Positively good news from Asterias for CIRM-funded stem cell clinical trial for spinal cord injury

AsteriasWhenever I give a talk on stem cells one of the questions I invariably get asked is “how do you know the cells are going where you want them to and doing what you want them to?”

The answer is pretty simple: you look. That’s what Asterias Biotherapeutics did in their clinical trial to treat people with spinal cord injuries. They used magnetic resonance imaging (MRI) scans to see what was happening at the injury site; and what they saw was very encouraging.

Asterias is transplanting what they call AST-OPC1 cells into patients who have suffered recent injuries that have left them paralyzed from the neck down.  AST-OPC1 are oligodendrocyte progenitor cells, which develop into cells that support and protect nerve cells in the central nervous system, the area damaged in spinal cord injury. It’s hoped the treatment will restore connections at the injury site, allowing patients to regain some movement and feeling.

Taking a closer look

Early results suggest the therapy is doing just that, and now follow-up studies, using MRIs, are adding weight to those findings.

The MRIs – taken six months after treatment – show that the five patients given a dose of 10 million AST-OPC1 cells had no evidence of lesion cavities in their spines. That’s important because often, after a spinal cord injury, the injury site expands and forms a cavity, caused by the death of nerve and support cells in the spine, that results in permanent loss of movement and function below the site, and additional neurological damage to the patient.

Another group of patients, treated in an earlier phase of the clinical trial, showed no signs of lesion cavities 12 months after their treatment.

Positively encouraging

In a news release, Dr. Edward Wirth, the Chief Medical Officer at Asterias, says this is very positive:

“These new follow-up results based on MRI scans are very encouraging, and strongly suggest that AST-OPC1 cells have engrafted in these patients post-implantation and have the potential to prevent lesion cavity formation, possibly reducing long-term spinal cord tissue deterioration after spinal cord injury.”

Because the safety data is also encouraging Asterias is now doubling the dose of cells that will be transplanted into patients to 20 million, in a separate arm of the trial. They are hopeful this dose will be even more effective in helping restore movement and function in patients.

We can’t wait to see what they find.

Scientists make stem cell-derived nerve cells damaged in spinal cord injury

The human spinal cord is an information highway that relays movement-related instructions from the brain to the rest of the body and sensory information from the body back to the brain. What keeps this highway flowing is a long tube of nerve cells and support cells bundled together within the spine.

When the spinal cord is injured, the nerve cells are damaged and can die – cutting off the flow of information to and from the brain. As a result, patients experience partial or complete paralysis and loss of sensation depending on the extent of their injury.

Unlike lizards which can grow back lost tails, the spinal cord cannot robustly regenerate damaged nerve cells and recreate lost connections. Because of this, scientists are looking to stem cells for potential solutions that can rebuild injured spines.

Making spinal nerve cells from stem cells

Yesterday, scientists from the Gladstone Institutes reported that they used human pluripotent stem cells to create a type of nerve cell that’s damaged in spinal cord injury. Their findings offer a new potential stem cell-based strategy for restoring movement in patients with spinal cord injury. The study was led by Gladstone Senior Investigator Dr. Todd McDevitt, a CIRM Research Leadership awardee, and was published in the journal Proceedings of the National Academy of Sciences.

The type of nerve cell they generated is called a spinal interneuron. These are specialized nerve cells in the spinal cord that act as middlemen – transporting signals between sensory neurons that connect to the brain to the movement-related, or motor, neurons that connect to muscles. Different types of interneurons exist in the brain and spinal cord, but the Gladstone team specifically created V2a interneurons, which are important for controlling movement.

V2a interneurons extend long distances in the spinal cord. Injuries to the spine can damage these important cells, severing the connection between the brain and the body. In a Gladstone news release, Todd McDevitt explained why his lab is particularly interested in making these cells to treat spinal cord injury.

Todd McDevitt, Gladstone Institutes

“Interneurons can reroute after spinal cord injuries, which makes them a promising therapeutic target. Our goal is to rewire the impaired circuitry by replacing damaged interneurons to create new pathways for signal transmission around the site of the injury.”

 

Transplanting nerve cells into the spines of mice

After creating V2a interneurons from human stem cells using a cocktail of chemicals in the lab, the team tested whether these interneurons could be successfully transplanted into the spinal cords of normal mice. Not only did the interneurons survive, they also set up shop by making connections with other nerve cells in the spinal cord. The mice that received the transplanted cells didn’t show differences in their movement suggesting that the transplanted cells don’t cause abnormalities in motor function.

