic causes of this terrible disease, and this research brings us closer to realizing that end.”

 

A cellular traffic jam is the culprit behind Huntington’s disease (Todd Dubnicoff)

Back in the 1983, the scientific community cheered the first ever mapping of a genetic disease to a specific area on a human chromosome which led to the isolation of the disease gene in 1993. That disease was Huntington’s, an inherited neurodegenerative disorder that typically strikes in a person’s thirties and leads to death about 10 to 15 years later. Because no effective therapy existed for the disease, this discovery of Huntingtin, as the gene was named, was seen as a critical step toward a better understand of Huntington’s and an eventual cure.

But flash forward to 2017 and researchers are still foggy on how mutations in the Huntingtin gene cause Huntington’s. New research, funded in part by CIRM, promises to clear some things up. The report, published this week in Neuron, establishes a connection between mutant Huntingtin and its impact on the transport of cell components between the nucleus and cytoplasm.

Roundup Picture1

The pores in the nuclear envelope allows proteins and molecules to pass between a cell’s nucleus and it’s cytoplasm. Image: Blausen.com staff (2014).

To function smoothly, a cell must be able to transport proteins and molecules in and out of the nucleus through holes called nuclear pores. The research team – a collaboration of scientists from Johns Hopkins University, the University of Florida and UC Irvine – found that in nerve cells, the mutant Huntingtin protein clumps up and plays havoc on the nuclear pore structure which leads to cell death. The study was performed in fly and mouse models of HD, in human HD brain samples as well as HD patient nerve cells derived with the induced pluripotent stem cell technique – all with this same finding.

Roundup Picture2

Huntington’s disease is caused by the loss of a nerve cells called medium spiny neurons. Image: Wikimedia commons

By artificially producing more of the proteins that make up the nuclear pores, the damaging effects caused by the mutant Huntingtin protein were reduced. Similar results were seen using drugs that help stabilize the nuclear pore structure. The implications of these results did not escape George Yohrling, a senior director at the Huntington’s Disease Society of America, who was not involved in the study. Yohrling told Baltimore Sun reporter Meredith Cohn:

“This is very exciting research because we didn’t know what mutant genes or proteins were doing in the body, and this points to new areas to target research. Scientists, biotech companies and pharmaceutical companies could capitalize on this and maybe develop therapies for this biological process”,

It’s important to temper that excitement with a reality check on how much work is still needed before the thought of clinical trials can begin. Researchers still don’t understand why the mutant protein only affects a specific type of nerve cells and it’s far from clear if these drugs would work or be safe to use in the context of the human brain.

Still, each new insight is one step in the march toward a cure.

Stem Cell Stories That Caught our Eye: Making blood and muscle from stem cells and helping students realize their “pluripotential”

Stem cells offer new drug for blood diseases. A new treatment for blood disorders might be in the works thanks to a stem cell-based study out of Harvard Medical School and Boston Children’s hospital. Their study was published in the journal Science Translational Medicine.

The teams made induced pluripotent stem cells (iPSCs) from the skin of patients with a rare blood disorder called Diamond-Blackfan anemia (DBA) – a bone marrow disease that prevents new blood cells from forming. iPSCs from DBA patients were then specialized into blood progenitor cells, the precursors to blood cells. However, these precursor cells were incapable of forming red blood cells in a dish like normal precursors do.

Red blood cells were successfully made via induced pluripotent stem cells from a Diamond-Blackfan anemia patient. Image: Daley lab, Boston Children’s

Red blood cells were successfully made via induced pluripotent stem cells from a Diamond-Blackfan anemia patient. Image: Daley lab, Boston Children’s

The blood progenitor cells from DBA patients were then used to screen a library of compounds to identify drugs that could get the DBA progenitor cells to develop into red blood cells. They found a compound called SMER28 that had this very effect on progenitor cells in a dish. When the compound was tested in zebrafish and mouse models of DBA, the researchers observed an increase in red blood cell production and a reduction of anemia symptoms.

Getting pluripotent stem cells like iPSCs to turn into blood progenitor cells and expand these cells into a population large enough for drug screening has not been an easy task for stem cell researchers.

