Injury

Stories that caught our eye: Spinal cord injury trial milestone, iPS for early cancer diagnosis, and storing videos in DNA

/ Todd Dubnicoff / Leave a comment

Spinal cord injury clinical trial hits another milestone (Kevin McCormack)
We began the week with good news about our CIRM-funded clinical trial with Asterias for spinal cord injury, and so it’s nice to end the week with more good news from that same trial. On Wednesday, Asterias announced it had completed enrolling and dosing patients in their AIS-B 10 million cell group.

asterias

People with AIS-B spinal cord injuries have some level of sensation and feeling but very little, if any, movement below the site of injury site. So for example, spinal cord injuries at the neck, would lead to very limited movement in their arms and hands. As a result, they face a challenging life and may be dependent on help in performing most daily functions, from getting out of bed to eating.astopc1

In another branch of the Asterias trial, people with even more serious AIS-A injuries – in which no feeling or movement remains below the site of spinal cord injury – experienced improvements after being treated with Asterias’ AST-OPC1 stem cell therapy. In some cases the improvements were quite dramatic. We blogged about those here.

In a news release Dr. Ed Wirth, Asterias’ Chief Medical Officer, said they hope that the five people treated in the AIS-B portion of the trial will experience similar improvements as the AIS-A group.

“Completing enrollment and dosing of the first cohort of AIS-B patients marks another important milestone for our AST-OPC1 program. We have already reported meaningful improvements in arm, hand and finger function for AIS-A patients dosed with 10 million AST-OPC1 cells and we are looking forward to reporting initial efficacy and safety data for this cohort early in 2018.”

Asterias is already treating some AIS-A patients with 20 million cells and hopes to start enrolling AIS-B patients for the 20 million cell therapy later this summer.

Earlier diagnosis of pancreatic cancer using induced pluripotent stem cells Reprogramming adult cells to an embryonic stem cell-like state is as common in research laboratories as hammers and nails are on a construction site. But a research article in this week’s edition of Science Translational Medicine used this induced pluripotent stem cell (iPSC) toolbox in a way I had never read about before. And the results of the study may lead to earlier detection of pancreatic cancer, the fourth leading cause of cancer death in the U.S.

Zaret STM pancreatic cancer tissue July 17

A pancreatic ductal adenocarcinoma
Credit: The lab of Ken Zaret, Perelman School of Medicine, University of Pennsylvania

We’ve summarized countless iPSCs studies over the years. For example, skin or blood samples from people with Parkinson’s disease can be converted to iPSCs and then specialized into brain cells to provide a means to examine the disease in a lab dish. The starting material – the skin or blood sample – typically has no connection to the disease so for all intents and purposes, it’s a healthy cell. It’s only after specializing it into a nerve cell that the disease reveals itself.

But the current study by researchers at the University of Pennsylvania used late stage pancreatic cancer cells as their iPSC cell source. One of the reasons pancreatic cancer is thought to be so deadly is because it’s usually diagnosed very late when standard treatments are less effective. So, this team aimed to reprogram the cancer cells back into an earlier stage of the cancer to hopefully find proteins or molecules that could act as early warning signals, or biomarkers, of pancreatic cancer.

Their “early-stage-cancer-in-a-dish” model strategy was a success. The team identified a protein called thrombospodin-2 (THBS2) as a new candidate biomarker. As team lead, Dr. Ken Zaret, described in a press release, measuring blood levels of THBS2 along with a late-stage cancer biomarker called CA19-9 beat out current detection tests:

“Positive results for THBS2 or CA19-9 concentrations in the blood consistently and correctly identified all stages of the cancer. Notably, THBS2 concentrations combined with CA19-9 identified early stages better than any other known method.”

DNA: the ultimate film archive device?
This last story for the week isn’t directly related to stem cells but is too cool to ignore. For the first time ever, researchers at Harvard report in Nature that they have converted a video into a DNA sequence which was then inserted into bacteria. As Gina Kolata states in her New York Times article about the research, the study represents the ultimate data archive system which can “be retrieved at will and multiplied indefinitely as the host [bacteria] divides and grows.”

A video file is nothing but a collection of “1s” and “0s” of binary code which describe the makeup of each pixel in each frame of a movie. The researchers used the genetic code within DNA to describe each pixel in a short clip of one of the world’s first motion pictures: a galloping horse captured by Eadward Muybridge in 1878.

Horse_1080.gif

The resulting DNA sequence was then inserted into the chromosome of E.Coli., a common bacteria that lives in your intestines, using the CRISPR gene editing method. The video code was still retrievable after the bacteria was allowed to multiply.

