Super stem cell exhibit opens in San Diego

Stem cell exhibit

The best science museums are like playgrounds. They allow you to wander around, reading, watching and learning and being amazed as you go. It’s not just a feast for the mind; it’s also fun for the hands.  You get to interact with and experience science, pushing buttons, pulling levers, watching balls drop and electricity spark.

The best science museums bring out the kid in all of us.

This Saturday a really great science museum is going to be host to a really great exhibition. The Reuben H. Fleet Science Center in San Diego is the first stop on a California tour for “Super Cells: The Power of Stem Cells”. The exhibit is coming here fresh from a successful tour of Canada and the UK.

The exhibit is a “hands-on” educational display that demonstrates the importance and the power of stem cells, calling them “our body’s master cells.” It uses animations, touch-screen displays, videos and stunning images to engage the eyes and delight the brain.

stem cell exhibit 2Each of the four sections focuses on a different aspect of stem cell research, from basic explanations about what a stem cell is, to how they change and become all the different cells in our body. It has a mini laboratory so visitors can see how research is done; it even has a “treatment” game where you get to implant and grow cells in the eye, to see if you can restore sight to someone who is blind.

 

In a news release the Fleet Science Center celebrated the role that stem cells play in our lives:

“Stem cells are important because each of us is the result of only a handful of tiny stem cells that multiply to produce the 200 different types of specialized cells that exist in our body. Our stem cells continue to be active our whole lives to keep us healthy. Without them we couldn’t survive for more than three hours!”

It is, in short, really fun and really cool.

Of course we might be a tad biased here as we helped produce and develop the exhibit in collaboration with the Sherbrooke Museum of Science and Nature in Canada, the Canadian Stem Cell Network, the Centre for Commercialization of Regenerative Medicine in Canada; the Cell Therapy Catapult in the UK, and EuroStemCell.

stem cell exhibit 3

The exhibit is tri-lingual (English, Spanish and French) because our goal was to create a multi-lingual global public education program. San Diego was an obvious choice for the first stop on the California tour (with LA and the Bay Area to follow) because it is one of the leading stem cell research hubs in the U.S., and a region where CIRM has invested almost $380 million over the last ten years.

As our CIRM Board Chair, Jonathan Thomas, said:

“One of our goals at CIRM is to help spread awareness for the importance of stem cell research. San Diego is an epicenter of stem cell science and having this exhibition displayed at the Reuben H. Fleet Science Center is a wonderful opportunity to engage curious science learners of all ages.”

The Super Cells exhibit runs from January 23 to May 1, 2016, in the Main Gallery of the Reuben H. Fleet Science Center. The exhibition is included with the cost of Fleet admission.

For more information, visit the Reuben H. Fleet Science Center website.

Patients beware: warnings about shady clinics and suspect treatments

stem-cells therapy?

Every day we get a call from someone seeking help. Some are battling a life-threatening or life-changing disease. Others call on behalf of a friend or loved one. All are looking for the same thing; a treatment, better still a cure, to ease their suffering.

Almost every day we have to tell them the same thing; that the science is advancing but it’s not there yet. You can almost feel the disappointment, the sense of despair, on the other end of the line.

If it’s hard for us to share that news, imagine how much harder it is for them to hear it. Usually by the time they call us they have exhausted all the conventional therapies. In some cases they are not just running out of options, they are also running out of time.

Chasing hope

Sometimes people mention that they went to the website of a clinic that was offering treatments for their condition, claiming they had successfully treated people with that disease or disorder. This week I had three people mention the same clinic, here in the US, that was offering them “treatments” for multiple sclerosis, traumatic brain injury and chronic obstructive pulmonary disease (COPD). Three very different problems, but the same approach was used for each one.

It’s easy to see why people would be persuaded that clinics like this could help them. Their websites are slick and well produced. They promise to take excellent care of patients, often helping take care of travel plans and accommodation.

