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.

duchennes-cardiomyocytes-body

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.

gene-edited-cardiomyocytes-body.jpg

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

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.

Raising awareness about Rare Disease Day

rare-disease-day-logo

One of the goals we set ourselves at CIRM in our 2016 Strategic Plan was to fund 50 new clinical trials over the next five years, including ten rare or orphan diseases. Since then we have funded 13 new clinical trials including four targeting rare diseases (retinitis pigmentosa, severe combined immunodeficiency, ALS or Lou Gehrig’s disease, and Duchenne’s Muscular Dystrophy). It’s a good start but clearly, with almost 7,000 rare diseases, this is just the tip of the iceberg. There is still so much work to do.

And all around the world people are doing that work. Today we have asked Emily Walsh, the Community Outreach Director at the Mesothelioma Cancer Alliance,  to write about the efforts underway to raise awareness about rare diseases, and to raise funds for research to develop new treatments for them.

“February 28th marks the annual worldwide event for Rare Disease Day. This is a day dedicated to raising awareness for rare diseases that affect people all over the world. The campaign works to target the general public as well as policy makers in hopes of bringing attention to diseases that receive little attention and funding. For the year 2017 it was decided that the focus would fall on “research,” with the slogan, “With research, possibilities are limitless.”

Getting involved for Rare Disease Day means taking this message and spreading it far and wide. Awareness for rare diseases is extremely important, especially among researchers, universities, students, companies, policy makers, and clinicians. It has long been known that the best advocates for rare diseases are the patients themselves. They use their specific perspectives to raise their voice, share their story, and shed light on the areas where additional funding and research are most necessary.

To see how you can help support the Rare Disease Day efforts this year, click here.

Groups like the Mesothelioma Cancer Alliance and the Mesothelioma Group are adding their voices to the cause to raise awareness about mesothelioma cancer, a rare form of cancer caused by exposure and inhalation of airborne asbestos fibers

Rare diseases affect 300 million people worldwide, but only 5% of them have an FDA approved treatment or cure. Malignant mesothelioma is among the 95 percent that doesn’t have a treatment or cure.

Asbestos has been used throughout history in building materials because of its fire retardant properties. Having a home with asbestos insulation, ceiling tiles, and roof shingles meant that the house was safer. However, it was found that once asbestos crumbled and became powder-like, the tiny fibers could become airborne and be inhaled and lodge themselves in lung tissue causing mesothelioma. The late stage discovery of mesothelioma is often what causes it to have such a high mortality rate. Symptoms can have a very sudden onset, even though the person may have been exposed decades prior.

Right now, treatment for mesothelioma includes the usual combination of chemotherapy, radiation, and surgery, but researchers are looking at other approaches to see if they can be more effective or can help in conjunction with the standard methods. For example one drug, Defactinib, has shown some promise in inhibiting the growth and spread of cancer stem cells – these are stem cells that can evade chemotherapy and cause patients to relapse.”

Some people might ask why spend limited resources on something that affects so few people. But the lessons we learn in developing treatments for a rare disease can often lead us to treatments for diseases that affect many millions of people.

But numbers aside, there is no hierarchy of need, no scale to say the suffering of people with Huntington’s disease is any greater or less than that of people with Alzheimer’s. We are not in the business of making value judgements about who has the greatest need. We are in the business of accelerating treatments to patients with unmet medical needs. And those suffering from rare disease are very clearly  people in need.

 


Related Links:

Stem Cells Profile in Courage: Pat Furlong, Patient Advocate

pat-furlong

Pat Furlong: Photo by Colin McGuire – http://www.colinmcguire.com

One of the true joys for me in helping put together this year’s Annual Report was getting to know the patients and patient advocates that we profiled in the report. These are some extraordinary individuals and the short profiles we posted only touch the surface of just how extraordinary.

So, over the next few weeks we are going to feature four of these people at greater length, allowing them, in their own words, to talk about what makes them tic, and how they keep going in the face of what is often heartbreak and tragedy.

We begin with Pat Furlong, a Patient Advocate and the Founding President and CEO of Parent Project Muscular Dystrophy (PPMD), the largest nonprofit organization in the United States solely focused on Duchenne muscular dystrophy (DMD).