The Harvard team envisions applications well beyond a mere biological hard drive. Dr. Seth Shipman, an author of the study, told Paul Rincon of BBC news that he thinks this cell system could be placed in various parts of the body to analyze cell function and “encode information about what’s going on in the cell and what’s going on in the cell environment by writing that information into their own genome”.

Perhaps then it could be used to monitor the real-time activity of stem cell therapies inside the body. For now, I’ll wait to hear about that in some upcoming science fiction film.

Nine months in, stem cell-based therapy for spinal cord injury continues to improve paralyzed patients’ lives

/ Todd Dubnicoff / 4 Comments

If you’ve been following the Stem Cellar blog this year, then you must be as encouraged as we are with Asterias Biotherapeutics’ CIRM-funded clinical trial, which is testing an embryonic stem cell-based therapy for spinal cord injury.

astopc1Over many months, we’ve covered the company’s string of positive announcements that their cell therapy product – called AST-OPC1 – appears safe, is doing what is it’s supposed to after injection into the damaged spinal cord, and shows signs of restoring upper body function at 3 and 6 months after treatment. We’ve also written about first-hand accounts from some of the clinical trial participants who describe their remarkable recoveries.

That streak of good news continues today with Asterias’ early morning press release. The announcement summarizes 9-month results for a group of six patients who received an injection of 10 million AST-OPC1 cells 2 to 4 weeks after their injury (this particular trial is not testing the therapy on those with less recent injuries). In a nut shell, their improvements in arm, hand and finger movement seen at the earlier time points have persisted and even gotten better at 9 months.

Two motors levels = a higher quality of life
These participants sustained severe spinal cord injuries in the neck, leading to a loss of feeling and movement in their body from the neck down. To quantify the results of the cell therapy, researchers refer to “motor levels” of improvement. These levels correspond to an increasing number of motor, or movement, abilities. For a spinal cord injury victim paralyzed from the neck down, recovering two motor levels of function can mean the difference between needing 24-hour a day home care versus dressing, feeding and bathing themselves. The impact of this level of improvement cannot be overstated. As mentioned in the press release, regaining these abilities, “can result in lower healthcare costs, significant improvements in quality of life, increased ability to engage in activities of daily living, and increased independence.”

asterias9mo_results

9-month follow-up results of Asterias’ spinal cord injury trial. Patients treated with stem cell-based therapy (green line) have greater movement recovery compared to historical data from 62 untreated patients (Blue dotted line). Image: Asterias Biotherapeutics.

With the new 9-month follow-up data, the clinical researchers have confirmed that 3 out of the 6 (50%) patients show two motor levels of improvement. This result is up from 2 of 6 patients at the earlier time points. And all six patients have at least one motor level of improvement up through 9 months post-treatment. Now, make no mistake, spontaneous recovery from spinal cord injuries does occur. But historical data collected from 62 untreated patients show that only 29% reached two motor levels of improvement after 12-months.

As you can imagine, the Asterias team is optimistic about these latest results. Here’s what Chief Medical Officer, Dr. Edward Wirth had to say:

Edward-Wirth

Edward Wirth
Photo: Asterias

“The new efficacy results show that previously reported meaningful improvements in arm, hand and finger function in the 10 million cell cohort treated with AST-OPC1 cells have been maintained and in some patients have been further enhanced even 9 months following dosing. We are increasingly encouraged by these continued positive results, which are remarkable compared with spontaneous recovery rates observed in a closely matched untreated patient population.”

Equally encouraging is the therapy’s steady safety profile with no serious adverse events reported through the 9-month follow up.

Looking ahead
Dr. Jane Lebkowski, Asterias’ President of R&D and Chief Scientific Officer, will be presenting these data today during the International Society for Stem Cell Research (ISSCR) 2017 Annual Meeting held in Boston. Asterias expects to share more results later this fall after all six patients complete their 12-month follow-up visit.

The clinical trial is also treating another group of patients with a maximum dose of 20 million cells. The hope is that this cohort will show even more effectiveness.

For the sake of the more than 17,000 people who are incapacitated by a severe spinal cord injury each year, let’s hope the streak of good news continues.

Could revving up stem cells help senior citizens heal as fast as high school seniors?

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All physicians, especially surgeons, sport medicine doctors, and military medical corps share a similar wish: to able to speed up the healing process for their patients’ incisions and injuries. Data published this week in Cell Reports may one day fulfill that wish. The study – reported by a Stanford University research team – pinpoints a single protein that revs up stem cells in the body, enabling them to repair tissue at a quicker rate.