There’s just one problem. They never offer any scientific evidence on their website that the treatments they offer work. They have testimonials, quotes from happy, satisfied patients, but no clinical studies, no results from FDA-approved clinical trials. In fact, if you explore their sites you’ll usually find an FAQ section that says something to the effect of they are “not offering stem cell therapy as a cure for any condition, disease, or injury. No statements or implied treatments on this website have been evaluated or approved by the FDA. This website contains no medical advice.”

What a damning but revealing phrase that is.

Now, it may be that the therapies they are offering won’t physically endanger patients – though without a clinical trial it’s impossible to know that – but they can harm in other ways. Financially it can make a huge dent in someone’s wallet with many treatments costing $10,000 or more. And there is also the emotional impact of giving someone false hope, knowing that there was little, if any, chance the treatment would work.

Shining a light in shady areas

U.C. Davis stem cell researcher, CIRM grantee, and avid blogger Paul Knoepfler, highlighted this in a recent post for his blog “The Niche” when he wrote:

Paul Knoepfler

Paul Knoepfler

“Patients are increasingly being used as guinea pigs in the stem cell for-profit clinic world via what I call stem cell shot-in-the-dark procedures. The clinics have no logical basis for claiming that these treatments work and are safe.

As the number of stem cell clinics continues to grow in the US and more physicians add on unproven stem cell injections into their practices as a la carte options, far more patients are being subjected to risky, even reckless physician conduct.”

As if to prove how real the problem is, within hours of posting that blog Paul posted another one, this time highlighting how the FDA had sent a Warning Letter to the Irvine Stem Cell Treatment Center saying it had serious concerns about the way it operates and the treatments it offers.

Paul has written about these practices many times in the past, sometimes incurring the wrath of the clinic owners (and very pointed letters from their lawyers). It’s to his credit that he refuses to be intimidated and keeps highlighting the potential risks that unapproved therapies pose to patients.

Making progress

As stem cell science advances we are now able to tell some patients that yes, there are promising therapies, based on good scientific research, that are being tested in clinical trials.

There are not as many as we would like and none have yet been approved by the FDA for wider use. But those will come in time.

For now we have to continue to work hard to raise awareness about the need for solid scientific evidence before more people risk undergoing an unproven stem cell therapy.

And we have to continue taking calls from people desperate for help, and tell them they have to be patient, just a little longer.

***

If you are considering a stem cell treatment, the International Society for Stem Cell Research had a terrific online resource, A Closer Look at Stem Cells. In particular, check out the Nine Things to Know about Stem Cell Treatments page.

 

Regenerating damaged muscle after a heart attack

Cardio cells image

Images of clusters of heart muscle cells (in red and green) derived from human embryonic stem cells 40 days after transplantation. Courtesy UCLA

Every year more than 735,000 Americans have a heart attack. Many of those who survive often have lasting damage to their heart muscle and are at increased risk for future attacks and heart failure. Now CIRM-funded researchers at UCLA have identified a way that could help regenerate heart muscle after a heart attack, potentially not only saving lives but also increasing the quality of life.

The researchers used human embryonic stem cells to create a kind of cell, called a cardiac mesoderm cell, which has the ability to turn into cardiomyocytes, fibroblasts, smooth muscle, and endothelial cells. All these types of cells play an important role in helping repair a damaged heart.

As those embryonic cells were in the process of changing into cardiac mesoderms, the team was able to identify two key markers on the cell surface. The markers, called CD13 and ROR2 – which makes them sound like extras in the latest Star Wars movie – pinpointed the cells that were likely to be the most efficient at changing into the kind of cells needed to repair damaged heart tissue.

The researchers then transplanted those cells into an animal model and found that not only did many of the cells survive but they also produced the cells needed to regenerate heart muscle and vessels.