Co-first author on the study, Sergei Doulatov, explained in a press release, “iPS cells have been hard to instruct when it comes to making blood. This is the first time iPS cells have been used to identify a drug to treat a blood disorder.”

In the future, the researchers will pursue the questions of why and how SMER28 boosts red blood cell generation. Further work will be done to determine whether this drug will be a useful treatment for DBA patients and other blood disorders.

 

Students realize their “pluripotential”. In last week’s stem cell stories, I gave a preview about an exciting stem cell “Day of Discovery” hosted by USC Stem Cell in southern California. The event happened this past Saturday. Over 500 local middle and high school students attended the event and participated in lab tours, poster sessions, and a career resource fair. Throughout the day, they were engaged by scientists and educators about stem cell science through interactive games, including the stem cell edition of Family Feud and a stem cell smartphone videogame developed by USC graduate students.

In a USC press release, Rohit Varma, dean of the Keck School of Medicine of USC, emphasized the importance of exposing young students to research and scientific careers.

“It was a true joy to welcome the middle and high school students from our neighboring communities in Boyle Heights, El Sereno, Lincoln Heights, the San Gabriel Valley and throughout Los Angeles. This bright young generation brings tremendous potential to their future pursuits in biotechnology and beyond.”

Maria Elena Kennedy, a consultant to the Bassett Unified School District, added, “The exposure to the Keck School of Medicine of USC is invaluable for the students. Our students come from a Title I School District, and they don’t often have the opportunity to come to a campus like the Keck School of Medicine.”

The day was a huge success with students posting photos of their experiences on social media and enthusiastically writing messages like “stem cells are our future” and “USC is my goal”. One high school student acknowledged the opportunity that this day offers to students, “California currently has biotechnology as the biggest growing sector. Right now, it’s really important that students are visiting labs and learning more about the industry, so they can potentially see where they’re going with their lives and careers.”

You can read more about USC’s Stem Cell Day of Discovery here. Below are a few pictures from the event courtesy of David Sprague and USC.

Students have fun with robots representing osteoblast and osteoclast cells at the Stem Cell Day of Discovery event held at the USC Health Sciences Campus in Los Angeles, CA. February 4th, 2017. The event encourages students to learn more about STEM opportunities, including stem cell study and biotech, and helps demystify the fields and encourage student engagement. Photo by David Sprague

Students have fun with robots representing osteoblast and osteoclast cells at the USC Stem Cell Day of Discovery. Photo by David Sprague

Dr. Francesca Mariana shows off a mouse skeleton that has been dyed to show bones and cartilage at the Stem Cell Day of Discovery event held at the USC Health Sciences Campus in Los Angeles, CA. February 4th, 2017. The event encourages students to learn more about STEM opportunities, including stem cell study and biotech, and helps demystify the fields and encourage student engagement. Photo by David Sprague

Dr. Francesca Mariana shows off a mouse skeleton that has been dyed to show bones and cartilage. Photo by David Sprague

USC masters student Shantae Thornton shows students how cells are held in long term cold storage tanks at -195 celsius at the Stem Cell Day of Discovery event held at the USC Health Sciences Campus in Los Angeles, CA. February 4th, 2017. The event encourages students to learn more about STEM opportunities, including stem cell study and biotech, and helps demystify the fields and encourage student engagement. Photo by David Sprague

USC masters student Shantae Thornton shows students how cells are held in long term cold storage tanks at -195 celsius. Photo by David Sprague

Genesis Archila, left, and Jasmine Archila get their picture taken at the Stem Cell Day of Discovery event held at the USC Health Sciences Campus in Los Angeles, CA. February 4th, 2017. The event encourages students to learn more about STEM opportunities, including stem cell study and biotech, and helps demystify the fields and encourage student engagement. Photo by David Sprague

Genesis Archila, left, and Jasmine Archila get their picture taken at the USC Stem Cell Day of Discovery. Photo by David Sprague

New stem cell recipes for making muscle: new inroads to study muscular dystrophy (Todd Dubnicoff)

Embryonic stem cells are amazing because scientists can change or specialize them into virtually any cell type. But it’s a lot easier said than done. Researchers essentially need to mimic the process of embryo development in a petri dish by adding the right combination of factors to the stem cells in just the right order at just the right time to obtain a desired type of cell.