Screen Shot 2017-04-19 at 5.37.38 PM

Muscle fibers (dark areas surrounding by green circles) are larger in mice injected with HGFA protein (right panel) compared to untreated mice (left panel), an indication of faster healing after muscle injury.
(Image: Cell Reports 19 (3) p. 479-486, fig 3C)

Most of the time, adult stem cells in the body keep to themselves and rarely divide. This calmness helps preserve this important, small pool of cells and avoids unnecessary mutations that may happen whenever DNA is copied during cell division.

To respond to injury, stem cells must be primed by dividing one time, which is a very slow process and can take several days. Once in this “alert” state, the stem cells are poised to start dividing much faster and help repair damaged tissue. The Stanford team, led by Dr. Thomas Rando, aimed to track down the signals that are responsible for this priming process with the hope of developing drugs that could help jump-start the healing process.

Super healing serum: it’s not just in video games
The team collected blood serum from mice two days after the animals had been subjected to a muscle injury (the mice were placed under anesthesia during the procedure and given pain medication afterwards). When that “injured” blood was injected into a different set of mice, their muscle stem cells became primed much faster than mice injected with “uninjured” blood.

“Clearly, blood from the injured animal contains a factor that alerts the stem cells,” said Rando in a press release. “We wanted to know, what is it in the blood that is doing this?”

 

A deeper examination of the priming process zeroed in on a muscle stem cell signal that is turned on by a protein in the blood called hepatocyte growth factor (HGF). So, it seemed likely that HGF was the protein that they had been looking for. But, to their surprise, there were no differences in the amount of HGF found in blood from injured and uninjured mice.

HGFA: the holy grail of healing?
It turns out, though, that HGF must first be chopped in two by an enzyme called HGFA to become active. When the team went back and examined the injured and uninjured blood, they found that it was HGFA which showed a difference: it was more active in the injured blood.

To show that HGFA was directly involved in stimulating tissue repair, the team injected mice with the enzyme two days before the muscle injury procedure. Twenty days post injury, the mice injected with HGFA had regenerated larger muscle fibers compared to untreated mice. Even more telling, nine days after the HGFA treatment, the mice had better recovery in terms of their wheel running activity compared to untreated mice.

To mimic tissue repair after a surgery incision, the team also looked at the impact of HGFA on skin wound healing. Like the muscle injury results, injecting animals with HGFA two days before creating a skin injury led to better wound healing compared to untreated mice. Even the hair that had been shaved at the surgical site grew back faster. First author Dr. Joseph Rodgers, now at USC, summed up the clinical implications of these results :

“Our research shows that by priming the body before an injury you can speed the process of tissue repair and recovery, similar to how a vaccine prepares the body to fight infection. We believe this could be a therapeutic approach to improve recovery in situations where injuries can be anticipated, such as surgery, combat or sports.”

Could we help senior citizens heal as fast as high school seniors?
Another application for this therapeutic approach may be for the elderly. Lots of things slow down when you get older including your body’s ability to heal itself. This observation sparks an intriguing question for Rando:

“Stem cell activity diminishes with advancing age, and older people heal more slowly and less effectively than younger people. Might it be possible to restore youthful healing by activating this [HGFA] pathway? We’d love to find out.”

I bet a lot of people would love for you to find out, too.

A horse, stem cells and an inspiring comeback story that may revolutionize tendon repair

/ Todd Dubnicoff / 2 Comments

Everyone loves a good comeback story. Probably because it leaves us feeling inspired and full of hope. But the comeback story about a horse named Dream Alliance may do more than that: his experience promises to help people with Achilles tendon injuries get fully healed and back on their feet more quickly.

Dream Alliance

Dream Alliance was bred and raised in a very poor Welsh town in the United Kingdom. One of the villagers had the dream of owning a thoroughbred racehorse. She convinced a group of her fellow townsfolk to pitch in $15 dollars a week to cover the costs of training the horse. Despite his lowly origins, Dream Alliance won his fourth race ever and his future looked bright. But during a race in 2008, one of his back hoofs cut a tendon in his front leg. The seemingly career-ending injury was so severe that the horse was nearly euthanized.

It works in horses, how about humans?
Instead, he received a novel stem cell procedure which healed the tendon and, incredibly, the thoroughbred went on to win the Welsh Grand National race 15 months later – one of the biggest races in the UK that is almost 4 miles long and involves jumping 22 fences. Researchers at the Royal Veterinary College in Liverpool developed the method and data gathered from the treatment of 1500 horses with this stem cell therapy show a 50% decrease in re-injury of the tendon.