Big step forward

The research was published in the journal Stem Cell Reports. Dr. Reza Ardehali, the senior author of the CIRM-funded study, says this is a big step forward in the use of embryonic stem cells to help treat heart attacks:

“In a major heart attack, a person loses an estimated 1 billion heart cells, which results in permanent scar tissue in the heart muscle. Our findings seek to unlock some of the mysteries of heart regeneration in order to move the possibility of cardiovascular cell therapies forward. We have now found a way to identify the right type of stem cells that create heart cells that successfully engraft when transplanted and generate muscle tissue in the heart, which means we’re one step closer to developing cell-based therapies for people living with heart disease.”

More good news

But wait, as they say in cheesy TV infomercials, there’s more. Ardehali and his team not only found the markers to help them identify the right kinds of cell to use in regenerating damaged heart muscle, they also found a way to track the transplanted cells so they could make sure they were going where they wanted them to, and doing what they needed them to.

In a study published in Stem Cells Translational Medicine,  Ardehali and his team used special particles that can be tracked using MRI. They used those particles to label the cardiac mesoderm cells. Once transplanted into the animal model the team was able to follow the cells for up to 40 days.

Ardehali says knowing how to identify the best cells to repair a damaged heart, and then being able to track them over a long period, gives us valuable tools to use as we work to develop better, more effective treatments for people who have had a heart attack.

CIRM is already funding a Phase 2 clinical trial, run by a company called Capricor, using stem cells to treat heart attack patients.

 

National honor for helping “the blind see”

Those of us fortunate to have good health take so many things for granted, not the least of which is our ability to see. But, according to the World Health Organization, there are 39 million people worldwide who are blind, and another 246 million who are visually impaired. Any therapy, any device, that can help change that is truly worthy of celebration.

Dr.MarkHumayun2 copy

Dr. Mark Humayun: Photo courtesy USC

That’s why we are celebrating the news that Professor Mark Humayun has been awarded the National Medal of Technology and Innovation, the nation’s top technology honor, by President Obama.

Humayun, a researcher at USC’s Keck School of Medicine and a CIRM grantee, is being honored for his work in developing an artificial retina, one that enables people with a relatively rare kind of blindness to see again.

But we are also celebrating the potential of his work that we are funding that could help restore sight to millions of people suffering from the leading cause of blindness among the elderly. But we’ll get back to that in a minute.

First, let’s talk about the invention that has earned him this prestigious award. It’s called the Argus II and it can help people with retinitis pigmentosa, an inherited degenerative disease that slowly destroys a person’s vision. It affects around 100,000 Americans.

The Argus II uses a camera mounted on glasses that send signals to an electronic receiver that has been implanted inside the eye. The receiver then relays those signals through the optic nerve to the brain where they are interpreted as a visual image.

In a story posted on the USC website, USC President C. L. Max Nikias praised Humayun’s work:

“He dreamed the impossible: to help the blind see. With fearless imagination, bold leadership and biomedical expertise, he and his team made that dream come true with the world’s first artificial retina. USC is tremendously proud to be Professor Humayun’s academic home.”

At CIRM we are tremendously proud to be funding the clinical trial that Humayun and his team are running to find a stem cell therapy for age-related macular degeneration (AMD), the leading cause of vision loss in the world.  It’s estimated that by 2020 more than 6 million Americans will suffer from AMD.

Humayun’s team is using embryonic stem cells to produce the support cells, or RPE cells, needed to replace those lost in AMD. We recently produced this video that highlights this work, and other CIRM-funded work that targets vision loss.

In a statement released by the White House honoring all the winners, President Obama said:

“Science and technology are fundamental to solving some of our nation’s biggest challenges. The knowledge produced by these Americans today will carry our country’s legacy of innovation forward and continue to help countless others around the world. Their work is a testament to American ingenuity.”

Which is why we are honored to be partners with Humayun and his team in advancing this research and, hopefully, helping find a treatment for millions of people who dream of one day being able to see again.