DMD is the most common fatal, genetic childhood disorder, which affects approximately 1 out of every 3,500 boys each year worldwide. It’s a progressive muscle disorder that leads to loss of muscle function, meaning you lose your ability to walk, to use your arms, and ultimately to breathe. And because the heart is a muscle, that is often seriously affected. There is no cure, and treatment options are limited. At the time her sons were diagnosed life expectancy was in the teens.

Pat’s story:

“When my sons, Chris and Pat were diagnosed with DMD, at the ages of 4 and 6, there was nothing available for them. Doctors cared about them but they didn’t have the tools they needed, or the National Institutes of Health the money it needed to do research.

Doctors were faced with diagnosing a disease and saying “there’s nothing we can do”. And then parents like me, coming to them hearing there was nothing they could do, no hope, no help. When your son is diagnosed with something like this you are told go home and love them.

When I asked questions, I was often ignored or dismissed by some doctors.

When my sons were diagnosed with DMD I would drop them off at school and go walking and that would help me deal with the anger.

For me staying in this is to be able to say to Chris and Pat in the universe, when you were here I tried my very best and when you were gone I continued to try my best so that others would have advantages that you didn’t receive.

I haven’t stood back and said I can’t go on.

The family is all scarred, we all suffered this loss. It’s much more apparent when we are together, there are empty chairs, emptiness. If we go to a family gathering we wish Chris and Pat were here, could be married. Now there’s my husband and our two daughters. We have a granddaughter, who is wonderful, but still we are incomplete and we will live with that forever.

I am trained as a nurse and I find DMD equal parts fascinating disease, heartbreaking and painful. I try to emphasize the fascinating so I can keep going. There are frustrations; lack of money, the slow process of regulatory approval, but I have an incredible team of very smart people and we are passionate about change so that helps keep us going.

Your only interest can’t be DMD, it can’t be. For me it’s certainly a priority, but it’s not my only interest. I love to go to an art museum and see how creative people work. I love Cirque du Soleil because they do things with their muscles I can’t imagine. Going outside and seeing these things makes the world better.

I am interested in the expression of art, to see how people dress, to see how people are creative, I love creativity, I think the human spirit is pretty amazing and the creativity around it. I think we are all pretty amazing but sometimes we don’t say it enough.

I recently saw a woman on the subway with a pair of tennis shoes that said “you are beautiful” and people around her were looking at her shoes and smiling, just because of those shoes. We forget to interact, and that was such a simple way of doing that.

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I relax by doing yoga, 90-minute hot yoga, as often as I can. I’ve also done a number of half marathons, but I’m more a walker than a runner. I find getting outside or hot yoga makes me concentrate on what I’m doing so that I can’t think of anything else. I can put it down and think about nothing and whisper prayers to my sons and say am I doing the right thing, is there something I should be doing differently? It’s my time to think about them and meditate about what they think would be important.

You need to give your mind time to cope, so it’s putting your phone down and your computer away. It’s getting rid of those interruptions. To put the phone, the computer down and get in a hot room and do yoga, or run around outside, to look at a tree and think about the changing season, the universe, the sun. It’s an incredible break for the brain to be able to rest.

I think the disease has made us kinder people and more thoughtful. When Chris died, we found a notebook he kept. In it was written “the meaning of life is a life of meaning”. I think that’s where we have all landed, what we all strive for, a life of meaning.

 

 

 

HOPE for patients with Duchenne Muscular Dystrophy-associated heart disease

It’s an exciting week for CIRM-funded clinical trials. Yesterday, we blogged about a young man named Kris Boesen who is responding positively to a stem cell therapy in a Phase 1/2a CIRM-funded clinical trial for spinal cord injury run by Asterias Biotherapeutics. Paralyzed from the chest down after a terrible car accident, Kris now has regained some use of his arms and hands following the stem cell transplant.

screen-shot-2016-09-08-at-9-18-46-amYesterday, Capricor Therapeutics also announced news about the progress of its CIRM-funded clinical trial that’s testing the safety and efficacy of a cardiac cell therapy called CAP-1002 for Duchenne Muscular Dystrophy-associated cardiomyopathy. Capricor has completed their Phase 1/2 trial enrollment of 25 patients. These patients are young boys (12 years of age or above) suffering from a build-up of scar tissue in their hearts due to DMD-associated cardiomyopathy. Reaching full enrollment is a key milestone for any clinical trial.