It’s been so successful in horses that researchers at the University College of London and the Royal National Orthopaedic Hospital are currently running a clinical trial to test the procedure in humans.  Over the weekend, the Daily Mail ran a news story about the clinical trial. In it, team lead Andrew Goldberg explained how they got the human trial off the ground:

“Tendon injuries in horses are identical to those in humans, and using this evidence [from the 1500 treated horses] we were able to persuade the regulators to allow us to launch a small safety study in humans.”

Tendon repair: there’s got to be another way

Achilles tendon connects the calf muscle to the heel bone

The Achilles tendon is the largest tendon in the body and connects the calf muscle to the heel bone. It takes on a lot of strain during running and jumping so it’s a well-known injury to professional and recreational athletes but injuries also occur in those with a sedentary lifestyle. Altogether Achilles tendon injury occurs in about 5-10 people per 100,000. And about 25%-45% of those injuries require surgery which involves many months of crutches and it doesn’t always work. That’s why this stem cell approach is sorely needed.

The procedure is pretty straight forward as far as stem cell therapies go. Bone marrow from the patient’s hip is collected and mesenchymal stem cells – making up a small fraction of the marrow – are isolated. The stem cells are transferred to petri dishes and allowed to divide until there are several million cells. Then they are injected directly into the injured tendon.

A reason to be cautiously optimistic
Early results from the clinical trial are encouraging with a couple of the patients experiencing improvements. The Daily Mail article featured the clinical trial’s first patient who went from a very active lifestyle to one of excruciating ankle pain due to a gradually deteriorating Achilles tendon. Though hesitant when she first learned about the trial, the 46-year-old ultimately figured that the benefits outweighed the risk. That turned out to be a good decision:

“I worried, because no one had ever had it before, except a horse. But I was more worried I’d end up in a wheelchair. The difference now is amazing. I can do five miles on the treadmill without pain, and take my dog Honey on long walks again.”

The researchers aren’t exactly sure how the therapy works but mesenchymal stem cells are known to release factors that promote regeneration and reduce inflammation. The first patient’s positive results are just anecdotal at this point. The clinical trial is still recruiting volunteers so definitive results are still on the horizon. And even if that small trial is successful, larger clinical trials will be required to confirm effectiveness and safety. It will take time but without the careful gathering of this data, doctors and patients will remain in the dark about their chances for success with this stem cell treatment.

Hopefully the treatment proves to be successful and ushers in a golden era of comeback stories. Not just for star athletes eager to get back on the field but also for the average person whose career, good health and quality of life depends on their mobility.

Stem cell stories that caught our eye: healing diabetic ulcers, new spinal cord injury insights & an expanding CRISPR toolbox

/ Todd Dubnicoff / Leave a comment

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Stem cells heal diabetic foot ulcers in pilot study
Foot ulcers are one of the many long-term complications that diabetics face. About 15 percent of patients develop these open sores which typically appear at the bottom of the foot. In a quarter of these cases, the ulcers lead to serious infection requiring amputation.

diabetic-foot-ulcers

Diabetic foot ulcers are open sores that don’t heal and in many cases leads to amputation. Image source: Izunpharma

But help may be on the horizon in the form of stem cells. Researchers at Mansoura University in Egypt recently presented results of a small study in which 10 patients with diabetic foot ulcers received standard care and another 10 patients received standard care plus injections of mesenchymal stem cells that had been collected from each patient’s own bone marrow. After just six weeks, the stem cell treated group showed a 50% reduction in the foot ulcers while the group with only standard care had a mere 7% reduction.

These superior results with the stem cells were observed even though the group receiving the stem cells had larger foot ulcers to begin with compared to the untreated patients. There are many examples of mesenchymal stem cells’ healing power which make them an extremely popular cell source for hundreds of on-going clinical trials. Mesenchymal stem cells are known to reduce inflammation and increase blood vessel formation, two properties that may be at work to give diabetic foot ulcers the chance to get better.

Medscape Medical News reported on these results which were presented at the 2016 annual meeting of the European Association for the Study of Diabetes (EASD) 2016 Annual Meeting

Suppressing nerve signals to help spinal cord injury victims
Losing the use of one’s limbs is a profound life-altering change for spinal cord injury victims. But their quality of life also suffers tremendously from the loss of bladder control and chronic pain sensations. So much so, victims often say that just improving these secondary symptoms would make a huge improvement in their lives.