Co-author on the paper, Dylan McCreedy, described how the transplanted stem cell-derived cells behaved like developing V2a interneurons in the spine.

“We were very encouraged to see that the transplanted cells sprouted long distances in both directions—a key characteristic of V2a interneurons—and that they started to connect with the relevant host neurons.”

Todd McDevitt (right), Jessica Butts (center) and Dylan McCreedy (left) created a special type of neuron from human stem cells that could potentially repair spinal cord injuries. (Photo: Chris Goodfellow, Gladstone)

A new clinical strategy?

Looking forward, the Gladstone team plans to test whether these V2a interneurons can improve movement in mice with spinal cord injury. If results look promising in mice, this strategy of transplanting V2a interneurons could be translated into human clinic trials although much more time and research are needed to get there.

Trials testing stem cell-based treatments for spinal cord injury are already ongoing. Many of them involve transplanting progenitor cells that develop into the different types of cells in the spine, including nerve and support cells. These progenitor cells are also thought to secrete important growth factors that help regenerate damaged tissue in the spine.

CIRM is funding one such clinical trial sponsored by Asterias Biotherapeutics. The company is transplanting oligodendrocyte progenitor cells (which make nerve support cells called oligodendrocytes) into patients with severe spinal cord injuries in their neck. The trial has reported encouraging preliminary results in all six patients that received a dose of 10 million cells. You can read more about this trial here.

What the Gladstone study offers is a different stem cell-based strategy for treating spinal cord injury – one that produces a specific type of spinal nerve cell that can reestablish important connections in the spinal cord essential for movement.

For more on this study, watch the Gladstone’s video abstract “Discovery Offers New Hope to Repair Spinal Cord.


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Good news from Asterias’ CIRM-funded spinal cord injury trial

This week in the stem cell field, all eyes are on Asterias Biotherapeutics, a California-based company that’s testing a stem cell based-therapy in a CIRM-funded clinical trial for spinal cord injury patients. The company launched its Phase 1/2a clinical trial back in 2014 with the goal of determining the safety of the therapy and the optimal dose of AST-OPC1 cells to transplant into patients.

astopc1AST-OPC1 cells are oligodendrocyte progenitor cells derived from embryonic stem cells. These are cells located in the brain and spinal cord that develop into support cells that help nerve cells function and communicate with each other.

Asterias is transplanting AST-OPC1 cells into patients that have recently suffered from severe spinal cord injuries in their neck. This type of injury leaves patients paralyzed without any feeling from their neck down. By transplanting cells that can help the nerve cells at the injury site reform their connections, Asterias hopes that their treatment will allow patients to regain some form of movement and feeling.

And it seems that their hope is turning into reality. Yesterday, Asterias reported in a news release that five patients who received a dose of 10 million cells showed improvements in their ability to move after six months after their treatment. All five patients improved one level on the motor function scale, while one patient improved by two levels. A total of six patients received the 10 million cell dose, but so far only five of them have completed the six-month follow-up study, three of which have completed the nine-month follow-up study.

We’ve profiled two of these six patients previously on the Stem Cellar. Kris Boesen was the first patient treated with 10 million cells and has experienced the most improvement. He has regained the use of his hands and arms and can now feed himself and lift weights. Local high school student, Jake Javier, was the fifth patient in this part of the trial, and you can read about his story here.

Kris Boesen, CIRM spinal cord injury clinical trial patient.

Kris Boesen, CIRM spinal cord injury clinical trial patient.

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Jake Javier and his Mom

The lead investigator on this trial, Dr. Richard Fessler, explained the remarkable progress that these patients have made since their treatment:

“With these patients, we are seeing what we believe are meaningful improvements in their ability to use their arms, hands and fingers at six months and nine months following AST-OPC1 administration. Recovery of upper extremity motor function is critically important to patients with complete cervical spinal cord injuries, since this can dramatically improve quality of life and their ability to live independently.”

Asterias will continue to monitor these patients for changes or improvements in movement and will give an update when these patients have passed the 12-month mark since their transplant. However, these encouraging preliminary results have prompted the company to look ahead towards advancing their treatment down the regulatory approval pathway, out of clinical trials and into patients.

Asterias CEO, Steve Cartt, commented,

Steve Cartt, CEO of Asterias Biotherapeutics

Steve Cartt, CEO of Asterias Biotherapeutics

“These results to date are quite encouraging, and we look forward to initiating discussions with the FDA in mid-2017 to begin to determine the most appropriate clinical and regulatory path forward for this innovative therapy.”