Duchenne Muscular Dystrophy (DMD) is an inherited disease that attacks muscle, causing muscle tissue to become weak and degenerate. The disease mainly appears in young boys between the ages of two and three. Patients with DMD often suffer from cardiomyopathy or weakened heart muscle caused by the thickening and hardening of the heart muscle and accumulation of scar tissue. DMD-associated cardiomyopathy is one of the leading causes of patient deaths.

President and CEO of Capricor, Dr. Linda Marban, believes there’s a potential for their CAP-1002 stem cell therapy to help DMD patients suffering from cardiomyopathy. She explained in a press release:

“In DMD, scar tissue progressively aggregates in the heart, leading to a deterioration of cardiac function for which treatment options are limited. We believe CAP-1002 is the only therapeutic candidate in development for the treatment of DMD that has been clinically shown to reduce scar tissue in the damaged heart.”

The Capricor trial was approved by the CIRM Board in March 2016 and since then Capricor has worked quickly to enroll patients in its HOPE-Duchenne trial (HOPE stands for Halt cardiomyopathy progression in Duchenne).

Dr. Marban commented on the trials recent progress:

Linda Marban, CEO of Capricor Therapeutics

Linda Marban, CEO of Capricor Therapeutics

“The rate of patient enrollment into HOPE-Duchenne far surpassed our expectations, signifying the need for therapeutic options as well as the desire of the DMD community to address the heart disease that is highly prevalent in this population. We look forward to announcing top-line six-month results from HOPE-Duchenne in the first quarter of next year, in which we will report on the safety as well as the potential efficacy of CAP-1002.”

Half of the enrolled patients will receive an infusion of the CAP-1002 cardiac cell therapy while the other half will receive regular care without the infusion. Capricor will monitor all these patients to make sure that the cell therapy is well tolerated and doesn’t cause any harm. It will also look for any positive signs that the therapy is benefiting patients using a series of tests that measure changes in scar tissue and heart function.

HOPE is high for this trial to succeed as there is currently no treatment that can successfully reduce the amount of cardiac scar tissue in patients suffering from DMD-associated cardiomyopathy. The Capricor trial is in its early stages, but check in with the Stem Cellar for an update on the safety and efficacy data from this trial in early 2017.


Related links:

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 underdogs come out on top at CIRM Board meeting

 

It seems like an oxymoron but one in ten Americans has a rare disease. With more than 7,000 known rare diseases it’s easy to see how each one could affect thousands of individuals and still be considered a rare or orphan condition.

Only 5% of rare diseases have FDA approved therapies

rare disease

(Source: Sermo)

People with rare diseases, and their families, consider themselves the underdogs of the medical world because they often have difficulty getting a proper diagnosis (most physicians have never come across many of these diseases and so don’t know how to identify them), and even when they do get a diagnosis they have limited treatment options, and those options they do have are often very expensive.  It’s no wonder these patients and their families feel isolated and alone.

Rare diseases affect more people than HIV and Cancer combined

Hopefully some will feel less isolated after yesterday’s CIRM Board meeting when several rare diseases were among the big winners, getting funding to tackle conditions such as ALS or Lou Gehrig’s disease, Severe Combined Immunodeficiency or SCID, Canavan disease, Tay-Sachs and Sandhoff disease. These all won awards under our Translation Research Program except for the SCID program which is a pre-clinical stage project.

As CIRM Board Chair Jonathan Thomas said in our news release, these awards have one purpose:

“The goal of our Translation program is to support the most promising stem cell-based projects and to help them accelerate that research out of the lab and into the real world, such as a clinical trial where they can be tested in people. The projects that our Board approved today are a great example of work that takes innovative approaches to developing new therapies for a wide variety of diseases.”

These awards are all for early-stage research projects, ones we hope will be successful and eventually move into clinical trials. One project approved yesterday is already in a clinical trial. Capricor Therapeutics was awarded $3.4 million to complete a combined Phase 1/2 clinical trial treating heart failure associated with Duchenne muscular dystrophy with its cardiosphere stem cell technology.  This same Capricor technology is being used in an ongoing CIRM-funded trial which aims to heal the scarring that occurs after a heart attack.

Duchenne muscular dystrophy (DMD) is a genetic disorder that is marked by progressive muscle degeneration and weakness. The symptoms usually start in early childhood, between ages 3 and 5, and the vast majority of cases are in boys. As the disease progresses it leads to heart failure, which typically leads to death before age 40.