 

 

 

 

The 10 Most Popular Stem Cellar Stories of 2015

Each new year is exciting for CIRM because it means we’re one year closer to funding a stem cell therapy that will be approved for the treatment of an unmet medical need.

strategy-wide2015 was especially exciting for us. Under our new president Randy Mills, we launched our accelerated funding process, CIRM 2.0, and received Board approval of our new Strategic Plan for the next five years. We’ve also funded a number of promising clinical trials for diseases and conditions such as blindness, cancer, and spinal cord injury. (For more about the 15 clinical trials we are funding, read our recent blog).

We’ve covered many of these accomplishments in our Stem Cellar blog, but we’ve also written about a plethora of other exciting and game-changing stem cell stories from around the world. It’s always fun at the end of the year to look back and see what were the most popular and impactful stories with our readers.

So here they are, the Top 10 Most Popular Stem Cellar Blogs of 2015 (in order):

  1. CIRM-Funded UC-Irvine Team Set to Launch Stem Cell Trial for Retinitis Pigmentosa in 2015
  1. Three teams empower patients’ immune systems to oust cancer
  1. CIRM-funded clinical trial for spinal cord injury reports promising results
  1. One-Time, Lasting Treatment for Sickle Cell Disease May be on Horizon, According to New CIRM-Funded Study
  1. From Stem Cells to Cures with Shinya Yamanaka and Google Ventures
  1. UCLA team cures infants of often-fatal “bubble baby” disease by inserting gene in their stem cells; sickle cell disease is next target
  1. Cartilage Repair using Embryonic Stem Cells: A Promising Path to Treating Millions of Osteoarthritis Sufferers
  1. Newly Identified Stem Cells Breathe Life into Lung Disease Therapy
  1. Stem Cell Therapy for Spinal Cord Injury Back on Track
  1. CIRM fights cancer: $56 million for 5 clinical trials to vanquish tumors for good

From Team Stem Cellar, we want to say a huge Thank You to all our loyal readers and to those who’ve supported our mission to bring stem cell therapies to patients. Have a happy New Year and see you in 2016!!

Using baking ingredient to create “nano” bombs and destroy cancer stem cells

Nixon_30-0316a

“I am not a cook”. Richard Nixon and the baking ingredient that could help win the “war on cancer”

In 1971 President Richard Nixon declared a “war on cancer” and signed the National Cancer Act into law. Forty years later we’re still waging that war, and cancer is still one of the leading causes of death. But now researchers in Ohio have unveiled a new weapon; a nanobomb that targets cancer stem cells.

In treating invasive cancers the standard weapons are chemotherapy and radiation, but cancer stem cells are somehow able to evade these and lie dormant. Eventually they emerge from hiding and multiply and spread throughout the body, leading to a recurrence of the cancer.

So researchers at The Ohio State University Comprehensive Cancer Center turned to nanoparticles to try and target them. Nanoparticles for those of who aren’t up on the latest trendy science topics (something I plead guilty to) are particles between 1 and 100 nanometers in size. Just to put it in context, that’s about one billionth of a meter. In other words, very small indeed.

In the past when scientists tried to use nanoparticles to carry anti-cancer therapies such as therapeutic RNA to the tumor, the cancer cells simply enfolded the RNA nanoparticles in a kind of compartment called an endosome, which rendered them useless.

In a news release, principal investigator Xiaoming He said their new approach helps the nanoparticles escape from the endosomes and attack the cancer:

“We believe we’ve overcome this challenge by developing nanoparticles that include ammonium bicarbonate, a small molecule that vaporizes when exposing the nanoparticles to near-infrared laser light, causing the nanoparticle and endosome to burst, releasing the therapeutic RNA.”

In the study, published in Advanced Materials,   He and his team put micro-RNA miR-34a inside the nanoparticles. This is a molecule known to lower the levels of a  protein that cancer stem cells need for survival. When the ammonium bicarbonate was hit with the near-infrared laser it caused the endosomes to burst and released the miR-34a, killing the cancer cell.

When they tested this approach in a mouse model of human prostate cancer it significantly reduced the size of the tumors.