Making human muscle tissue from embryonic stem cells has proven to be a challenge. The development of muscle, as well as cartilage and bone, are well characterized and known to form from an embryonic structure called a somite. Researches have even been successful working out the conditions for making somites from animal stem cells. But those recipes didn’t work well with human stem cells.

Now, a team of researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA has overcome this roadblock by carrying out a systematic approach using human tissue. As described in Cell Reports, the scientists isolated somites from early human embryos and studied their gene activity. By comparing somites that were just beginning to emerge with fully formed somites, the researchers pinpointed differences in gene activity patterns. With this data in hand, the team added factors to the cells that were known to affect the activity of those genes. Through some trial and error, they produced a recipe – different than those used in animal cells – that could convert 90 percent of the human stem cells into somites in only four days. Those somites could then readily transform into muscle or bone or cartilage.

This new method for making human muscle will be critical for the lab’s goal to develop therapies for Duchenne muscular dystrophy, an incurable muscle wasting disease that strikes young boys and is usually fatal by their 20’s.

The new protocol turned 90 percent of human pluripotent stem cells into somite cells in just four days; those somite cells then generated (left to right) cartilage, bone and muscle cells.  Image: April Pyle Lab/UCLA

The new protocol turned 90 percent of human pluripotent stem cells into somite cells in just four days; those somite cells then generated (left to right) cartilage, bone and muscle cells. Image: April Pyle Lab/UCLA

Scientists find new stem cell target for regenerating aging muscles

Young Arnold (wiki)

Young Arnold (wiki)

Today I’m going to use our former governor Arnold Schwarzenegger as an example of what happens to our muscles when we age.

One of Arnold’s many talents when he was younger was being a professional bodybuilder. As you can see in this photo, Arnold worked hard to generate an impressive amount of muscle that landed him lead roles in movies Conan the Barbarian and The Terminator.

Older Arnold

Older Arnold

If you look at pictures of Arnold now (who is now 68), while still being an impressively large human being, it’s obvious that much of his muscular bulk has diminished. That’s because as humans age, so do their muscles.

Muscles shrink with age

As muscles age, they slowly lose mass and shrink (a condition called sarcopenia) because of a number of reasons – one of them being their inability to regenerate new muscle tissue efficiently. The adult stem cells responsible for muscle regeneration are called satellite cells. When muscles are injured, satellite cells are activated to divide and generate new muscle fibers that can repair injury and also improve muscle function.

However, satellite cells become less efficient at doing their job over time because of environmental and internal reasons, and scientists are looking for new targets that can restore and promote the regenerative abilities of muscle stem cells for human therapeutic applications.

A study published earlier this week in Nature Medicine, identified a potential new target that could boost muscle stem cell regeneration and improved muscle function in a mouse model of Duchenne muscular dystrophy.

β1-integrin is important for muscle regeneration

Scientists from the Carnegie Institute of Washington found that β1-integrin is important for maintaining the homeostasis (or balance) of the muscle stem cell environment. If β1-integrin is doing its job properly, muscle stem cells are able to go about their regular routine of being dormant, activating in response to injury, dividing to create new muscle tissue, and then going back to sleep.

When the scientists studied the function of β1-integrin in the muscles of aged mice, they found that the integrin wasn’t functioning properly. Without β1-integrin, mouse satellite cells spontaneously turned into muscle tissue and were unable to maintain their regenerative capacity following muscle injury.

Upon further inspection, they found that β1-integrin interacts with a growth factor called fibroblast growth factor 2 (Fgf2) and this relationship was essential for promoting muscle regeneration following injury. When β1-integrin function deteriorates as in the muscles of aged mice, the mice lose sensitivity to the regenerative capacity of Fgf2.

Restoring muscle function in mice with muscular dystrophy

By using an antibody to artificially activate β1-integrin function in the muscles of aged mice, they were able to restore Fgf2 responsiveness and boosted muscle regeneration after injury. When a similar technique was used in mice with Duchenne muscular dystrophy, they observed muscle regeneration and improved muscle function.