While current stem cell-based clinical trials, like the CIRM-funded Asterias study, aim to reverse paralysis by restoring loss nerve signals, recent CIRM-funded animal data published in Cell Stem Cell from UC San Francisco suggest that nerve cells that naturally suppress nerve signals may be helpful for these other symptoms of spinal cord injury.

mgecell-integrated.jpg

Mature inhibitory neuron derived from human embryonic stem cells is shown after successfully migrated and integrated into the injured mouse spinal cord.
Photo by Jiadong Chen, UCSF

It turns out that the bladder control loss and chronic pain may be due to overactive nerve signals. So the lab of Arnold Kriegstein transplanted inhibitory nerve cells – derived from human embryonic stem cells – into mice with spinal cord injuries. The scientists observed that these human inhibitory nerve cells, or interneurons, successfully made working connections in the damaged mouse spinal cords. The rewiring introduced by these interneurons also led to reduced pain behaviors in the mice as well as improvements in bladder control.

 

 

In a Yahoo Finance interview, Kreigstein told reporters he’s eager to push forward with these intriguing results:

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Arnold Kriegstein, UCSF

“As a clinician, I’m very aware of the urgency that’s felt among patients who are often very desperate for treatment. As a result, we’re very interested in accelerating this work toward clinical trials as soon as possible, but there are many steps along the way. We have to demonstrate that this is safe, as well as replicating it in other animals. This involves scaling up the production of these human interneurons in a way that would be compatible with a clinical product.”

 

Expanding the CRISPR toolbox
If science had a fashion week, the relatively new gene editing technology called CRISPR/Cas9 would be sure to dominate the runway. You can think of CRISPR/Cas9 as a protein and RNA complex that acts as a molecular scissor which directly targets and cuts specific sequences of DNA in the human genome. Scientists are using CRISPR/Cas9 to develop innovative biomedical techniques such as removing disease-causing mutations in stem cells in hopes of developing potential treatments for patients suffering from diseases that have no cures.

What’s particularly interesting about the CRISPR/Cas9 system is that the Cas9 protein responsible for cutting DNA is part of a family of CRISPR associated proteins (Cas) that have similar but slightly different functions. Scientists are currently expanding the CRISPR toolbox by exploring the functions of other CRISPR associated proteins for gene editing applications.

A CIRM-funded team at UC Berkeley is particularly interested in a CRISPR protein called C2c2, which is different from Cas9 in that it targets and cuts RNA rather than DNA. Led by Berkeley professor Jennifer Doudna, the team discovered that the CRISPR/C2c2 complex has not just one, but two, distinct ways that it cuts RNA. Their findings were published this week in the journal Nature.

The first way involves creation: C2c2 helps make the guide RNAs that are used to find the RNA molecules that it wants to cut. The second way involves destruction: after the CRISPR/C2c2 complex finds it’s RNAs of choice, C2c2 can then cut and destroy the RNAs.

Doudna commented on the potential applications for this newly added CRISPR tool in a Berkeley News release:

Jennifer-Doudna

Jennifer Doudna: Photo courtesy of iPSCell.com

“This study expands our molecular understanding of C2c2 to guide RNA processing and provides the first application of this novel RNase. C2c2 is essentially a self-arming sentinel that attacks all RNAs upon detecting its target. This activity can be harnessed as an auto-amplifying detector that may be useful as a low-cost diagnostic.”

 

Watch Spinal Cord Cells Take a Hike!

/ Karen Ring / 2 Comments

magic school busWhat exactly goes on inside the human body? If you asked this question to the children’s book character Ms. Frizzle, she would throw you into her Magic School Bus and take you on a wild ride “Inside the Human Body” to get you up close and personal with the different organs and structures within our bodies.

Ms. Frizzle had a wild imagination, but she was on to something with her crazy adventures. Recently, scientists took a page out of one of Ms. Frizzle children’s books and took their own wild ride to check out what’s going on with the human spinal cord.

In a paper published yesterday in Neuron, scientists from the Salk Institute in San Diego reported that they were able to watch spinal cord cells walk around the spine of mice in real-time. They used a special microscope that could track and record the movement of motor neurons, an important nerve cell that controls the movement of muscles in your body. What they found when they watched these cells was equivalent to a pot of gold at the end of the rainbow.

Check out their stunning movie here:

The scientists not only recorded the activity of these motor neurons, but they identified the other spinal cord cells that these neurons interact and make connections with. One of their most significant findings was a population of spinal cord cells that connected to a subtype of motor neurons to foster important muscle movements like walking.