Because near-infrared lasers penetrate to about half an inch this method could be used for tumors near the skin surface, and for deeper ones would only require a minimally invasive surgery to deliver the necessary dose of light.

Ammonium bicarbonate, the ingredient used to help the nanoparticles swell up, is used by the food industry for some baked goods such as cookies and crackers. It’s a little odd to think that something used in such tasty treats could also be potentially deadly – think about that next time you are browsing the cookie aisle at the supermarket.

 

 

 

 

 

 

 

 

Meet the proteins that tell stem cells where to move and how

 

Protein word art

Word cloud art work which shows all the proteins identified by the researchers

The environment you grow up in can have a huge influence on how you turn out. That applies to people, and to stem cells too. Now a new study has identified 60 proteins that can have a big impact on how cells react to the world around them, and how they communicate with each other.

Just as it is easier for us to move across firm ground than it is to slosh our way through a soggy, muddy field, it’s easier for stem cells to move smoothly and quickly over a solid surface than over a soft, giving surface. This is particularly true for tumor cells, which move much faster on a hard surface than any other kind.

It’s not just speed that is affected by the kind of surface you place stem cells on. For example certain stem cells placed on a hard surface will specialize and turn into bone, whereas if you place those same cells on a very soft surface they will turn into nerve cells.

The problem is we didn’t know much about why that was the case, we didn’t understand the mechanism at play that caused those cells to behave that way.

Now we do.

A team at the University of Manchester in England tackled this problem by researching integrins; these are receptors that are responsible for cell-to-cell communication, cell growth and function. Integrins are typically found at the surfaces and edges of cells and provide proteins with a convenient place to hang out when they interact with the world around them.

The researchers looked at 2400 examples of these integrin-protein clusters and, using mass spectrometry, narrowed their search down to 60 proteins that they identified as being essential in linking information from the integrins to the rest of the cellular world.

The work was published in Nature Cell Biology. In an accompanying news release Dr. Jon Humphries, one of the lead researchers, talked about the significance of the work:

“Understanding how cells sense their environment is an important step in understanding how, for example, cancer cells move or how stem cells take on different jobs.”

His colleague, Professor Martin Humphries, says understanding how cells sense where they are and how to behave gives us new insights into how we can use that knowledge to better control their movement:

“Our findings on how cells sense their environment have unlocked an important key to understanding how we can persuade cells to form different tissues and how we might stop cell movement in diseases such as cancer.”

 

 

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.

 

 

 

 

 

How do you know if they really know what they’re saying “yes” to?

How can you not love something titled “Money, Mischief and Science.” It just smacks of intrigue and high stakes.

And when the rest of the title is “What Have We Learned About Doing Stem Cell Research?” you have an altogether intriguing topic for a panel discussion.

Sue and Bill Gross Hall: Photo by Hoang Xuan Pham/ UC Irvine

Sue and Bill Gross Hall: Photo by Hoang Xuan Pham/ UC Irvine

That panel – featuring CIRM’s own Dr. Geoff Lomax, a regular contributor to The Stem Cellar – is just one element in a day-long event at the University of California, Irvine this Friday, November 13.

Super Symposium

The 2015 Stem Cell Symposium: “The Challenge of Informed Consent in Times of Controversy” looks at some of the problems researchers, companies, institutions and organizations face when trying to put together a clinical trial.

In many cases the individuals who want to sign up for a clinical trial involving the use of stem cells are facing life-threatening diseases or problems. Often they have tried every other option available and this trial may be their last hope. So how can you ensure that they fully understand the risks involved in signing up for a trial?

Equally important is that many of the trials now underway now are Phase 1 trials. The main goal of this kind of trial is to show that the therapy is safe and so the number of cells they use is often too small to have any obvious benefit to the patient. So how can you explain that to a patient who may chose to ignore your caveats and focus instead on the hope, distant as it may be, that this could help them?

Challenging questions

The symposium will feature experts in the fields of science, law, technology and ethics as they consider:

  • Does informed consent convey different meanings depending on who invokes the term?
  • When do we know that consent is informed?
  • What are human research subjects entitled to know before, during and after agreeing to participate in clinical trials?
  • How might the pushback on fetal tissue research impact the scientific development of vaccines, research on Alzheimer’s disease or other medical advancements?

So if you are looking for something thought provoking and engaging to do this Friday, here you are:

“The Challenge of Informed Consent in Times of Controversy,” Friday, Nov. 13, 9am – 4:30pm, at the Sue & Bill Gross Stem Cell Research Center on the University of California, Irvine campus.

The symposium will be livestreamed, and a video recording will be available on www.law.uci.edu following the event.

REGISTER: The symposium is free to UCI student, staff and faculty. There is a $20 registration fee for non-UCI attendees. Visit the event page to register.

Gene editing in blood stem cells just got easier

Genome editing is a field of science that’s been around for awhile, but has experienced an explosion of activity and interest in recent years. Chances are that even your grandmother has heard about the recent story where for the first time, gene editing saved a one-year-old girl from dying of leukemia.

Microsoft word versus genome editing

To give you an idea of what this technique involves, think back to the last time you had to write a report. You let all your ideas flow out onto the page, but then realize that certain sentences or paragraphs need to be rearranged, removed, or added. So you copy, paste, and move stuff around with your mouse and keyboard until you’re satisfied.

Image source: Broad Institute

Image source: Broad Institute

Tools for editing the genome (which contain all of our genes) work a similar way, but they cut and paste DNA sequences in the human genome instead of words on a page. Scientists have figured out how to use these “genetic scissors” to delete genes (so they no longer have function) and to correct disease-causing mutations (by pasting in the normal DNA sequence of a gene to restore function). Both these abilities make genome editing a highly valuable tool for scientists to model diseases and to develop therapies to treat them.

There are multiple tools that researchers are currently using to modify the human genome. The main ones are fancifully named ZFNs, TALENs, and CRISPRs. All three use engineered proteins called nucleases to cut strands of DNA at specific locations in the genome. A cell’s DNA repair machinery will then either glue the DNA strands back together (this typically results in the loss of DNA and gene function), or repair the break by copying and pasting in the missing sequence of DNA from a template (you can correct disease-causing mutations this way by providing a donor template). We don’t have time to get into more details about how these tools work, but you can learn more by reading this fact sheet from Science Media Centre.

Some cells are more stubborn than others

While genome editing technologies offer many advantages for modifying human genes, it’s not a perfect science. There are still many limitations and roadblocks that need to be addressed to make sure that these tools can be safely and effectively used as therapies in humans.

Besides the obvious worry about “off-target effects” (when the genetic scissors cut random sections of DNA, which can cause big problems), another issue with genome editing tools is that some types of cells are harder to genetically modify than others.

Such is the case with blood stem cells, also known as hematopoietic stem and progenitor cells (HSPCs), that live in our bone marrow and make all the different blood cells in our body. Initial studies reported difficulty in delivering genome editing tools into human HSPCs, which is a problem if you want to use these tools to help cure patients suffering from genetic blood or immune diseases.

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

Have no fear, blood-stem cell editing is here

We are happy to inform you that a CIRM-funded study published today in Nature Biotechnology has developed a solution to the problem of hard-to-edit blood stem cells. Scientists from the USC Keck School of Medicine and from Sangamo BioSciences developed a new delivery method that allows for efficient genome editing of human HSPCs using zinc finger nucleases (ZFNs).

They used a viral delivery system to deliver ZFNs to distinct locations in the genome of HSPCs and successfully inserted a gene sequence that made the cells turn green under a fluorescent microscope. The virus they used was a harmless form of an adeno-associated virus (AAV), which can enter certain cells and delivery the researcher’s DNA cargo with a very low chance of altering or inserting its own DNA into the HSPC genome.

Using an AAV that was exceptionally good at entering HPSCs, they virally delivered ZFNs to specific gene locations in HSPCs that had been isolated from human blood and from fetal liver tissue. They found that delivering the ZFNs as mRNA molecules allowed the protein versions they turned into to be temporarily expressed in HSPCs. This produced a high rate of gene insertion (ranging from 15-40% of cells treated), while keeping off-target effects and cell death low. Even the most hard-to-edit HSPCs, called the primitive HSPCs, were modified. This result was really exciting because no other study has reported gene editing with this level of efficiency in this primitive population of blood stem cells.

The tools work but what about the cells?

After proving that they were able to successfully edit the genomes of HSPCs with high efficiency, they next asked whether the modified cells could grow in culture and create new blood cells when transplanted into mice.

While their method to deliver ZFNs into the HSPCs did cause some of the cells to die (around 20%), the majority that survived were able to multiply in a dish and specialize into various blood cells when grown in cultures. When the modified HSPCs were taken a step further and transplanted into immune-deficient mice (meaning their immune system is compromised and won’t attack transplanted cells), they not only survived, but they also specialized into many different types of blood cells while still retaining their genomic modifications.

Now here is where I want to give the researchers a high five. They decided that once wasn’t enough, and challenged their modified HSPCs to a second round of transplantation. They collected the bone marrow from mice that received the first transplant of modified HSPCs, and transferred it into another immune-deficient mouse. Five months later, they found that the modified cells were still there and had generated other blood cell types. Because these modified HSPCs lasted for so long and through two rounds of transplants, the authors concluded that they had successfully edited the primitive, long-term repopulating HSPCs.

Next stop, the clinic?

In summary, this study offers a new and improved method to genetically modify blood stem cells in all their forms.

So what’s next? The obvious hope is the clinic.

HIV (yellow) infecting a human immune cell. CREDIT: SETH PINCUS, ELIZABETH FISCHER AND AUSTIN ATHMAN, NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES, NATIONAL INSTITUTES OF HEALTH

HIV (yellow) infecting a human immune cell. Photo credit: Seth Pincus, Elizabeth Fischer and Austin Athman, NIH.

It’s a likely future as the study was conducted in collaboration with Sangamo BioSciences. They specialize in ZFN-mediated gene therapy and have a number of preclinical therapeutic programs, many of which focus on genetic diseases that affect the blood and immune system, as well as ongoing clinical trials using ZFNs to treat patients with HIV/AIDs. (One of these trials is funded by CIRM, read more here).

In a USC press release, Dr. Michael Holmes, VP of Research at Sangamo and co-senior author on the paper hinted at future clinical applications:

Michael Holmes, Sangamo BioSciences

Michael Holmes, Sangamo BioSciences

 

Our results provide a strategy for broadening the application of gene editing technologies in HSPCs. This significantly advances our progress towards applying gene editing to the treatment of human diseases of the blood and immune systems.

 

 

Co-senior author and USC Professor Dr. Paula Cannon echoed Dr. Holmes:

Gene therapy using HSPCs has enormous potential for treating HIV and other diseases of the blood and immune systems.

One last question

A question that I had after reading this exciting study was whether other genome editing tools such as CRISPR could produce better results in blood stem cells using a similar viral delivery method.

CRISPR is described as a faster, cheaper, and easier gene editing technology compared to ZFNs and TALENS (for a comparison, check out this fun article by The Jackson Laboratory). And many scientists, both in academia and industry, are pushing CRISPR gene editing towards clinical applications.

When I asked Paula Cannon about which gene editing technology, ZFNs or CRISPRs, is better for therapeutic development, she said:

Paula Cannon, USC Professor

Paula Cannon, USC Professor

In terms of advantages, CRISPRs are easier to work with initially, and this makes them a great lab research tool. But when it comes to developing something for a clinical trial, its much more of a long game, so that initial advantage disappears. The ZFNs I work with have been previously optimized and are well characterized, and the CCR5 ZFNs are already in the clinic so they have a big advantage in that regard when you are trying to develop something for the next clinical application.


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