Seeing is believing. Proof a CIRM-funded therapy is making a difference

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Thelma, participant in the CAMELLIA clinical trial

You have almost certainly never heard of Thelma, or met her, or know anything about her. She’s a lady living in England who, if it wasn’t for a CIRM-funded therapy, might not be living at all. She’s proof that what we do, is helping people.

Thelma is featured in a video about a treatment for acute myeloid leukemia, one of the most severe forms of blood cancer. Thelma took part in a clinical trial, called CAMELLIA, at Oxford Cancer Centre in Oxford, UK. The clinical trial uses a therapy that blocks a protein called CD47 that is found on the surface of cancer cells, including cancer stem cells which can evade traditional therapies. The video was shot to thank the charity Bloodwise for raising the funds to pay for the trial.

Prof. Paresh Vyas of Oxford University, who was part of the clinical trial team that treated Thelma, says patients with this condition face long odds.

“Patients with acute myeloid leukemia have the most aggressive blood cancer. We really haven’t had good treatments for this condition for the last 40 years.”

While this video was shot in England, featuring English nurses and doctors and patients, the therapy itself was developed here in California, first at Stanford University under the guidance of Irv Weissman and, more recently, at Forty Seven Inc. That company is now about to test their approach in a CIRM-funded clinical trial here in the US.

This is an example of how CIRM doesn’t just fund research, we invest in it. We help support it at every stage, from the earliest research through to clinical trials. Without our early support this work may not have made it this far.

The Forty Seven Inc. therapy uses the patient’s own immune system to help fight back against cancer stem cells. It’s looking very promising. But you don’t have to take our word for it. Take Thelma’s.

Creating a platform to help transplanted stem cells survive after a heart attack

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Developing new tools to repair damaged hearts

Repairing, even reversing, the damage caused by a heart attack is the Holy Grail of stem cell researchers. For years the Grail seemed out of reach because the cells that researchers transplanted into heart attack patients didn’t stick around long enough to do much good. Now researchers at Stanford may have found a way around that problem.

In a heart attack, a blockage cuts off the oxygen supply to muscle cells. Like any part of our body starved off oxygen the muscle cells start to die, and as they do the body responds by creating a layer of scars, effectively walling off the dead tissue from the surviving healthy tissue.  But that scar tissue makes it harder for the heart to effectively and efficiently pump blood around the body. That reduced blood flow has a big impact on a person’s ability to return to a normal life.

In the past, efforts to transplant stem cells into the heart had limited success. Researchers tried pairing the cells with factors called peptides to help boost their odds of surviving. That worked a little better but most of the peptides were also short-lived and weren’t able to make a big difference in the ability of transplanted cells to stick around long enough to help the heart heal.

Slow and steady approach

Now, in a CIRM-funded study published in the journal Nature Biomedical Engineering, a team at Stanford – led by Dr. Joseph Wu – believe they have managed to create a new way of delivering these cells, one that combines them with a slow-release delivery mechanism to increase their chances of success.

The team began by working with a subset of bone marrow cells that had been shown in previous studies to have what are called “pro-survival factors.” Then, working in mice, they identified three peptides that lived longer than other peptides. That was step one.

Step two involved creating a matrix, a kind of supporting scaffold, that would enable the researchers to link the three peptides and combine them with a delivery system they hoped would produce a slow release of pro-survival factors.

Step three was seeing if it worked. Using fluorescent markers, they were able to show, in laboratory tests, that unlinked peptides were rapidly released over two or three days. However, the linked peptides had a much slower release, lasting more than 15 days.

Out of the lab and into animals

While these petri dish experiments looked promising the big question was could this approach work in an animal model and, ultimately, in people. So, the team focused on cardiac progenitor cells (CPCs) which have shown potential to help repair damaged hearts, but which also have a low survival rate when transplanted into hearts that have experienced a heart attack.

The team delivered CPCs to the hearts of mice and found the cells without the pro-survival matrix didn’t last long – 80 percent of the cells were gone four days after they were injected, 90 percent were gone by day ten. In contrast the cells on the peptide-infused matrix were found in large numbers up to eight weeks after injection. And the cells didn’t just survive, they also engrafted and activated the heart’s own survival pathways.

Impact on heart

The team then tested to see if the treatment was helping improve heart function. They did echocardiograms and magnetic resonance imaging up to 8 weeks after the transplant surgery and found that the mice treated with the matrix combination had a statistically improved left ventricular function compared to the other mice.