Muscle loss seen in muscular dystrophy mice (left). Treatment with beta1 intern boosts muscle regeneration in the same mice (right). (Nature Medicine)

Muscle loss seen in muscular dystrophy mice (left). Treatment with B1-integrin boosts muscle regeneration in the same mice (right). (Nature Medicine)

The authors believe that β1-integrin acts as a sensor of the muscle stem cell environment that it maintains a balance between a dormant and a regenerative stem cell state. They conclude in their publication:

“β1-integrin senses the SC [satellite cell] niche to maintain responsiveness to Fgf2, and this integrin represents a potential therapeutic target for pathological conditions of the muscle in which the stem cell niche is compromised.”

Co-author on the study Dr. Chen-Ming Fan also spoke to the clinical relevance of their findings in a piece by GenBio:

“Inefficient muscular healing in the elderly is a significant clinical problem and therapeutic approaches are much needed, especially given the aging population. Finding a way to target muscle stem cells could greatly improve muscle renewal in older individuals.”

Does this mean anyone can be a body builder?

So does this study mean that one day we can prevent muscle loss in the elderly and all be body builders like Arnold? I highly doubt that. It’s important to remember these are preclinical studies done in mouse models and much work needs to be done to test whether β1-integrin is an appropriate therapeutic target in humans.

However, I do think this study sheds new light on the inner workings of the muscle stem cell environment. Finding out more clues about how to promote the health and regenerative function of this environment will bring the field closer to generating new treatments for patients suffering from muscle wasting diseases like muscular dystrophy.

Rare Disease Day, a chance to raise awareness and hope.

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Battling a deadly disease like cancer or Alzheimer’s is difficult; but battling a rare and deadly disease is doubly so. At least with common diseases there is a lot of research seeking to develop new treatments. With rare diseases there is often very little research, and so there are fewer options for treatment. Even just getting a diagnosis can be hard because most doctors may never have heard about, let alone seen, a case of a disease that only affects a few thousand individuals.

That’s why the last day of February, every year, has been designated Rare Disease Day.  It’s a time to raise awareness amongst the public, researchers, health  professionals and policy makers about the impact these diseases have on the lives of those affected by them. This means not just the individual with the problem, but their family and friends too.

There are nearly 7,000 diseases in the U.S. that are considered rare, meaning they affect fewer than 200,000 people at any given time.

No numbers no money

The reason why so many of these diseases have so few treatment options is obvious. With diseases that affect large numbers of people a new treatment or cure stands to make the company behind it a lot of money. With diseases that affect very small numbers of people the chances of seeing any return on investment are equally small.

Fortunately at CIRM we don’t have to worry about making a profit, all we are concerned with is accelerating stem cell treatments to patients with unmet medical needs. And in the case of people with rare diseases, those needs are almost invariably unmet.

That’s why over the years we have invested heavily in diseases that are often overlooked because they affect relatively small numbers of people. In fact right now we are funding clinical trials in several of these including sickle cell anemia, retinitis pigmentosa and chronic granulomatous disease. We are also funding work in conditions like Huntington’s disease, ALS or Lou Gehrig’s disease, and SCID or “bubble baby” disease.

Focus on the people

As in everything we do our involvement is not just about funding research – important as that is – it’s also about engaging with the people most affected by these diseases, the patient advocate community. Patient advocates help us in several ways:

  • Collaborating with us and other key stakeholders to try and change the way the Food and Drug Administration (FDA) works. Our goal is to create an easier and faster, but no less safe, method of approving the most promising stem cell therapies for clinical trial. With so few available treatments for rare diseases having a smoother route to a clinical trial will benefit these communities.
  • Spreading the word to researchers and companies about CIRM 2.0, our new, faster and more streamlined funding opportunities to help us move the most promising therapies along as fast as possible. The good news is that this means anyone, anywhere can apply for funding. We don’t care how many people are affected by a disease, we only care about the quality of the proposed research project that could help them.
  • Recruiting Patient Advocates to our Clinical Advisory Panels (CAPs), teams that we assign to each project in a clinical trial to help guide and inform the researchers at every stage of their work. This not only gives each project the best possible chance of succeeding but it also helps the team stay focused on the mission, of saving, and changing, people’s lives.
  • Helping us recruit patients for clinical trials. The inability to recruit and retain enough patients to meet a project’s enrollment requirements is one of the biggest reasons many clinical trials fail. This is particularly problematic for rare diseases. By using Patient Advocates to increase our ability to enroll and retain patients we will increase the likelihood a clinical trial is able to succeed.