 

Talking with the US FDA will likely mean that Asterias will need to show further proof that their stem cell-based therapy actually improves movement in patients, rather than the patients spontaneously regaining movement (which has been observed in patients before). FierceBiotech made this point in a piece they published yesterday on this trial.

“Those discussions with FDA could lead to a more rigorous examination of the effect of AST-OPC1. Some patients with spinal injury experience spontaneous recovery. Asterias has put together matched historical data it claims show “a meaningful difference in the motor function recovery seen to date in patients treated with the 10 million cell dose of AST-OPC1.” But the jury will remain out until Asterias pushes ahead with plans to run a randomized controlled trial.”

In the meantime, Asterias is testing a higher dose of 20 million AST-OPC1 cells in a separate group of spinal cord injury patients. They believe this number is the optimal dose of cells for achieving the highest motor improvement in patients.

2017 will bring more results and hopefully more good news about Asterias’ clinical trial for spinal cord injury. And as always, we’ll keep you informed with any updates on our Stem Cellar Blog.

Avalanches of exciting new stem cell research at the Keystone Symposia near Lake Tahoe

From January 8th to 13th, nearly 300 scientists and trainees from around the world ascended the mountains near Lake Tahoe to attend the joint Keystone Symposia on Neurogenesis and Stem Cells at the Resort at Squaw Creek. With record-high snowfall in the area (almost five feet!), attendees had to stay inside to stay warm and dry, and even when we lost power on the third day on the mountain there was no shortage of great science to keep us entertained.

Boy did it snow at the Keystone Conference in Tahoe!

Boy did it snow at the Keystone Conference in Tahoe!

One of the great sessions at the meeting was a workshop chaired by CIRM’s Senior Science Officer, Dr. Kent Fitzgerald, called, “Bridging and Understanding of Basic Science to Enable/Predict Clinical Outcome.” This workshop featured updates from the scientists in charge of three labs currently conducting clinical trials funded and supported by CIRM.

Regenerating injured connections in the spinal cord with neural stem cells

Mark Tuszynski, UCSD

Mark Tuszynski, UCSD

The first was a stunning talk by Dr. Mark from UCSD who is investigating how neural stem cells can help outcomes for those with spinal cord injury. The spinal cord contains nerves that connect your brain to the rest of your body so you can sense and move around in your environment, but in cases of severe injury, these connections are cut and the signal is lost. The most severe of these injuries is a complete transection, which is when all connections have been cut at a given spot, meaning no signal can pass through, just like how no cars could get through if a section of the Golden Gate Bridge was missing. His lab works in animal models of complete spinal cord transections since it is the most challenging to repair.

As Dr. Tuszynski put it, “the adult central nervous system does not spontaneously regenerate [after injury], which is surprising given that it does have its own set of stem cells present throughout.” Their approach to tackle this problem is to put in new stem cells with special growth factors and supportive components to let this process occur.

Just as most patients wouldn’t be able to come in for treatment right away after injury, they don’t start their tests until two weeks after the injury. After that, they inject neural stem cells from either the mouse, rat, or human spinal cord at the injury site and then wait a bit to see if any new connections form. Their group has shown very dramatic increases in both the number of new connections that regenerate from the injury site and extend much further than previous efforts have shown. These connections conduct electrochemical messages as normal neurons do, and over a year later they see no functional decline or tumors forming, which is often a concern when transplanting stem cells that normally like to divide a lot.

While very exciting, he cautions, “this research shows a major opportunity in neural repair that deserves proper study and the best clinical chance to succeed”. He says it requires thorough testing in multiple animal models before going into humans to avoid a case where “a clinical trial fails, not because the biology is wrong, but because the methods need tweaking.”

Everyone needs support – even dying cells

The second great talk was by Dr. Clive Svendsen of Cedars-Sinai Regenerative Medicine Institute on how stem cells might help provide healthy support cells to rescue dying neurons in the brains of patients with neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS) and Parkinson’s. Some ALS cases are hereditary and would be candidates for a treatment using gene editing techniques. However, around 90 percent of ALS cases are “sporadic” meaning there is no known genetic cause. Dr. Svendsen explained how in these cases, a stem cell-based approach to at least fix the cellular cause of the disease, would be the best option.

While neurons often capture all the attention in the brain, since they are the cells that actually send messages that underlie our thoughts and behaviors, the Svendsen lab spends a great deal of time thinking about another type of cell that they think will be a powerhouse in the clinic: astrocytes. Astrocytes are often labeled as the support cells of the brain as they are crucial for maintaining a balance of chemicals to keep neurons healthy and functioning. So Dr. Svendsen reasoned that perhaps astrocytes might unlock a new route to treating neurodegenerative diseases where neurons are unhealthy and losing function.