Jayakumar Rajadas, one of the authors on the paper told CIRM that, because the matrix was partly made out of collagen, a substance the FDA has already approved for use in people, this could help in applying for approval to test it in people in the future:

“This paper is the first comprehensive report to demonstrate an FDA-compliant biomaterial to improve stem cell engraftment in the ischemic heart. Importantly, the biomaterial is collagen-based and can be readily tested in humans once regulatory approval is obtained.”

 

Stem Cell Roundup: New understanding of Huntington’s; how stem cells can double your DNA; and using “the Gary Oldman of cell types” to reverse aging

This week’s roundup highlights how we are constantly finding out new and exciting ways that stem cells could help change the way we treat disease.

Our Cool Stem Cell Image of the Week comes from our first story, about unlocking some of the secrets of Huntington’s disease. It comes from the Laboratory of Stem Cell Biology and Molecular Embryology at The Rockefeller University

Huntington's neurons

A new approach to studying and developing therapies for Huntington’s disease

Researchers at Rockefeller University report new findings that may upend the way scientists study and ultimately develop therapies for Huntington’s disease, a devastating, inherited neurodegenerative disorder that has no cure. Though mouse models of the disease are well-established, the team wanted to focus on human biology since our brains are more complex than those of mice. So, they used CRISPR gene editing technology in human embryonic stem cells to introduce the genetic mutations that cause HD.

Though symptoms typically do not appear until adulthood, the researchers were surprised to find that in their human cell-based model of HD, abnormalities in nerve cells occur at the earliest steps in brain development. These results suggest that HD therapies should focus on treatments much earlier in life.

The researchers observed another unexpected twist: cells that lack Huntingtin, the gene responsible for HD, are very similar to cells found in HD. This suggests that too little Huntingtin may be causing the disease. Up until now, the prevailing idea has been that Huntington’s symptoms are caused by the toxicity of too much mutant Huntingtin activity.

We’ll certainly be keeping an eye on how further studies using this new model affect our understanding of and therapy development for HD.

This study was published in Development and was picked by Science Daily.

How you can double your DNA

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As you can imagine we get lots of questions about stem cell research here at CIRM. Last week we got an email asking if a stem cell transplant could alter your DNA? The answer is, under certain circumstances, yes it could.

A fascinating article in the Herald Review explains how this can happen. In a bone marrow transplant bad blood stem cells are killed and replaced with healthy ones from a donor. As those cells multiply, creating a new blood supply, they also carry the DNA for the donor.

But that’s not the only way that people may end up with dual DNA. And the really fascinating part of the article is how this can cause all sorts of legal and criminal problems.

One researcher’s efforts to reverse aging

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Gary Oldman: Photo courtesy Variety

“Stem cells are the Gary Oldman of cell types.” As a fan of Gary Oldman (terrific as Winston Churchill in the movie “Darkest Hour”) that one line made me want to read on in a profile of Stanford University researcher Vittorio Sebastiano.

Sebastiano’s goal is, to say the least, rather ambitious. He wants to reverse aging in people. He believes that if you can induce a person’s stem cells to revert to a younger state, without changing their function, you can effectively turn back the clock.

Sebastiano says if you want to achieve big things you have to think big:

“Yes, the ambition is huge, the potential applications could be dramatic, but that doesn’t mean that we are going to become immortal in some problematic way. After all, one way or the other, we have to die. We will just understand aging in a better way, and develop better drugs, and keep people happier and healthier for a few more years.”

The profile is in the journal Nautilus.

Listen up! Stem cell scientists craft new ears using children’s own cells

Imagine growing up without an ear, or with one that was stunted and deformed. It would likely have an impact on almost every part of your life, not just your hearing. But now scientists in China say they have found a way to help give children born with this condition a new ear, one that is grown using their own cells.

Microtia is a rare condition where children are born with a deformed or underdeveloped outer ear. This is what it can look like.

Microtia ear

In an interview in New Scientist, Dr. Tessa Hadlock, at Massachusetts Eye and Ear Infirmary in Boston, said:

“Children with the condition often feel self-conscious and are picked on, and are unable to wear glasses.”

In the past repairing it required several cosmetic surgeries that had to be repeated as the child grew. But now Chinese scientists say they have helped five children born with microtia grown their own ears.

In the study, published in the journal EBioMedicine, the researchers explained how they used a CT scan of the child’s normal ear to create a 3D mold, using biodegradable material. They took cartilage cells from the child’s ear, grew them in the lab, and then used them to fill in tiny holes in the ear mold. Over the course of 12 weeks the cells continued to multiply and grow and slowly replaced the biodegradable material in the mold.

While the new “ear” was being prepared in the lab, the scientists used a mechanical device to slowly expand the skin on the child’s affected ear. After 12 weeks there was enough expanded skin for the scientists to take the engineered ear, surgically implant it on the child’s head, and cover it with skin.

Over the course of the next two and a half years the engineered ear took on a more and more “natural” appearance. The children did undergo minor surgeries, to remove scar tissue, but other than that the engineered ear shows no signs of complications or of being rejected.

Here is a photo montage showing the pre and post-surgical pictures of a six-year old girl, the first person treated in the study.

Microtia

Other scientists, in the US and UK, are already working on using stem cells taken from the patient’s fat tissue, that are then re-engineered to become ear cells.

Surgeons, like Dr. Hadlock, say this study proves the concept is sound and can make a dramatic difference in the lives of children.

“It’s a very exciting approach. They’ve shown that it is possible to get close to restoring the ear structure.”

Stem Cell Roundup: Rainbow Sherbet Fruit Fly Brains, a CRISPR/iPSC Mash-up and more

This week’s Round Up is all about the brain with some CRISPR and iPSCs sprinkled in:

Our Cool Stem Cell Image of the Week comes from Columbia University’s Zuckerman Institute:

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(Credit: Jon Enriquez/Mann Lab/Columbia’s Zuckerman Institute).

This rainbow sherbet-colored scientific art is a microscopy image of a fruit fly nervous system in which brain cells were randomly labeled with different colors. It was a figure in a Neuron study published this week showing how cells derived from the same stem cells can go down very different developmental paths but then later are “reunited” to carry out key functions, such as in this case, the nervous system control of leg movements.


A new therapeutic avenue for Parkinson’s diseaseBuck Institute

Many animal models of Parkinson’s disease are created by mutating specific genes to cause symptoms that mimic this incurable, neurodegenerative disorder. But, by far, most cases of Parkinson’s are idiopathic, a fancy term for spontaneous with no known genetic cause. So, researchers at the Buck Institute took another approach: they generated a mouse model of Parkinson’s disease using the pesticide, paraquat, exposure to which is known to increase the risk of the idiopathic form of Parkinson’s.

Their CIRM-funded study in Cell Reports showed that exposure to paraquat leads to cell senescence – in which cells shut down and stop dividing – particularly in astrocytes, brain cells that support the function of nerve cells. Ridding the mice of these astrocytes relieved some of the Parkinson’s like symptoms. What makes these results so intriguing is the team’s analysis of post-mortem brains from Parkinson’s patients also showed the hallmarks of increased senescence in astrocytes. Perhaps, therapeutic approaches that can remove senescent cells may yield novel Parkinson’s treatments.


Discovery may advance neural stem cell treatments for brain disordersSanford-Burnham Prebys Medical Discovery Institute (via Eureka Alert)

Another CIRM-funded study published this week in Nature Neuroscience may also help pave the way to new treatment strategies for neurologic disorders like Parkinson’s disease. A team at Sanford Burnham Prebys Medical Discovery Institute (SBP) discovered a novel gene regulation system that brain stem cells use to maintain their ability to self-renew.

The study centers around messenger RNA, a molecular courier that transcribes a gene’s DNA code and carries it off to be translated into a protein. The team found that the removal of a chemical tag on mRNA inside mouse brain stem cells caused them to lose their stem cell properties. Instead, too many cells specialized into mature brain cells leading to abnormal brain development in animal studies. Team lead Jing Crystal Zhao, explained how this finding is important for future therapeutic development:

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Crystal Zhao

“As NSCs are increasingly explored as a cell replacement therapy for neurological disorders, understanding the basic biology of NSCs–including how they self-renew–is essential to harnessing control of their in vivo functions in the brain.”


Researchers Create First Stem Cells Using CRISPR Genome ActivationThe Gladstone Institutes

Our regular readers are most likely familiar with both CRISPR gene editing and induced pluripotent stem cell (iPSC) technologies. But, in case you missed it late last week, a Cell Stem Cell study out of Sheng Ding’s lab at the Gladstone Institutes, for the first time, combined the two by using CRISPR to make iPSCs. The study got a lot of attention including a review by Paul Knoepfler in his blog The Niche. Check it out for more details!

 

Stem Cell RoundUp: CIRM Clinical Trial Updates & Mapping Human Brain

It was a very CIRMy news week on both the clinical trial and discovery research fronts. Here are some the highlights:

Stanford cancer-fighting spinout to Genentech: ‘Don’t eat me’San Francisco Business Times

Ron Leuty, of the San Francisco Business Times, reported this week on not one, but two news releases from CIRM grantee Forty Seven, Inc. The company, which originated from discoveries made in the Stanford University lab of Irv Weissman, partnered with Genentech and Merck KGaA to launch clinical trials testing their drug, Hu5F9-G4, in combination with cancer immunotherapies. The drug is a protein antibody that blocks a “don’t eat me” signal that cancer stem cells hijack into order to evade destruction by a cancer patient’s immune system.

Genentech will sponsor two clinical trials using its FDA-approved cancer drug, atezolizumab (TECENTRIQ®), in combination with Forty Seven, Inc’s product in patients with acute myeloid leukemia (AML) and bladder cancer. CIRM has invested $5 million in another Phase 1 trial testing Hu5F9-G4 in AML patients. Merck KGaA will test a combination treatment of its drug avelumab, or Bavencio, with Forty-Seven’s Hu5F9-G4 in ovarian cancer patients.

In total, CIRM has awarded Forty Seven $40.5 million in funding to support the development of their Hu5F9-G4 therapy product.


Novel regenerative drug for osteoarthritis entering clinical trialsThe Scripps Research Institute

The California Institute for Biomedical Research (Calibr), a nonprofit affiliate of The Scripps Research Institute, announced on Tuesday that its CIRM-funded trial for the treatment of osteoarthritis will start treating patients in March. The trial is testing a drug called KA34 which prompts adult stem cells in joints to specialize into cartilage-producing cells. It’s hoped that therapy will regenerate the cartilage that’s lost in OA, a degenerative joint disease that causes the cartilage that cushions joints to break down, leading to debilitating pain, stiffness and swelling. This news is particularly gratifying for CIRM because we helped fund the early, preclinical stage research that led to the US Food and Drug Administration’s go-ahead for this current trial which is supported by a $8.4 million investment from CIRM.


And finally, for our Cool Stem Cell Image of the Week….

Genetic ‘switches’ behind human brain evolutionScience Daily

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This artsy scientific imagery was produced by UCLA researcher Luis del la Torre-Ubieta, the first author of a CIRM-funded studied published this week in the journal, Cell. The image shows slices of the mouse (bottom middle), macaque monkey (center middle), and human (top middle) brain to scale.

The dramatic differences in brain size highlights what sets us humans apart from those animals: our very large cerebral cortex, a region of the brain responsible for thinking and complex communication. Torre-Ubieta and colleagues in Dr. Daniel Geschwind’s laboratory for the first time mapped out the genetic on/off switches that regulate the growth of our brains. Their results reveal, among other things, that psychiatric disorders like schizophrenia, depression and Attention-Deficit/Hyperactivity Disorder (ADHD) have their origins in gene activity occurring in the very earliest stages of brain development in the fetus. The swirling strings running diagonally across the brain slices in the image depict DNA structures, called chromatin, that play a direct role in the genetic on/off switches.

CHLA study explains how stem cells slow progression of kidney disorder

Not all stem cell-based therapies act by replacing diseased or damaged cells. Many treatments in clinical development rely on the injected stem cells releasing proteins which trigger the slow down or even reversal of damage caused by disease or injury. A new CIRM-funded study that’s developing a stem cell therapy for a rare kidney disease uncovered a similar mechanism but with an intriguing twist. The research, published this week in Scientific Reports, suggests that the stem cells shed tiny vesicles that essentially act like sponges by trapping proteins thought to be responsible for damaging the kidney.

Amniotic fluid stem cells: a promising approach to treating kidney disease

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Network of blood-filtering blood vessels in the kidney. Image: Wikipedia

In previous studies the research team, from the Saban Research Institute of Children’s Hospital Los Angeles (CHLA), had shown that amniotic fluid stem cells can help slow the progress of Alport syndrome when injected into the kidneys of mice engineered to mimic symptoms of the disease. Alport syndrome is a genetic disease that damages the kidney’s capillaries – tiny blood vessels – which help filter the body’s blood supply. This progressive damage causes blood and proteins to leak into the urine, and leads to high blood pressure and swelling in the legs and around the eyes.

Cells in the kidney release a protein called VEGF, a stimulator of new blood vessel growth, which plays an important role in maintaining just the right balance of capillaries within the blood-filtering structures of the kidney. Excessive levels of VEGF have been associated with many diseases including kidney disorders like Alport syndrome. Although the protective effects of amniotic fluid stem cells in the mouse model of Alport syndrome were not understood, the CHLA team suspected that the cells could be interfering with the effects of the extra VEGF.

Extracellular vesicles: just another trick that nature has up its sleeve
Specifically, the scientists examined whether so-called extracellular vesicles released from the stem cells are responsible for reducing VEGF activity and slowing the disease. These vesicles are tiny pieces of cell membrane that bud off from the stem cell and carry along proteins and other cell components. Scientists used to think the vesicles were just cellular discards but countless studies have established that they actually play an important role in communication between cells.

The team showed that the vesicles released by amniotic fluid stem cells contained receptors for VEGF. When those vesicles were added to a petri dish containing VEGF and kidney blood vessel cells, the vesicles reduced the VEGF activity and protected the cells from damage. But when vesicles from stem cells lacking the VEGF receptors were used, that protection was lost. First author Sargis Sedrakyan, PhD summed up the results in a press release:

“We have demonstrated that these vesicles can be used to regulate VEGF activity and prevent the [kidney] capillary damage. We can efficiently use the vesicles to help restore normal kidney function by curbing the progression of endothelial damage in the filtration unit of the kidney.”

Back in 2013, first author Sargis Sedrakyan summarized his research in this 30 second video for the CIRM Grantee Elevator Pitch Challenge. 

Vesicles from aminotic fluid stem cells beat out FDA-approved VEGF blocker
Now anti-VEGF antibody proteins that can tightly bind and inhibit VEGF are readily available and have even been approved by the Food and Drug Administration for other disorders. So why even bother with these vesicles as a possible therapeutic strategy for Alport syndrome? Well, in side-by-side comparisons, it turns out the stem cell-derived vesicles, but not the anti-VEGF antibodies, could not only trap the VEGF but also put the brakes on VEGF production. So, it seems that the vesicles have additional properties that could make them more ideal than current approaches.

And as indicated in the press release, the CHLA team is eager to continue exploring this therapeutic strategy:

“The team’s next step will be to validate the stem cell-derived vesicle in different types of kidney disease with the final aim of finding a therapy that is effective for all patients who suffer from chronic kidney disease.”

 

Stem Cell Stories that Caught Our Eye: GPS for Skin & Different Therapies for Aging vs. Injured Muscles?

Skin stem cells specialize into new skin by sensing neighborhood crowding
When embarking on a road trip, the GPS technology inside our smartphones helps us know where we are and how to get where we’re going. The stem cells buried in the deepest layers of our skin don’t have a GPS and yet, they do just fine determining their location, finding their correct destination and becoming the appropriate type of skin cell. And as a single organ, all the skin covering your body maintains the right density and just the right balance of skin stem cells versus mature skin cells as we grow from a newborn into adult.

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Skin cells growing in a petri dish (green: cytoskeleton, red: cell-cell junction protein).
Credit: MPI for Biology of Aging

This easily overlooked but amazing feat is accomplished as skin cells are continually born and die about every 30 days over your lifetime. How does this happen? It’s an important question to answer considering the skin is our first line of defense against germs, toxins and other harmful substances.

This week, researchers at the Max Planck Institute for Biology of Aging in Cologne, Germany reported a new insight into this poorly understood topic. The team showed that it all comes down to the skin cells sensing the level of crowding in their local environment. As skin stem cells divide, it puts the squeeze on neighboring stem cells. This physical change in tension on these cells “next door” triggers signals that cause them to move upward toward the skin surface and to begin maturing into skin cells.

Lead author Yekaterina Miroshnikova explained in a press release the beauty of this mechanism:

“The fact that cells sense what their neighbors are doing and do the exact opposite provides a very efficient and simple way to maintain tissue size, architecture and function.”

The research was picked up by Phys.Org on Tuesday and was published in Nature Cell Biology.

Stem cells respond differently to aging vs. injured muscle
From aging skin, we now move on to our aging and injured muscles, two topics I know oh too well as a late-to-the-game runner. Researchers at the Sanford Burnham Prebys Medical Discovery Institute (SBP) in La Jolla report a surprising discovery that muscle stem cells respond differently to aging versus injury. This important new insight could help guide future therapeutic strategies for repairing muscle injuries or disorders.

muscle stem cell

Muscle stem cell (pink with green outline) sits along a muscle fiber.
Image: Michael Rudnicki/OIRM

Muscle stem cells, also called satellite cells, make a small, dormant population of cells in muscle tissue that springs to life when muscle is in need of repair. It turns out that these stem cells are not identical clones of each other but instead are a diverse pool of cells.  To understand how the assortment of muscle stem cells might respond differently to the normal wear and tear of aging, versus damage due to injury or disease, the research team used a technology that tracks the fate of individual muscle stem cells within living mice.

The analysis showed a clear but unexpected result. In aging muscle, the muscle stem cells maintained their diversity but their ability to divide and grow declined. However, the opposite result was observed in injured muscle: the muscle stem cell diversity became limited but the capacity to divide was not affected. In a press release, team leader Alessandra Sacco explains the implications of these findings for therapy development:

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Alessandra Sacco, PhD

“This study has shown clear-cut differences in the dynamics of muscle stem cell pools during the aging process compared to a sudden injury. This means that there probably isn’t a ‘one size fits all’ approach to prevent the decline of muscle stem cells. Therapeutic strategies to maintain muscle mass and strength in seniors will most likely need to differ from those for patients with degenerative diseases.”

This report was picked up yesterday by Eureka Alert and published in Cell Stem Cell.

A new study suggests CRISPR gene editing therapies should be customized for each patient

You know a scientific advance is a big deal when it becomes the main premise and title of a Jennifer Lopez-produced TV drama. That’s the case for CRISPR, a revolutionary gene-editing technology that promises to yield treatments for a wide range of genetic diseases.

In fact, clinical trials using the CRISPR method are already underway with more on the horizon. And at CIRM, we’re funding several CRISPR projects including a candidate gene and stem cell therapy that applies CRISPR to repair a genetic mutation found in sickle cell anemia patients.

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Animation by Todd Dubnicoff/CIRM

While these projects are moving full steam ahead, a study published this week in PNAS suggests a note of caution. They report that the natural genetic variability that is found when comparing  the DNA sequences of individuals has the potential to negatively impact the effectiveness of a CRISPR-based treatment and in some cases, could lead to dangerous side effects. As a result, the research team – a collaboration between Boston Children’s Hospital and the University of Montreal – recommends that therapy products using CRISPR should be customized to take into account the genetic variation between patients.

CRISPR 101
While other gene-editing methods pre-date CRISPR, the gene-editing technique has taken the research community by storm because of its ease of use. Pretty much any lab can incorporate it into their studies. CRISPR protein can cut specific DNA sequence within a person’s cells with the help of an attached piece of RNA. It’s pretty straight-forward to customize this “guide” RNA molecule so that it recognizes a desired DNA sequence that is in need of repair or modification.

https://player.vimeo.com/video/112757040

Because CRISPR activity heavily relies on the guide RNA molecule’s binding to a specific DNA sequence, there have been on-going concerns that a patient’s genetic variability could hamper the effectiveness of a given CRISPR therapy if it didn’t bind well. Even worse, if the genetic variability caused the CRISPR product to bind and inactivate a different region of DNA, say a gene responsible for suppressing cancer growth, it could lead to dangerous, so-called off target effects.

Although, studies have been carried out to measure the frequency of these potential CRISPR mismatches, many of the analyses depend on a reference DNA sequence from one individual. But as senior author Stuart Orkin, of Dana-Farber Boston Children’s Cancer and Blood Disorders Center, points out in a press release, this is not an ideal way to gauge CRISPR effectiveness and safety:

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Stuart Orkin

“Humans vary in their DNA sequences, and what is taken as the ‘normal’ DNA sequence for reference cannot account for all these differences.”

 

 

One DNA sequence is not like the other
So, in this study, the research team analyzed previously published DNA sequence data from 7,444 people. And they focused on 30 disease genes that various researchers were targeting with CRISPR gene-editing. The team also generated 3,000 different guide RNAs with which to target those 30 disease genes.

The analysis showed that, in fact, about 50 percent of the guide RNAs could potentially have mismatches due to genetic variability found in these patients’ DNA sequences. These mismatches could lead to less effective binding of CRISPR to the disease gene target, which would reduce the effectiveness of the gene editing. And, though rare, the team also found cases in which an individual’s genetic variability could cause the CRISPR guide RNA to bind and cut in the wrong spot.

Matthew Canver, an MD-PhD student at Harvard Medical School who is also an author in the study, points out these less-than-ideal activities could also impact other gene editing techniques. Canver gives an overall recommendation how to best move forward with CRISPR-based therapy development:

canver, matthew

Matthew Canver

“The unifying theme is that all these technologies rely on identifying stretches of DNA bases very specifically. As these gene-editing therapies continue to develop and start to approach the clinic, it’s important to make sure each therapy is going to be tailored to the patient that’s going to be treated.”

 

Hey, what’s the big idea? CIRM Board is putting up more than $16.4 million to find out

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David Higgins, CIRM Board member and Patient Advocate for Parkinson’s disease; Photo courtesy San Diego Union Tribune

When you have a life-changing, life-threatening disease, medical research never moves as quickly as you want to find a new treatment. Sometimes, as in the case of Parkinson’s disease, it doesn’t seem to move at all.

At our Board meeting last week David Higgins, our Board member and Patient Advocate for Parkinson’s disease, made that point as he championed one project that is taking a new approach to finding treatments for the condition. As he said in a news release:

“I’m a fourth generation Parkinson’s patient and I’m taking the same medicines that my grandmother took. They work but not for everyone and not for long. People with Parkinson’s need new treatment options and we need them now. That’s why this project is worth supporting. It has the potential to identify some promising candidates that might one day lead to new treatments.”

The project is from Zenobia Therapeutics. They were awarded $150,000 as part of our Discovery Inception program, which targets great new ideas that could have a big impact on the field of stem cell research but need some funding to help test those ideas and see if they work.

Zenobia’s idea is to generate induced pluripotent stem cells (iPSCs) that have been turned into dopaminergic neurons – the kind of brain cell that is dysfunctional in Parkinson’s disease. These iPSCs will then be used to screen hundreds of different compounds to see if any hold potential as a therapy for Parkinson’s disease. Being able to test compounds against real human brain cells, as opposed to animal models, could increase the odds of finding something effective.

Discovering a new way

The Zenobia project was one of 14 programs approved for the Discovery Inception award. You can see the others on our news release. They cover a broad array of ideas targeting a wide range of diseases from generating human airway stem cells for new approaches to respiratory disease treatments, to developing a novel drug that targets cancer stem cells.

Dr. Maria Millan, CIRM’s President and CEO, said the Stem Cell Agency supports this kind of work because we never know where the next great idea is going to come from:

“This research is critically important in advancing our knowledge of stem cells and are the foundation for future therapeutic candidates and treatments. Exploring and testing new ideas increases the chances of finding treatments for patients with unmet medical needs. Without CIRM’s support many of these projects might never get off the ground. That’s why our ability to fund research, particularly at the earliest stage, is so important to the field as a whole.”

The CIRM Board also agreed to invest $13.4 million in three projects at the Translation stage. These are programs that have shown promise in early stage research and need funding to do the work to advance to the next level of development.

  • $5.56 million to Anthony Oro at Stanford to test a stem cell therapy to help people with a form of Epidermolysis bullosa, a painful, blistering skin disease that leaves patients with wounds that won’t heal.
  • $5.15 million to Dan Kaufman at UC San Diego to produce natural killer (NK) cells from embryonic stem cells and see if they can help people with acute myelogenous leukemia (AML) who are not responding to treatment.
  • $2.7 million to Catriona Jamieson at UC San Diego to test a novel therapeutic approach targeting cancer stem cells in AML. These cells are believed to be the cause of the high relapse rate in AML and other cancers.

At CIRM we are trying to create a pipeline of projects, ones that hold out the promise of one day being able to help patients in need. That’s why we fund research from the earliest Discovery level, through Translation and ultimately, we hope into clinical trials.

The writer Victor Hugo once said:

“There is one thing stronger than all the armies in the world, and that is an idea whose time has come.”

We are in the business of finding those ideas whose time has come, and then doing all we can to help them get there.