The Capricor clinical trial hopes to treat that aspect of DMD, one that currently has no effective treatment.

As our President and CEO Randy Mills said in our news release:

Randy Mills, Stem Cell Agency President & CEO

Randy Mills, Stem Cell Agency President & CEO

“There can be nothing worse than for a parent to watch their child slowly lose a fight against a deadly disease. Many of the programs we are funding today are focused on helping find treatments for diseases that affect children, often in infancy. Because many of these diseases are rare there are limited treatment options for them, which makes it all the more important for CIRM to focus on targeting these unmet medical needs.”

Speaking on Rare Disease Day (you can read our blog about that here) Massachusetts Senator Karen Spilka said that “Rare diseases impact over 30 Million patients and caregivers in the United States alone.”

Hopefully the steps that the CIRM Board took yesterday will ultimately help ease the struggles of some of those families.

Family ties help drive UCLA’s search for a stem cell treatment for Duchenne muscular dystrophy

Duchenne

April Pyle, Courtney Young and Melissa Spencer: Photo courtesy UCLA Broad Stem Cell Research Center

People get into science for all sorts of different reasons. For Courtney Young the reason was easy; she has a cousin with Duchenne muscular dystrophy.

Now her work as part of a team at UCLA has led to a new approach that could eventually help many of those suffering from Duchenne, the most common fatal childhood genetic disease.

The disease, which usually affects boys, leads to progressive muscle weakness, which means children may lose their ability to walk by age 12 and eventually results in breathing difficulties and heart disease.

Duchenne is caused by a defective gene, which leads to very low levels of a protein called dystrophin – an important element in building strong, healthy muscles. There are many sections of the gene where this defect or mutation can be found, but in 60 percent of cases it occurs within one particular hot spot of DNA. That’s the area that the UCLA team focused on, helped in part by a grant from CIRM.

Skin in the game

First they obtained skin cells from people with Duchenne muscular dystrophy and turned those into iPS cells. Those cells have the ability to become any other cell in the body and, just as importantly for this research, still retain the genetic code from the person they came from. In this case it meant they still had the genetic defect that led to Duchenne muscular dystrophy.

Then the researchers used a gene editing tool called CRISPR (we’ve written about this a lot in the past, you can a couple of those articles  here and here  and here)  to remove the genetic mutations that cause Duchenne. They then turned those iPS cells into skeletal muscle cells and transplanted them into mice that had the genetic mutation that meant they couldn’t produce dystrophin.

To their delight they found that the transplanted cells produced dystrophin in the mice.

Breaking new ground

April Pyle, a co-senior author of the study, which appears in the journal Cell Stem Cell,  said, in a news release, this was the first study to use human iPS cells to correct the problem in muscle tissue caused by Duchenne:

“This work demonstrates the feasibility of using a single gene editing platform, plus the regenerative power of stem cells to correct genetic mutations and restore dystrophin production for 60 percent of Duchenne patients.”

The researchers say this is an important step towards developing a new treatment for Duchenne muscular dystrophy, but caution there are still many years of work before this approach will be ready to test in people.

For Courtney Young advancing the science is not just professionally gratifying, it’s also personally satisfying:

“I already knew I was interested in science, so after my cousin’s diagnosis, I decided to dedicate my career to finding a cure for Duchenne. It makes everything a lot more meaningful, knowing that I’m doing something to help all the boys who will come after my cousin. I feel like I’m contributing and I’m excited because the field of Duchenne research is advancing in a really positive direction.”

 

 

While You Were Away: Gene Editing Treats Mice with Duchenne Muscular Dystrophy

Welcome back everyone! I hope you enjoyed your holiday and are looking forward to an exciting new year. My favorite thing about coming back from vacation is to see what cool new science was published. Because as you know, science doesn’t take a vacation!

As I was reading over the news for this past week, one particular story stood out. On New Year’s Eve, Science magazine published three articles (here, here, here) simultaneously that successfully used CRISPR/Cas9 gene editing to treat mice that have Duchenne muscular dystrophy (DMD).

DMD is a rare, genetic disease that affects approximately 1 in 3,600 boys in the US. It’s caused by a mutation in the dystrophin gene, which generates a protein that is essential for normal muscle function. DMD causes the body’s muscles to weaken and degenerate, leaving patients deformed and unable to move. It’s a progressive disease, and the average life expectancy is around 25 years. Though there are treatments that help prolong or control the onset of symptoms, there is no cure for DMD.