Understanding how the different cells of the spinal cord work together is very important because it will allow scientists and doctors to figure out better ways to treat patients with spinal cord injuries or neurodegenerative diseases, like ALS, that affect motor neurons.

Senior author Samuel Pfaff commented in a press release on the importance of this study and how easy his team’s technology is to use:

Pfaff_S09

Samuel Pfaff

Using optical methods to be able to watch neuron activity has been a dream over the past decade. Now, it’s one of those rare times when the technology is actually coming together to show you things you hadn’t been able to see before. You don’t need to do any kind of post-image processing to interpret this. These are just raw signals you can see through the eyepiece of a microscope. It’s really a jaw-dropping kind of visualization for a neuroscientist.

While this study doesn’t provide a direct avenue for therapeutic development, it does pave the way for a better understanding of the normal, healthy processes that go on in the human spine. Having more knowledge of “what is right” will help scientists to develop better strategies to fix “what is wrong” in spinal cord injuries and diseases like ALS.

Related Links:

CIRM-funded clinical trial for spinal cord injury reports promising results

/ Karen Ring / 3 Comments

Today, the Menlo Park-based biotech company Asterias Biotherapeutics reported positive results from the first three patients treated in its Phase 1/2a clinical study using stem cell therapy to treat patients with spinal cord injury. This trial is funded by a CIRM Strategic Partnerships Award grant of $14.3 million.

asteriasAsterias has developed a stem cell therapy called AST-OPC1 that uses oligodendrocyte progenitor cells (OPCs), a kind of cell found in the nervous system, to treat patients that have suffered from different types of spinal cord injury. Damage to the spinal cord causes a range of paralysis based on where it occurs. People with spinal cord trauma to the mid-back often retain the use of their hands and arms but can no longer walk and may lose bladder function. Patients with spinal cord injuries in their neck  can be paralyzed completely from their neck down.

astopc1OPCs are precursors to an important cell type in the central nervous system called the oligodendrocyte. These cells are responsible for forming a conductive sheet around nerve cells that allows nerves to send electrical signals and messages safely from one nerve to another. Both OPCs and oligodendrocytes provide support and protection to nerves in the spinal cord and brain, and they can also facilitate repair of damaged nerves by secreting survival and growth factors as well as promoting the formation of new blood vessels.

In this first part of the Phase 1/2a clinical trial three patients with complete cervical (neck) spinal cord injuries were given a “low dose” of two million AST-OPC1 cells to test the safety and feasibility of their stem cell treatment. The first patient was treated at the Shepard Center in Atlanta,  and at the two month post-injection assessment, the patient experienced no side effects and an improvement from a complete to an incomplete injury on the ASIA impairment injury scale. The other two patients received injections at the Rush University Medical Center in Chicago. Both procedures were reported to have gone smoothly, and the patients are still being monitored.

Asterias plans to treat a second group of patients with higher doses of AST-OPC1 cells (10-20 millions cells). Chief Medical Officer Dr. Edward Wirth explained their strategy:

 The safety data in the first cohort now paves the way for testing the higher doses of AST-OPC1 (10-20 million cells) that we believe correspond most closely to the doses that showed the greatest efficacy in animal studies.

If both the low dose and high dose groups report no serious side effects, Asterias will turn to the Food and Drug Administration (FDA) for approval to expand the patient population of this clinical trial phase from 13 patients up to 40. Asterias hopes that adding more patients “will increase the statistical confidence of the safety and efficacy readouts, reduce the risks of the AST-OPC1 program and position the product for potential accelerated regulatory approvals.”

Spinal cord injury affects more than 12,000 people every year. It remains a major unmet medical need without any FDA-approved therapies or medical devices that improve or restore patient spinal cord function. CIRM is hopeful that Asterias will continue to see positive results with the SCiStar trial and will be able to progress its AST-OPC1 program into late-stage clinical trials and eventually into an FDA-approved stem cell therapy for spinal cord injury.

Related links

New Regenerative Liver Cells Identified

/ Karen Ring / Leave a comment

It’s common knowledge that your liver is a champion when it comes to regeneration. It’s actually one of the few internal organs in the human body that can robustly regenerate itself after injury. Other organs such as the heart and lungs do not have the same regenerative response and instead generate scar tissue to protect the injured area. Liver regeneration is very important to human health as the liver conducts many fundamental processes such as making proteins, breaking down toxic substances, and making new chemicals required to digest your food.

The human liver.

The human liver

Over the years, scientists have suggested multiple theories for why the liver has this amazing regenerative capacity. What’s known for sure is that mature hepatocytes (the main cell type in the liver) will respond to injury by dividing and proliferating to make more hepatocytes. In this way, the liver can regrow up to 70% of itself within a matter of a few weeks. Pretty amazing right?

So what is the source of these regenerative hepatocytes? It was originally thought that adult liver stem cells (called oval cells) were the source, but this theory has been disproved in the past few years. The answer to this million-dollar question, however, likely comes from a study published last week in the journal Cell.

Hybrid hepatocytes (shown in green) divide and regenerate the liver in response to injury. (Image source: Font-Burgada et al., 2015)

Hybrid hepatocytes (green) divide and regenerate the liver in response to injury. (Image source: Font-Burgada et al., 2015)

A group at UCSD led by Dr. Michael Karin reported a new population of liver cells called “hybrid hepatocytes”. These cells were discovered in an area of the healthy liver called the portal triad. Using mouse models, the CIRM-funded group found that hybrid hepatocytes respond to chemical-induced injury by massively dividing to replace damaged or lost liver tissue. When they took a closer look at these newly-identified cells, they found that hybrid hepatocytes were very similar to normal hepatocytes but differed slightly with respect to the types of liver genes that they expressed.

A common concern associated with regenerative tissue and cells is the development of cancer. Actively dividing cells in the liver can acquire genetic mutations that can cause hepatocellular carcinoma, a common form of liver cancer.

What makes this group’s discovery so exciting is that they found evidence that hybrid hepatocytes do not cause cancer in mice. They showed this by transplanting a population of hybrid hepatocytes into multiple mouse models of liver cancer. When they dissected the liver tumors from these mice, none of the transplanted hybrid cells were present. They concluded that hybrid hepatocytes are robust and efficient at regenerating the liver in response to injury, and that they are a safe and non-cancer causing source of regenerating liver cells.

Currently, liver transplantation is the only therapy for end-stage liver diseases (often caused by cirrhosis or hepatitis) and aggressive forms of liver cancer. Patients receiving liver transplants from donors have a good chance of survival, however donated livers are in short supply, and patients who actually get liver transplants have to take immunosuppressant drugs for the rest of their lives. Stem cell-derived liver tissue, either from embryonic or induced pluripotent stem cells (iPSC), has been proposed as an alternative source of transplantable liver tissue. However, safety of iPSC-derived tissue for clinical applications is still being addressed due to the potential risk of tumor formation caused by iPSCs that haven’t fully matured.

This study gives hope to the future of cell-based therapies for liver disease and avoids the current hurdles associated with iPSC-based therapy. In a press release from UCSD, Dr. Karin succinctly summarized the implications of their findings.

“Hybrid hepatocytes represent not only the most effective way to repair a diseased liver, but also the safest way to prevent fatal liver failure by cell transplantation.”

This exciting and potentially game-changing research was supported by CIRM funding. The first author, Dr. Joan Font-Burgada, was a CIRM postdoctoral scholar from 2012-2014. He reached out to CIRM regarding his publication and provided the following feedback:

CIRM Postdoctoral Fellow Jean Font-Burgada

CIRM postdoctoral scholar Joan Font-Burgada

“I’m excited to let you know that work CIRM funded through the training program will be published in Cell. I would like to express my most sincere gratitude for the opportunity I was given. I am convinced that without CIRM support, I could not have finished my project. Not only the training was excellent but the resources I was offered allowed me to work with enough independence to explore new avenues in my project that finally ended up in this publication.”

 

We at CIRM are always thrilled and proud to hear about these success stories. More importantly, we value feedback from our grantees on how our funding and training has supported their science and helped them achieve their goals. Our mission is to develop stem cell therapies for patients with unmet medical needs, and studies such as this one are an encouraging sign that we are making progress towards to achieving this goal.

Related links:

UCSD Press Release

CIRM Spotlight on Liver Disease Research

CIRM Spotlight on Living with Liver Disease

Building a Bridge to Therapies: Stem Cell-Derived Neurons Restore Feeling to Injured Limbs

/ Todd Dubnicoff / Leave a comment

It’s been a great week for spinal cord injury-related stem cell research – and it’s only Tuesday. In case you missed it, Asterias Biotherapeutics announced yesterday that they had treated their first clinical trial participant with an embryonic stem cell-based therapy for complete spinal cord injury. “Complete” refers to injuries that cause a total loss of feeling and movement below the site of injury.

Transplant human neurons (red) provide a bridge for the mice nerve fibers (green) to enter the spinal cord (spc). Image credit Hoeber et al. Scientific Reports

Transplanted human neurons (red) provide a bridge for the mice nerve fibers (green) to enter the spinal cord surface (spc). Image credit: Hoeber et al. Scientific Reports 5:10666

In another study also reported yesterday in Nature’s Scientific Reports, researchers at Uppsala University in Sweden made significant progress toward understanding and treating a related but different sort of injury that disrupts nerve signals coming into and out of the spinal cord. These so-called avulsion injuries are frequently seen after traffic, particularly motorcycle, accidents and lead to paralysis, loss of sensation, and chronic pain in the affected limbs. Although the ruptured nerve fibers from the limbs have the ability to extend back toward the spinal cord, inflammation from the site of injury makes the spinal cord impenetrable and blocks any restoration of normal sensory function.

To explore the potential of overcoming this spinal cord barrier, the research team transplanted human embryonic stem cell-derived neurons into mice mimicking human avulsion injury. Five months after the transplant, growth of nerve fibers into the spinal cord was seen. But these nerve fibers that had reconnected with the spinal cord were host animal cells and not the transplanted human stem cell-derived neurons. It turns out the human neuron fibers provide a physical bridge permitting the mouse nerve fibers to extend into the spinal cord. The human neurons also encourage this regrowth by releasing proteins that reduce the scar left by the injury and promote nerve fiber growth. The reconnected nerve fibers is an exciting result but did it have any impact on the animals? The answer is yes. Using standard behavior tests the team found that injured mice with the transplanted neurons had more sensitivity to touch stimulation and greater grip strength compared to untreated injured mice.

Because stem cells have the ability for unlimited growth, any future therapy based on these findings must shown that the transplant doesn’t lead to excessive cell growth. In an encouraging sign, no tumor formation or extreme growth of human neurons in the animals were observed.

Molecular Trick Diminishes Appearance of Scars, Stanford Study Finds

/ cirmweb / Leave a comment

Every scar tells a story, but that story may soon be coming to a close, as new research from Stanford University reveals clues to why scars form—and offers clues on how scarring could become a thing of the past.

Reported last week in the journal Science, the research team pinpointed the type of skin cell responsible for scarring and, importantly, also identified a molecule that, when activated, can actually prevent the skin cells from forming a scar. As one of the study’s senior authors Michael Longaker explained in a press release, the biomedical burden of scarring is vast.

Scars, both internal and external, present a significant biomedical burden.

Scars, both internal and external, present a significant biomedical burden.

“About 80 million incisions a year in this country heal with a scar, and that’s just on the skin alone,” said Longaker, who also co-directs Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. “Internal scarring is responsible for many medical conditions, including liver cirrhosis, pulmonary fibrosis, intestinal adhesions and even the damage left behind after a heart attack.”

Scars are normally formed when a type of skin cell called a fibroblast secretes a protein called collagen at the injury site. Collagen acts like a biological Band-Aid that supports and stabilizes the damaged skin.

In this study, which was funded in part by a grant from CIRM, Longaker, along with co-first authors Yuval Rinkevich and Graham Walmsley, as well as co-senior author and Institute Director Irving Weissman, focused their efforts on a type of fibroblast that appeared to play a role in the earliest stages of wound healing.

This type of fibroblast stands out because it secretes a particular protein called engrailed, which initial experiments revealed was responsible for laying down layers of collagen during healing. In laboratory experiments in mouse embryos, the researchers labeled these so-called ‘engrailed-positive fibroblast cells,’ or EPF cells, with a green fluorescent dye. This helped the team track how the cells behaved as the mouse embryo developed.

Interestingly, these cells were also engineered to self-destruct—activated with the application of diphtheria toxin—so the team could monitor what would happen in the absence of EPF cells entirely.

Their results revealed strong evidence that EPF cells were critical for scar formation. The scarring process was so tied to these EPF cells that when the team administered the toxin to shut them down, scarring reduced significantly.

Six days later the team found continued differences between mice with deactivated EPF cells, and a group of controls. Indeed, the experimental group had repaired skin that more closely resembled uninjured skin, rather than the distinctive scarring pattern that normally occurs.

Further examination of EPF cells’ precise function revealed a protein called CD26 and that blocking EPF’s production of CD26 had the same effect as shutting off EPF cells entirely. Wounds treated with a CD26 inhibitor had scars that covered only 5% of the original injury site, as opposed to 30%.

Pharmaceutical companies Merck and Novartis have already manufactured two types of CD26 inhibitor, originally developed to treat Type II diabetes, which could be modified to block CD26 production during wound healing—a prospect that the research team is examining more closely.