Organizing to fight back

There are some great organizations supporting and advocating on behalf of families affected by rare diseases, such as the EveryLife Foundation  and the National Organization for Rare Diseases (NORD).  They are working hard to raise awareness about these diseases, to get funding to do research, and to clear away some of the regulatory hurdles researchers face in being able to move the most promising therapies out of the lab and into clinical trials where they can be tested on people.

For the individuals and families affected by conditions like beta thalassemia and muscular dystrophy – potentially fatal genetic disorders – every day is Rare Disease Day. They live with the reality of these problems every single day. That’s why we are committed to working hard every single day, to find a treatment that can help them and their loved ones.

CIRM-Funded Scientists Test Recipe for Building New Muscles

When muscles get damaged due to disease or injury, the body activates its reserves—muscle stem cells that head to the injury site and mature into fully functioning muscle cells. But when the reserves are all used up, things get tricky.

Scientists at Sanford-Burnham may have uncovered the key to muscle repair.

Scientists at Sanford-Burnham may have uncovered the key to muscle repair.

This is especially the case for people living with muscle diseases, such as muscular dystrophy, in which the muscle degrades at a far faster rate than average and the body’s reserve stem cell supply becomes exhausted. With no more supply from which to draw new muscle cells, the muscles degrade further, resulting in the disease’s debilitating symptoms, such as progressive difficulty walking, running or speaking.

So, scientists have long tried to find a way to replenish the dwindling supply of muscle stem cells (called ‘satellite cells’), thus slowing—or even halting—muscle decay.

And now, researchers at the Sanford-Burnham Medical Research Institute have found a way to tweak the normal cycle, and boost the production of muscle cells even when supplies appear to be diminished. These findings, reported in the latest issue of Nature Medicine, offer an alternative treatment for the millions of people suffering not only from muscular dystrophy, but also other diseases that result in muscle decay—such as some forms of cancer and age-related diseases.

In this study, Sanford-Burnham researchers found that introducing a particular protein, called a STAT3 inhibitor, into the cycle of muscle-cell regeneration could boost the production of muscle cells—even after multiple rounds of repair that would otherwise render regeneration virtually impossible.

The STAT3 inhibitor, as its name suggests, works by ‘inhibiting,’ or effectively neutralizing, another protein called STAT3. Normally, STAT3 gets switched on in response to muscle injury, setting in motion a series of steps that replenishes muscle cells.

In experiments first in animal models of muscular dystrophy—and next in human cells in a petri dish—the team decided to modify how STAT3 functions. Instead of keeping STAT3 active, as would normally occur, the team introduced the STAT3 inhibitor at specific times during the muscle regeneration process. And in so doing, noticed a significant boost in muscle cell production. As Dr. Alessandra Sacco, the study’s senior author, stated in a news release:

“We’ve discovered that by timing the inhibition of STAT3—like an ‘on/off’ light switch—we can transiently expand the satellite cell population followed by their differentiation into mature cells.”

This approach to spurring muscle regeneration, which was funded in part by a CIRM training grant, is not only innovative, but offers new hope to a disease for which treatments have offered little. As Dr. Vittorio Sartorelli, deputy scientific director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), stated:

“Currently, there is no cure to stop or reverse any form of muscle-wasting disorders—only medication and therapy that can slow the process. A treatment approach consisting of cyclic bursts of STAT3 inhibitors could potentially restore muscle mass and function in patients, and this would be a very significant breakthrough.”

Sacco and her colleagues are encouraged by these results, and plan to explore their findings in greater detail—hopefully moving towards clinical trials:

“Our next step is to see how long we can extend the cycling pattern, and test some of the STAT3 inhibitors currently in clinical trials for other indications such as cancer, as this could accelerate testing in humans.”