ALS is a devastating disease that starts with early muscle twitches and leads to complete paralysis and death usually within four years, due to the rapid degeneration of motor neurons that are important for movement all over the body. Svendsen’s team found that by getting astrocytes to secrete a special growth factor, called “GDNF”, they could improve the survival of the neurons that normally die in their model of ALS by five to six times.

After testing this out in several animal models, the first FDA-approved trial to test whether astrocytes from fetal tissue can slow spinal motor neuron loss will begin next month! They will be injecting the precursor cells that can make these GDNF-releasing astrocytes into one leg of ALS patients. That way they can compare leg function and track whether the cells and GDNF are enough to slow the disease progression.

Dr. Svendsen shared with us how long it takes to create and test a treatment that is committed to safety and success for its patients. He says,

Clive Svendsen has been on a 15-year quest to develop an ALS therapy

Clive Svendsen 

“We filed in March 2016, submitted the improvements Oct 2016, and we’re starting our first patient in Feb 2017. [One document is over] 4500 pages… to go to the clinic is a lot of work. Without CIRM’s funding and support we wouldn’t have been able to do this. This isn’t easy. But it is doable!”

 

Improving outcomes in long-term stroke patients in unknown ways

Gary Steinberg

Gary Steinberg

The last speaker for the workshop, Dr. Gary Steinberg, a neurosurgeon at Stanford who is looking to change the lives of patients with severe limitations after having a stroke. The deficits seen after a stroke are thought to be caused by the death of neurons around the area where the stroke occurred, such that whatever functions they were involved with is now impaired. Outcomes can vary for stroke patients depending on how long it takes for them to get to the emergency department, and some people think that there might be a sweet spot for when to start rehabilitative treatments — too late and you might never see dramatic recovery.

But Dr. Steinberg has some evidence that might make those people change their mind. He thinks, “these circuits are not irreversibly damaged. We thought they were but they aren’t… we just need to continue figuring out how to resurrect them.”

He showed stunning videos from his Phase 1/2a clinical trial of several patients who had suffered from a stroke years before walking into his clinic. He tested patients before treatment and showed us videos of their difficulty to perform very basic movements like touching their nose or raising their legs. After carefully injecting into the brain some stem cells taken from donors and then modified to boost their ability to repair damage, he saw a dramatic recovery in some patients as quickly as one day later. A patient who couldn’t lift her leg was holding it up for five whole seconds. She could also touch her arm to her nose, whereas before all she could do was wiggle her thumb. One year later she is even walking, albeit slowly.

He shared another case of a 39 year-old patient who suffered a stroke didn’t want to get married because she felt she’d be embarrassed walking down the aisle, not to mention she couldn’t move her arm. After Dr. Steinberg’s trial, she was able to raise her arm above her head and walk more smoothly, and now, four years later, she is married and recently gave birth to a boy.

But while these studies are incredibly promising, especially for any stroke victims, Dr. Steinberg himself still is not sure exactly how this stem cell treatment works, and the dramatic improvements are not always consistent. He will be continuing his clinical trial to try to better understand what is going on in the injured and recovering brain so he can deliver better care to more patients in the future.

The road to safe and effective therapies using stem cells is long but promising

These were just three of many excellent presentations at the conference, and while these talks involved moving science into human patients for clinical trials, the work described truly stands on the shoulders of all the other research shared at conferences, both present and past. In fact, the reason why scientists gather at conferences is to give one another feedback and to learn from each other to better their own work.

Some of the other exciting talks that are surely laying down the framework for future clinical trials involved research on modeling mini-brains in a dish (so-called cerebral organoids). Researchers like Jürgen Knoblich at the Institute of Molecular Biotechnology in Austria talked about the new ways we can engineer these mini-brains to be more consistent and representative of the real brain. We also heard from really fundamental biology studies trying to understand how one type of cell becomes one vs. another type using the model organism C. elegans (a microscopic, transparent worm) by Dr. Oliver Hobert of Columbia University. Dr. Austin Smith, from the University of Cambridge in the UK, shared the latest about the biology of pluripotent cells that can make any cell type, and Stanford’s Dr. Marius Wernig, one of the meeting’s organizers, told us more of what he’s learned about the road to reprogramming an ordinary skin cell directly into a neuron.

Stay up to date with the latest research on stem cells by continuing to follow this blog and if you’re reading this because you’re considering a stem cell treatment, make sure you find out what’s possible and learn about what to ask by checking out closerlookatstemcells.org.


Samantha Yammine

Samantha Yammine

Samantha Yammine is a science communicator and a PhD candidate in Dr. Derek van der Kooy’s lab at the University of Toronto. You can learn more about Sam and her research on her website.

First spinal cord injury trial patient gets maximum stem cell dose

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Kris Boesen, CIRM spinal cord injury clinical trial patient.

There comes a pivotal point in every experiment where you say “ok, now we are going to see if this really works.” We may be at that point in the clinical trial we are funding to see if stem cells can help people with spinal cord injuries.

Today Asterias Biotherapeutics announced they have given the first patient in the clinical trial the highest dose of 20 million cells. The therapy was administered at Santa Clara Valley Medical Center (SCVMC) in San Jose, California where Jake Javier – a young man who was treated at an earlier stage of the trial – was treated. You can read Jake’s story here.

The goal of the trial is to test the safety of transplanting three escalating doses of AST-OPC1 cells. These are a form of cell called oligodendrocyte progenitors, which are capable of becoming several different kinds of nerve cells, some of which play a supporting role and help protect nerve cells in the central nervous system – the area damaged in spinal cord injury.

In a news release, Dr. Edward Wirth, Asterias’ Chief Medical Officer, says this could be a crucial phase in the trial:

“We have been very encouraged by the early clinical efficacy and safety data for AST-OPC1, and we now look forward to evaluating the 20 million cell dose in complete cervical spinal cord injury patients. Based on extensive pre-clinical research, this is in the dosing range where we would expect to see optimal clinical improvement in these patients.”

To be eligible, individuals have to have experienced a severe neck injury in the last 30 days, one that has left them with no sensation or movement below the level of their injury, and that means they have typically lost all lower limb function and most hand and arm function.

In the first phase individuals were given 2 million cells. This was primarily to make sure that this approach was safe and wouldn’t cause any problems for the patients. The second phase boosted that dose to ten million cells. That was thought to be about half the therapeutic dose but it seemed to help all those enrolled. By 90 days after the transplant all five patients treated with ten million cells had shown some level of recovery of at least one motor level, meaning they had regained some use of their arms and/or hands on at least one side of their body. Two of the patients experienced an improvement of two motor levels. Perhaps the most impressive was Kris Boesen, who regained movement and strength in both his arms and hands. He says he is even experiencing some movement in his legs.

All this is, of course, tremendously encouraging, but we also have to sound a note of caution. Sometimes individuals experience spontaneous recovery after an accident like this. The fact that all five patients in the 10 million cell group did well suggests that this may be more than just a coincidence. That’s why this next group, the 20 million cell cohort, is so important.

As Steve McKenna, Chief of the Trauma Center at SCVMC, says; if we are truly going to see an improvement in people’s condition because of the stem cell transplant, this is when we would expect to see it:

“The early efficacy results presented in September from the 10 million cell AIS-A cohort were quite encouraging, and we’re looking forward to seeing if those meaningful functional improvements are maintained through six months and beyond. We are also looking forward to seeing the results in patients from the higher 20 million cell AST-OPC1 dose, as well as results in the first AIS-B patients.”

For more information about the Asterias clinical trial, including locations and eligibility requirements, go here: www.clinicaltrials.gov, using Identifier NCT02302157, and at the SCiStar Study Website (www.SCiStar-study.com).

We can never talk about this clinical trial without paying tribute to a tremendous patient advocate and a great champion of stem cell research, Roman Reed. He’s the driving force behind the Roman Reed Spinal Cord Injury Research Act  which helped fund the pioneering research of Dr. Hans Keirstead that laid the groundwork for this clinical trial.

 

 

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

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.

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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:

3e3a4-kriegsteinsmall

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.”

 

Full Steam Ahead: First Patient is Dosed in Expanded CIRM Spinal Cord Injury Trial

Today we bring you more good news about a CIRM-funded clinical trial for spinal cord injury that’s received a lot of attention lately in the news. Asterias Biotherapeutics has treated its first patient in an expanded patient population of spinal cord injury patients who suffer from cervical, or neck, injuries.

In late August, Asterias reported that they had passed the first hurdle in their Phase 1/2a trial and showed that their stem cell therapy is safe to use in patients with a more serious form of cervical spinal cord injuries.

Earlier this month, we received more exciting updates from Asterias – this time reporting that the their embryonic stem cell-based therapy, called AST-OPC1, appeared to benefit treated patients. Five patients with severe spinal cord injuries to their neck were dosed, or transplanted, with 10 million cells. These patients are classified as AIS-A on the ASIA impairment scale – meaning they have complete injuries in which the spinal cord tissue is severed and patients lose all feeling and use of their limbs below the injury site. Amazingly, after three months, all five of the AIS-A patients have seen improvements in their movement.

Today, Asterias announced that it has treated its first patient with an AIS-B grade cervical spinal cord injury with a dose of 10 million cells at the Sheperd Center in Atlanta. AIS-B patients have incomplete neck injuries, meaning that they still have some spinal cord tissue at the injury site, some feeling in their arms and legs, but no movement. This type of spinal cord injury is still severe, but these patients have a better chance at gaining back some of their function and movement after treatment.

In a press release by Asterias, Chief Medical Officer Dr. Edward Wirth said:

“We have been very encouraged by the first look at the early efficacy data, as well as the safety profile, for AST-OPC1 in AIS-A patients, and now look forward to also evaluating efficacy and safety in AIS-B patients. AIS-B patients also have severe spinal cord injuries, but compared to AIS-A patients they have more spared tissue in their spinal cords.  This may allow these patients to have a greater chance of meaningful functional improvement after being treated with AST-OPC1 cells.”

Dr. Donald Peck Leslie, who directs the Sheperd Center and is the lead investigator at the Atlanta clinical trial site, expressed his excitement about the trials’ progress.

“As someone who regularly treats patients who have sustained paralyzing spinal cord injuries, I am encouraged by the progress we’ve seen in evaluations of AST-OPC1 in people with AIS-A injuries, particularly the improvements in hand, finger and arm function. Now, I am looking forward to continuing the evaluation of this promising new treatment in AIS-B patients, as well.”

Asterias has plans to enroll a total of five to eight AIS-B patients who will receive a dose of 10 million cells. They will continue to monitor all patients in this trial (both AIS-A and B) and will conduct long-term follow up studies to make sure that the AST-OPC1 treatment remains safe.

We hope that the brave patients who have participated in the Asterias trial continue to show improvements following treatment. Inspiring stories like that of Kris Boesen, who was the first AIS-A patient to get 10 million cells in the Asterias trial and now has regained the use of his arms and hands (and regaining some sensation in his legs), are the reason why CIRM exists and why we are working so hard to fund promising clinical trials. If we can develop even one stem cell therapy that gives patients back their life, then our efforts here at CIRM will be worthwhile.

Kris Boesen, CIRM spinal cord injury clinical trial patient.

Kris Boesen, CIRM spinal cord injury clinical trial patient.


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Asterias’ stem cell clinical trial shows encouraging results for spinal cord injury patients

jake and family

Jake Javier; Asterias spinal cord injury clinical trial participant

When researchers are carrying out a clinical trial they have two goals: first, show that it is safe (the old “do no harm” maxim) and second, show it works. One without the other doesn’t do anyone any good in the long run.

A few weeks ago Asterias Biotherapeutics showed that their CIRM-funded stem cell therapy for spinal cord injuries appeared to be safe. Now their data suggests it’s working. And that is a pretty exciting combination.

Asterias announced the news at the annual scientific meeting of the International Spinal Cord Society in Vienna, Austria. These results cover five people who got a transplant of 10 million cells. While the language is muted, the implications are very encouraging:

“While early in the study, with only 4 of the 5 patients in the cohort having reached 90 days after dosing, all patients have shown at least one motor level of improvement so far and the efficacy target of 2 of 5 patients in the cohort achieving two motor levels of improvement on at least one side of their body has already been achieved.”

What does that mean for the people treated? A lot. Remember these are people who qualified for this clinical trial because of an injury that left them pretty much paralyzed from the chest down. Seeing an improvement of two motor levels means they are regaining some use of their arms, hands and fingers, and that means they are regaining the ability to do things like feeding, dressing and bathing themselves. In effect, it is not only improving their quality of life but it is also giving them a chance to lead an independent life.

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Kris Boesen, Asterias clinical trial participant

One of those patients is Kris Boesen who regained the use of his arms and hands after becoming the first patient in this trial to get a transplant of 10 million cells. We blogged about Kris here

Asterias says of the 5 patients who got 10 million cells, 4 are now 90 days out from their transplant. Of those:

  • All four have improved one motor level on at least one side
  • 2 patients have improved two motor levels on one side
  • One has improved two motor levels on both sides

What’s also encouraging is that none of the people treated experienced any serious side effects or adverse events from the transplant or the temporary use of immunosuppressive drugs.

Steve Cartt, CEO of Asterias, was understandably happy with the news and that it allows them to move to the next phase:

“We are quite encouraged by this first look at efficacy results and look forward to reporting six-month efficacy data as planned in January 2017.  We have also just recently been cleared to begin enrolling a new cohort and administering to these new patients a much higher dose of 20 million cells.  We look forward to begin evaluating efficacy results in this higher-dose cohort in the coming months as well.”

People with spinal cord injuries can regain some function spontaneously so no one is yet leaping to the conclusion that all the progress in this trial is due to the stem cells. But to see all of the patients in the 10 million stem cell group do well is at the very least a positive sign. Now the hope is that these folks will continue to do well, and that the next group of people who get a 20 million cell transplant will also see improvements.

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Roman Reed, spinal cord injury patient advocate

While the team at Asterias were being cautiously optimistic, Roman Reed, whose foundation helped fund the early research that led to this clinical trial, was much less subdued in his response. He was positively giddy:

“If one patient only improves out of the five, it can be an outlier, but with everyone improving out of the five this is legit, this is real. Cures are happening!”

 

Young man with spinal cord injury regains use of hands and arms after stem cell therapy

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Kris Boesen – Photo courtesy USC

Hope is such a fragile thing. We cling to it in bad times. It offers us a sense that we can bear whatever hardships we are facing today, and that tomorrow will be better.

Kris Boesen knows all about holding on to hope during bad times. On March 6th of this year he was left paralyzed from the neck down after a car accident. Kris and his parents were warned the damage might be permanent.

Kris says at that point, life was pretty bleak:

“I couldn’t drink, couldn’t feed myself, couldn’t text or pretty much do anything, I was basically just existing. I wasn’t living my life, I was existing.”

For Kris and his family hope came in the form of a stem cell clinical trial, run by Asterias Biotherapeutics and funded by CIRM. The Asterias team had already enrolled three patients in the trial, each of whom had 2 million cells transplanted into their necks, primarily to test for safety. In early April Kris became the first patient in the trial to get a transplant of 10 million stem cells.

Within two weeks he began to show signs of improvement, regaining movement and strength in his arms and hands:

“Now I have grip strength and do things like open a bottle of soda and feed myself. Whereas before I was relying on my parents, now after the stem cell therapy I am able to live my life.”

The therapy involves human embryonic stem cells that have been differentiated, or converted, into cells called oligodendrocyte progenitors. These are capable of becoming the kind of cells which help protect nerve cells in the central nervous system, the area damaged in spinal cord injury.

The surgery was performed by Keck Medicine of USC’s Dr. Charles Liu. In a news release about the procedure, he says improvements of the kind Kris has experienced can make a huge difference in someone’s life:

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Dr. Charles Liu, Keck School of Medicine: Photo courtesy USC

“As of 90 days post-treatment, Kris has gained significant improvement in his motor function, up to two spinal cord levels. In Kris’ case, two spinal cord levels means the difference between using your hands to brush your teeth, operate a computer or do other things you wouldn’t otherwise be able to do, so having this level of functional independence cannot be overstated.”

We blogged about this work as recently as last week, when Asterias announced that the trial had passed two important safety hurdles.  But Kris’ story is the first to suggest this treatment might actually be working.

Randy Mills, CIRM’s President & CEO, says:

 “With each patient treated in this clinical trial we learn.  We gain more experience, all of which helps us put into better context the significance of this type of event for all people afflicted with debilitating spinal cord injuries. But let us not lose sight of the individual here.  While each participant in a clinical trial is part of the group, for them success is binary.  They either improve or they do not.  Kris bravely and selflessly volunteered for this clinical trial so that others may benefit from what we learn.  So it is fitting that today we celebrate Kris’ improvements and stop to thank all those participating in clinical trials for their selfless efforts.”

For patient advocates like Roman Reed, this was a moment to celebrate. Roman has been championing stem cell research for years and through his Roman Reed Foundation helped lay the groundwork for the research that led to this clinical trial:

This is clear affirmative affirmation that we are making Medical History!  We were able to give a paralyzed quadriplegic patient back the use of his hands! With only half a clinical dosage. Now this person may hold and grasp his loved ones hands in his own hands because of the actions of our last two decades for medical research for paralysis CURE! CARPE DIEM!”

It’s not unheard of for people with the kind of injury Kris had to make a partial recovery, to regain some use of their arms and hands, so it’s impossible to know right now if the stem cell transplant was the deciding factor.

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Kris at home: photo courtesy USC

Kris’ dad, Rodney, says he doesn’t care how it happened, he’s just delighted it did:

“He’s going to have a life, even if (the progress) stops just this second, and this is what he has, he’s going to have a better life than he would have definitely had before, because there are so many things that this opens up the world for him, he’s going to be able to use his hands.”


Related Articles:

Stem cell stories that caught our eye: turning on T cells; fixing our brains; progress and trends in stem cells; and one young man’s journey to recover from a devastating injury

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A healthy T cell

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.

Directing the creation of T cells. To paraphrase the GOP Presidential nominee, any sane person LOVES, LOVES LOVES their T cells, in a HUGE way, so HUGE. They scamper around the body getting rid of viruses and the tiny cancers we all have in us all the time. A CIRM-funded team at CalTech has worked out the steps our genetic machinery must take to make more of them, a first step in letting physicians turn up the action of our immune systems.

We have known for some time the identity of the genetic switch that is the last, critical step in turning blood stem cells into T cells, but nothing in our body is as simple as a single on-off event. The Caltech team isolated four genetic factors in the path leading to that main switch and, somewhat unsuspected, they found out those four steps had to be activated sequentially, not all at the same time. They discovered the path by engineering mouse cells so that the main T cell switch, Bcl11b, glows under a microscope when it is turned on.

“We identify the contributions of four regulators of Bcl11b, which are all needed for its activation but carry out surprisingly different functions in enabling the gene to be turned on,” said Ellen Rothenberg, the senior author in a university press release picked up by Innovations Report. “It’s interesting–the gene still needs the full quorum of transcription factors, but we now find that it also needs them to work in the right order.”

Video primer on stem cells in the brain.  In conjunction with an article in its August issue, Scientific American posted a video from the Brain Forum in Switzerland of Elena Cattaneo of the University of Milan explaining the basics of adult versus pluripotent stem cells, and in particular how we are thinking about using them to repair diseases in the brain.

The 20-minute talk gives a brief review of pioneers who “stood alone in unmarked territory.” She asks how can stem cells be so powerful; and answers by saying they have lots of secrets and those secrets are what stem cell scientist like her are working to unravel.  She notes stem cells have never seen a brain, but if you show them a few factors they can become specialized nerves. After discussing collaborations in Europe to grow replacement dopamine neurons for Parkinson’s disease, she went on to describe her own effort to do the same thing in Huntington’s disease, but in this case create the striatal nerves lost in that disease.

The video closes with a discussion of how basic stem cell research can answer evolutionary questions, in particular how genetic changes allowed higher organisms to develop more complex nervous systems.

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CIRM Science Officers Kelly Shepard and Kent Fitzgerald

A stem cell review that hits close to home.  IEEE Pulse, a publication for scientists who mix engineering and medicine and biology, had one of their reporters interview two of our colleagues on CIRM’s science team. They asked senior science officers Kelly Shepard and Kent Fitzgerald to reflect on how the stem cell field has progressed based on their experience working to attract top researchers to apply for our grants and watching our panel of outside reviewers select the top 20 to 30 percent of each set of applicants.

One of the biggest changes has been a move from animal stem cell models to work with human stem cells, and because of CIRM’s dedicated and sustained funding through the voter initiative Proposition 71, California scientists have led the way in this change. Kelly described examples of how mouse and human systems are different and having data on human cells has been critical to moving toward therapies.

Kelly and Kent address several technology trends. They note how quickly stem cell scientists have wrapped their arms around the new trendy gene editing technology CRISPR and discuss ways it is being used in the field. They also discuss the important role of our recently developed ability to perform single cell analysis and other technologies like using vessels called exosomes that carry some of the same factors as stem cells without having to go through all the issues around transplanting whole cells.

“We’re really looking to move things from discovery to the clinic. CIRM has laid the foundation by establishing a good understanding of mechanistic biology and how stem cells work and is now taking the knowledge and applying it for the benefit of patients,” Kent said toward the end of the interview.

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Jake Javier and his family

Jake’s story: one young man’s journey to and through a stem cell transplant; As a former TV writer and producer I tend to be quite critical about the way TV news typically covers medical stories. But a recent story on KTVU, the Fox News affiliate here in the San Francisco Bay Area, showed how these stories can be done in a way that balances hope, and accuracy.

Reporter Julie Haener followed the story of Jake Javier – we have blogged about Jake before – a young man who broke his spine and was then given a stem cell transplant as part of the Asterias Biotherapeutics clinical trial that CIRM is funding.

It’s a touching story that highlights the difficulty treating these injuries, but also the hope that stem cell therapies holds out for people like Jake, and of course for his family too.

If you want to see how a TV story can be done well, this is a great example.