Three studies use CRISPR to treat DMD in mice

For those suffering from this debilitating disease, there is hope for a new therapy – a gene therapy that is. Three groups from UT Southwestern, Harvard, and Duke, used the CRISPR gene editing method to remove and correct the mutation in the dystrophin gene in mice with DMD. All three used a safe viral delivery method to transport the CRISPR/Cas9 gene editing complex to the proper location on the dystrophin gene in the mouse genome. There, the complex was able to cut out the mutated section of DNA and paste together a version of the gene that could produce a functional dystrophin protein.

Dystrophin protein (green) in healthy heart muscle (left), absent in DMD mice (center), and partially restored in DMD mice treated with CRISPR/Cas9 (right). (Nelson et al., 2015)

Dystrophin protein (green) in healthy heart muscle (left), absent in DMD mice (center), and partially restored in DMD mice treated with CRISPR/Cas9 (right). (Nelson et al., 2015)

This technique was tested in newly born mice as well as in adult mice by injecting the virus into the mouse circulatory system (so that the gene editing could happen everywhere) or into specific areas like the leg muscle to target muscle cells and stem cells. After the gene editing treatment, all three studies found restored expression of the dystrophin protein in heart and skeletal muscle tissue, which are the main tissues affected in DMD. They were also able to measure improved muscle function and strength in the animals.

This is really exciting news for the DMD field, which has been waiting patiently for an approved therapy. Currently, two clinical trials are underway by BioMarin and Sarepta Therapeutics, but the future of these drugs is uncertain. A gene therapy that could offer a “one-time cure” would certainly be a more attractive option for these patients.

Charles Gersbach, Duke University

Charles Gersbach, Duke University

It’s important to note that none of these gene editing studies reported a complete cure. However, the results are still very promising. Charles Gersbach, senior author on the Duke study, commented, “There’s a ton of room for optimization of these approaches.”

Strong media coverage of DMD studies

The implications of these studies are potentially huge and suitably, these studies were covered by prominent news outlets like Science News, STAT News, The Scientist, and The New York Times.

What I like about the news coverage on the DMD studies is that the results and implications aren’t over hyped. All of the articles mention the promise of this research, but also mention that more work needs to be done in mice and larger animals before gene therapy can be applied to human DMD patients. The words “safe” or “safety” was used in each article, which signals to me that both the science and media worlds understand the importance of testing promising therapies rigorously before attempting in humans on a larger scale.

However, it does seem that CRISPR gene editing for DMD could reach clinical trials in the next few years. Charles Gersbach told STATnews that he could see human clinical trials using this technology in a few years after scientists properly test its safety. He also mentioned that they first will need to understand “how the human immune system will react to delivery of  the CRISPR complex within the body.” He went on, “The hope for gene editing is that if we do this right, we will only need to do one treatment. This method, if proven safe, could be applied to patients in the foreseeable future.”

Eric Olson, UT Southwestern

Eric Olson, UT Southwestern

Eric Olson, senior author on the UT Southwestern study, had a similar opinion, “To launch a clinical trial, we need to scale up, improve efficiency and assess safety. I think within a few years, those issues can be addressed.”

 


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Stem cells could offer hope for deadly childhood muscle wasting disease

Duchenne muscular dystrophy (DMD) is a particularly nasty rare and fatal disease. It predominantly affects boys, slowly robbing them of their ability to control their muscles. By 10 years of age, boys with DMD start to lose the ability to walk; by 12, most need a wheelchair to get around. Eventually they become paralyzed, and need round-the-clock care.

There are no effective long-term treatments and the average life expectancy is just 25.

Crucial discovery

Duchenne MD team

DMD Research team: Photo courtesy Ottawa Hospital Research Inst.

But now researchers in Canada have made a discovery that could pave the way to new approaches to treating DMD. In a study published in the journal Nature Medicine, they show that DMD is caused by defective muscle stem cells.

In a news release Dr. Michael Rudnicki, senior author of the study, says this discovery is completely changing the way they think about the condition:

“For nearly 20 years, we’ve thought that the muscle weakness observed in patients with Duchenne muscular dystrophy is primarily due to problems in their muscle fibers, but our research shows that it is also due to intrinsic defects in the function of their muscle stem cells. This completely changes our understanding of Duchenne muscular dystrophy and could eventually lead to far more effective treatments.”

Loss and confused

DMD is caused by a genetic mutation that results in the loss of a protein called dystrophin. Rudnicki and his team found that without dystrophin muscle stem cells – which are responsible for repairing damage after injury – produce far fewer functional muscle fibers. The cells are also confused about where they are:

“Muscle stem cells that lack dystrophin cannot tell which way is up and which way is down. This is crucial because muscle stem cells need to sense their environment to decide whether to produce more stem cells or to form new muscle fibers. Without this information, muscle stem cells cannot divide properly and cannot properly repair damaged muscle.”

While the work was done in mice the researchers are confident it will also apply to humans, as the missing protein is almost identical in all animals.

Next steps

The researchers are already looking for ways they can use this discovery to develop new treatments for DMD, hopefully one day turning it from a fatal condition, to a chronic one.

Dr. Ronald Worton, the co-discoverer of the DMD gene in 1987, says this discovery has been a long-time coming but is both welcome and exciting:

“When we discovered the gene for Duchenne muscular dystrophy, there was great hope that we would be able to develop a new treatment fairly quickly. This has been much more difficult than we initially thought, but Dr. Rudnicki’s research is a major breakthrough that should renew hope for researchers, patients and families.”

In this video CIRM grantee, Dr. Helen Blau from Stanford University, talks about a new mouse model created by her lab that more accurately mimics the Duchenne symptoms observed in people. This opens up opportunities to better understand the disease and to develop new therapies.

 

 

 

 

 

Extending the Lease: Stanford Scientists Turn Back Clock on Aging Cells

In the end, all living things—even the cells in our bodies—must die. But what if we could delay the inevitable, even just for a bit? What new scientific advances could come as a result?

Stanford scientists have found a way to temporarily extend the life of an aging cell.

Stanford scientists have found a way to temporarily extend the life of an aging cell.

In research published this week in the FASEB Journal, scientists at the Stanford University School of Medicine have devised a new method that gives aging DNA a molecular facelift.

The procedure, developed by Stanford Stem Cell Scientist Helen Blau and her team at the Baxter Laboratory for Stem Cell Biology, physically lengthens the telomeres—the caps on the ends of chromosomes that protect the cell from the effects of aging.

When born, all cells contain chromosomes capped with telomeres. But during each round of cell division, those telomeres shrink. Eventually, the telomeres shorten to such an extent that the chromosomes can no longer replicate at the rate they once could. For the cell, this is the beginning of the end.

The link between telomeres and cellular aging has been an intense focus in recent years, including the subject of the 2009 Nobel Prize in Physiology or Medicine. Extending the lifespan of cells by preventing—or reversing— the shortening of telomeres can not only boost cell division during laboratory studies, but can also lead to new therapeutic strategies to treat age-related diseases.

“Now we have found a way to lengthen human telomeres… turning back the internal clock in these cells by the equivalent of many years of human life,” explained Blau in a press release. “This greatly increases the number of cells available for studies such as drug testing or disease modeling.”

The method Blau and her team describe involves the use of a modified bit of RNA that boosts the production of the protein telomerase. Telomerase is normally present in high levels in stem cells, but drops off once the cells mature. Blau’s modified RNA gives the aging cells a shot of telomerase, after which they begin behaving like cells half their age. But only for about 48 hours, after which they begin to degrade again.

The temporary nature of this change, say the researchers, offers significant advantages. On the biological level, it means that the treated cells won’t begin dividing out of control indefinitely, minimizing the risk of tumor formation. The study’s first author John Ramunas offers up some additional pluses to their method:

“Existing methods of extending telomeres act slowly, whereas our method acts over just a few days to reverse telomere shortening that occurs over more than a decade of normal aging. This suggests that a treatment using our method could be brief and infrequent.”

Indeed, the genetic disease Duchenne muscular dystrophy is in part characterized by abnormally short telomeres. Blau reasons that their discovery could lead to better treatments for this disease. Their immediate future steps involve testing their method in a variety of cell types. Said Blau:

“We’re working to understand more about the differences among cell types, and how we can overcome those differences to allow this approach to be more universally successful.”

Hear more about stem cells and muscular dystrophy in our recent Spotlight on Disease featuring Helen Blau: