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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Curing the Incurable through Definitive Medicine

“Curing the Incurable”. That was the theme for the first annual Center for Definitive and Curative Medicine (CDCM) Symposium held last week at Stanford University, in Palo Alto, California.

The CDCM is a joint initiative amongst Stanford Healthcare, Stanford Children’s Health and the Stanford School of Medicine. Its mission is to foster an environment that accelerates the development and translation of cell and gene therapies into clinical trials.

The research symposium focused on “the exciting first-in-human cell and gene therapies currently under development at Stanford in bone marrow, skin, cardiac, neural, pancreatic and neoplastic diseases.” These talks were organized into four different sessions: cell therapies for neurological disorders, stem cell-derived tissue replacement therapies, genome-edited cell therapies and anti-cancer cell-based therapies.

A few of the symposium speakers are CIRM-funded grantees, and we’ll briefly touch on their talks below.

Targeting cancer

The keynote speaker was Irv Weissman, who talked about hematopoietic or blood-forming stem cells and their value as a cell therapy for patients with blood disorders and cancer. One of the projects he discussed is a molecule called CD47 that is found on the surface of cancer cells. He explained that CD47 appears on all types of cancer cells more abundantly than on normal cells and is a promising therapeutic target for cancer.

Irv Weissman

Irv Weissman

“CD47 is the first gene whose overexpression is common to all cancer. We know it’s molecular mechanism from which we can develop targeted therapies. This would be impossible without collaborations between clinicians and scientists.”

 

At the end of his talk, Weissman acknowledged the importance of CIRM’s funding for advancing an antibody therapeutic targeting CD47 into a clinical trial for solid cancer tumors. He said CIRM’s existence is essential because it “funds [stem cell-based] research through the [financial] valley of death.” He further explained that CIRM is the only funding entity that takes basic stem cell research all the way through the clinical pipeline into a therapy.

Improving bone marrow transplants

judith shizuru

Judith Shizuru

Next, we heard a talk from Judith Shizuru on ways to improve current bone-marrow transplantation techniques. She explained how this form of stem cell transplant is “the most powerful form of cell therapy out there, for cancers or deficiencies in blood formation.” Inducing immune system tolerance, improving organ transplant outcomes in patients, and treating autoimmune diseases are all applications of bone marrow transplants. But this technique also carries with it toxic and potentially deadly side effects, including weakening of the immune system and graft vs host disease.

Shizuru talked about her team’s goal of improving the engraftment, or survival and integration, of bone marrow stem cells after transplantation. They are using an antibody against a molecule called CD117 which sits on the surface of blood stem cells and acts as an elimination signal. By blocking CD117 with an antibody, they improved the engraftment of bone marrow stem cells in mice and also removed the need for chemotherapy treatment, which is used to kill off bone marrow stem cells in the host. Shizuru is now testing her antibody therapy in a CIRM-funded clinical trial in humans and mentioned that this therapy has the potential to treat a wide variety of diseases such as sickle cell anemia, leukemias, and multiple sclerosis.

Tackling stroke and heart disease

img_1327We also heard from two CIRM-funded professors working on cell-based therapies for stroke and heart disease. Gary Steinberg’s team is using human neural progenitor cells, which develop into cells of the brain and spinal cord, to treat patients who’ve suffered from stroke. A stroke cuts off the blood supply to the brain, causing the death of brain cells and consequently the loss of function of different parts of the body.  He showed emotional videos of stroke patients whose function and speech dramatically improved following the stem cell transplant. One of these patients was Sonia Olea, a young woman in her 30’s who lost the ability to use most of her right side following her stroke. You can read about her inspiring recover post stem cell transplant in our Stories of Hope.

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

Joe Wu followed with a talk on adult stem cell therapies for heart disease. His work, which is funded by a CIRM disease team grant, involves making heart cells called cardiomyocytes from human embryonic stem cells and transplanting these cells into patient with end stage heart failure to improve heart function. His team’s work has advanced to the point where Wu said they are planning to file for an investigational new drug (IND) application with the US Food and Drug Administration (FDA) in six months. This is the crucial next step before a treatment can be tested in clinical trials. Joe ended his talk by making an important statement about expectations on how long it will take before stem cell treatments are available to patients.

He said, “Time changes everything. It [stem cell research] takes time. There is a lot of promise for the future of stem cell therapy.”

Eye on the prize: two stem cell studies restore vision in blind mice

For the 39 million people in the world who are blind, a vision-restoring therapy would be the ultimate prize. So far, this prize has remained out of reach, but two studies published this week have entered the ring as promising contenders in the fight against blindness.

In the red corner, we have a study published in Stem Cell Reports from the RIKEN Institute in Japan led by scientist Masayo Takahashi. Her team restored vision in blind mice with an advanced stage of retinal disease by transplanting sheets of light-sensing photoreceptor cells that were made from induced pluripotent stem cells (iPSCs).

In the blue corner, we have a study published in Cell Stem Cell from the Buck Institute in California led by scientist Deepak Lamba. His team restored long-term vision in blind mice by transplanting embryonic stem cell-derived photoreceptor cells and preventing the immune system from rejecting the transplant.

Transplanting Retinal sheets

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Synaptic integration of graft retina into model mouse
Credit: RIKEN

Let’s first talk about the Riken study led by Masayo Takahashi. She is well known for her pioneering work on iPSC-derived treatments for macular degeneration – a disease that damages the retina and causes blindness.

In previous work, Takahashi and her team transplanted sheets of mouse stem cell-derived retinal progenitor cells, which mature into light-sensing cells called photoreceptors, into the eyes of mice. The cells within the sheet formed connections with the resident cells in the mouse eye, proving the feasibility of transplanting retinal sheets to restore vision.

In their current study, published in Stem Cell Reports, Takahashi’s team found that the retinal sheets could restore vision in mice that had a very severe form of retinal disease that left them unable to see light. After the mice received the retinal transplants, they responded to light, which they were unable to do previously. Like their other findings, they found that the cells in the transplant made connections with the host cells in the eye including nerve cells that send light-sensing signals to the brain.

First author on the study, Michiko Mandai explained the importance of their findings and their future plans in a news release,

“These results are a proof of concept for using iPSC-derived retinal tissue to treat retinal degeneration. We are planning to proceed to clinical trials in humans after a few more necessary studies using human iPSC-derived retinal tissue in animals. Clinical trials are the only way to determine how many new connections are needed for a person to be able to ‘see’ again.”

While excited by their results, Mandai and the rest of the RIKEN team aren’t claiming the prize for a successful treatment that will cure blindness in people just yet. Mandai commented,

“We cannot expect to restore practical vision at the moment. We will start from seeing a simple light, then possibly move on to larger figures in the next stage.”

Blocking the immune system

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Image showing transplanted GFP-expressing human stem cell derived photoreceptors (green) integrated in a host rodent retina stained for Otx2 (red).
Credit Jie Zhu, Buck Institute for Research on Aging

In the Buck Institute study, Lamba and his team took on the challenge of answering a controversial question about why retinal cell transplants typically don’t survive long-term in the eye. Some scientists think that the transplanted cells die off over time because they don’t integrate into the eye while others think that they are rejected and killed off by the immune system.

To answer this question, Lamba transplanted human embryonic stem cell-derived retinal cells into immunodeficient mice that lacked a protein receptor that’s vital for a functioning immune system. The retinal cells transplanted into immunodeficient mice survived much better than retinal cells transplanted into normal mice and developed into ten times as many photoreceptors that integrated themselves into the host eye.

Their next step was to transplant the retinal cells into mice that were blind and also lacked the same immune receptor as the other mice. After the transplant, the blind mice became responsive to light and showed brain activity associated with sensing light. Their newfound ability to see lasted for nine months to a year following the transplant.

Lamba believes that backing down the immune response is responsible for the long-term vision restoration in the blind mice. He explained the importance of their findings in a Buck Institute news release,

“That finding gives us a lot of hope for patients, that we can create some sort of advantage for these stem cell therapies so it won’t be just a transient response when these cells are put in, but a sustained vision for a long time. Even though the retina is often considered to be ‘immune privileged,’ we have found that we can’t ignore cell rejection when trying to transplant stem cells into the eye.”

In the future, Lamba will explore the potential for using drugs that target the specific protein receptor they blocked earlier to improve the outcome of embryonic stem cell-derived retinal transplants,

“We can also potentially identify other small molecules or recombinant proteins to reduce this interleukin 2 receptor gamma activity in the body – even eye-specific immune responses – that might reduce cell rejection. Of course it is not validated yet, but now that we have a target, that is the future of how we can apply this work to humans.”

Who will be the winner?

The Buck Institute study is interesting because it suggests that embryonic stem cell-based transplants combined with immunosuppression could be a promising strategy to improve vision in patients. But it also begs the question of whether the field should focus instead on iPSC-based therapies where a patient’s own stem cells are used to make the transplanted cells. This strategy would side step the immune response and prevent patients from a taking a lifetime of immunosuppressive drugs.

However, I’m not saying that RIKEN’s iPSC-based strategy is necessarily the way to go for treating blindness (at least not yet). It takes a lot of time and money to make iPSC lines and it’s not feasible given our current output to generate iPSC lines for every blind patient.

So, it sounds like a winner in this fight to cure blindness won’t be announced any time soon. In the meantime, both teams need to conduct further preclinical studies before they can move on to testing these treatments in human clinical trials.

Here at CIRM, we’re funding a promising Phase 1 clinical trial sponsored by jCyte for a form of blindness called Retinis Pigmentosa. Based on preliminary results with a small cohort of patient, the treatment seems safe and may even be showing hints of effectiveness in some patients.

Ultimately, more is better. As the number of stem cell clinical trials for blindness grows, the sooner we can find out which therapies work best for which patients.

Translating great stem cell ideas into effective therapies

alzheimers

CIRM funds research trying to solve the Alzheimer’s puzzle

In science, there are a lot of terms that could easily mystify people without a research background; “translational” is not one of them. Translational research simply means to take findings from basic research and advance them into something that is ready to be tested in people in a clinical trial.

Yesterday our Governing Board approved $15 million in funding for four projects as part of our Translational Awards program, giving them the funding and support that we hope will ultimately result in them being tested in people.

Those projects use a variety of different approaches in tackling some very different diseases. For example, researchers at the Gladstone Institutes in San Francisco received $5.9 million to develop a new way to help the more than five million Americans battling Alzheimer’s disease. They want to generate brain cells to replace those damaged by Alzheimer’s, using induced pluripotent stem cells (iPSCs) – an adult cell that has been changed or reprogrammed so that it can then be changed into virtually any other cell in the body.

CIRM’s mission is to accelerate stem cell treatments to patients with unmet medical needs and Alzheimer’s – which has no cure and no effective long-term treatments – clearly represents an unmet medical need.

Another project approved by the Board is run by a team at Children’s Hospital Oakland Research Institute (CHORI). They got almost $4.5 million for their research helping people with sickle cell anemia, an inherited blood disorder that causes intense pain, and can result in strokes and organ damage. Sickle cell affects around 100,000 people in the US, mostly African Americans.

The CHORI team wants to use a new gene-editing tool called CRISPR-Cas9 to develop a method of editing the defective gene that causes Sickle Cell, creating a healthy, sickle-free blood supply for patients.

Right now, the only effective long-term treatment for sickle cell disease is a bone marrow transplant, but that requires a patient to have a matched donor – something that is hard to find. Even with a perfect donor the procedure can be risky, carrying with it potentially life-threatening complications. Using the patient’s own blood stem cells to create a therapy would remove those complications and even make it possible to talk about curing the disease.

While damaged cartilage isn’t life-threatening it does have huge quality of life implications for millions of people. Untreated cartilage damage can, over time lead to the degeneration of the joint, arthritis and chronic pain. Researchers at the University of Southern California (USC) were awarded $2.5 million to develop an off-the-shelf stem cell product that could be used to repair the damage.

The fourth and final award ($2.09 million) went to Ankasa Regenerative Therapeutics, which hopes to create a stem cell therapy for osteonecrosis. This is a painful, progressive disease caused by insufficient blood flow to the bones. Eventually the bones start to rot and die.

As Jonathan Thomas, Chair of the CIRM Board, said in a news release, we are hoping this is just the next step for these programs on their way to helping patients:

“These Translational Awards highlight our goal of creating a pipeline of projects, moving through different stages of research with an ultimate goal of a successful treatment. We are hopeful these projects will be able to use our newly created Stem Cell Center to speed up their progress and pave the way for approval by the FDA for a clinical trial in the next few years.”

Stem cell agency funds clinical trials in three life-threatening conditions

strategy-wide

A year ago the CIRM Board unanimously approved a new Strategic Plan for the stem cell agency. In the plan are some rather ambitious goals, including funding ten new clinical trials in 2016. For much of the last year that has looked very ambitious indeed. But today the Board took a big step towards reaching that goal, approving three clinical trials focused on some deadly or life-threatening conditions.

The first is Forty Seven Inc.’s work targeting colorectal cancer, using a monoclonal antibody that can strip away the cancer cells ability to evade  the immune system. The immune system can then attack the cancer. But just in case that’s not enough they’re going to hit the tumor from another side with an anti-cancer drug called cetuximab. It’s hoped this one-two punch combination will get rid of the cancer.

Finding something to help the estimated 49,000 people who die of colorectal cancer in the U.S. every year would be no small achievement. The CIRM Board thought this looked so promising they awarded Forty Seven Inc. $10.2 million to carry out a clinical trial to test if this approach is safe. We funded a similar approach by researchers at Stanford targeting solid tumors in the lung and that is showing encouraging results.

Our Board also awarded $7.35 million to a team at Cedars-Sinai in Los Angeles that is using stem cells to treat pulmonary hypertension, a form of high blood pressure in the lungs. This can have a devastating, life-changing impact on a person leaving them constantly short of breath, dizzy and feeling exhausted. Ultimately it can lead to heart failure.

The team at Cedars-Sinai will use cells called cardiospheres, derived from heart stem cells, to reduce inflammation in the arteries and reduce blood pressure. CIRM is funding another project by this team using a similar  approach to treat people who have suffered a heart attack. This work showed such promise in its Phase 1 trial it’s now in a larger Phase 2 clinical trial.

The largest award, worth $20 million, went to target one of the rarest diseases. A team from UCLA, led by Don Kohn, is focusing on Adenosine Deaminase Severe Combined Immune Deficiency (ADA-SCID), which is a rare form of a rare disease. Children born with this have no functioning immune system. It is often fatal in the first few years of life.

The UCLA team will take the patient’s own blood stem cells, genetically modify them to fix the mutation that is causing the problem, then return them to the patient to create a new healthy blood and immune system. The team have successfully used this approach in curing 23 SCID children in the last few years – we blogged about it here – and now they have FDA approval to move this modified approach into a Phase 2 clinical trial.

So why is CIRM putting money into projects that it has either already funded in earlier clinical trials or that have already shown to be effective? There are a number of reasons. First, our mission is to accelerate stem cell treatments to patients with unmet medical needs. Each of the diseases funded today represent an unmet medical need. Secondly, if something appears to be working for one problem why not try it on another similar one – provided the scientific rationale and evidence shows it is appropriate of course.

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

“Our Board’s support for these programs highlights how every member of the CIRM team shares that commitment to moving the most promising research out of the lab and into patients as quickly as we can. These are very different projects, but they all share the same goal, accelerating treatments to patients with unmet medical needs.”

We are trying to create a pipeline of projects that are all moving towards the same goal, clinical trials in people. Pipelines can be horizontal as well as vertical. So we don’t really care if the pipeline moves projects up or sideways as long as they succeed in moving treatments to patients. And I’m guessing that patients who get treatments that change their lives don’t particularly

Creating a “Pitching Machine” to speed up our delivery of stem cell treatments to patients

hitting-machine

When baseball players are trying to improve their hitting they’ll use a pitching machine to help them fine tune their stroke. Having a device that delivers a ball at a consistent speed can help a batter be more consistent and effective in their swing, and hopefully get more hits.

That’s what we are hoping our new Translating and Accelerating Centers will do. We call these our “Pitching Machine”, because we hope they’ll help researchers be better prepared when they apply to the Food and Drug Administration (FDA) for approval to start a clinical trial, and be more efficient and effective in the way they set up and run that clinical trial once they get approval.

The CIRM Board approved the Accelerating Center earlier this summer. The $15 million award went to QuintilesIMS, a leading integrated information and technology-enabled healthcare service provider.

The Accelerating Center will provide key core services for researchers who have been given approval to run a clinical trial, including:

  • Regulatory support and management services
  • Clinical trial operations and management services
  • Data management, biostatistical and analytical services

The reason why these kinds of service are needed is simple, as Randy Mills, our President and CEO explained at the time:

“Many scientists are brilliant researchers but have little experience or expertise in navigating the regulatory process; this Accelerating Center means they don’t have to develop those skills; we provide them for them.”

The Translating Center is the second part of the “Pitching Machine”. That is due to go to our Board for a vote tomorrow. This is an innovative new center that will support the stem cell research, manufacturing, preclinical safety testing, and other activities needed to successfully apply to the FDA for approval to start a clinical trial.

The Translating Center will:

  • Provide consultation and guidance to researchers about the translational process for their stem cell product.
  • Initiate, plan, track, and coordinate activities necessary for preclinical Investigational New Drug (IND)-enabling development projects.
  • Conduct preclinical research activities, including pivotal pharmacology and toxicology studies.
  • Manufacture stem cell and gene modified stem cell products under the highest quality standards for use in preclinical and clinical studies.

The two centers will work together, helping researchers create a comprehensive development plan for every aspect of their project.

For the researchers this is important in giving them the support they need. For the FDA it could also be useful in ensuring that the applications they get from CIRM-funded projects are consistent, high quality and meet all their requirements.

We want to do everything we can to ensure that when a CIRM-funded therapy is ready to start a clinical trial that its application is more likely to be a hit with the FDA, and not to strike out.

Just as batting practice is crucial to improving performance in baseball, we are hoping our “Pitching Machine” will raise our game to the next level, and enable us to deliver some game-changing treatments to patients with unmet medical needs.

 

From Pig Parts to Stem Cells: Scientist Douglas Melton Wins Ogawa-Yamanaka Prize for Work on Diabetes

Since the 1920s, insulin injections have remained the best solution for managing type 1 diabetes. Patients with this disease do not make enough insulin – a hormone that regulates the sugar levels in your blood – because the insulin-producing cells, or beta cells, in their pancreas are destroyed.

Back then, it took two tons of pig parts to make eight ounces of insulin, which was enough to treat 10,000 diabetic patients for six months. Biotech and pharmaceutical companies have since developed different types of human insulin treatments that include fast and long acting versions of the hormone. It’s estimated that $22 billion will be spent on developing insulin products for patients this year and that costs will rise to $32 billion in the year 2019.

These costs are necessary to keep insulin-dependent diabetes patients alive and healthy, but what if there was a different, potentially simpler solution to manage diabetes? One that looks to insulin-producing beta cells as the solution rather than daily hormone shots?

Douglas Melton Receives Stem Cell Prize for Work on Diabetes

Harvard scientist Douglas Melton envisions a world where one day, insulin-dependent diabetic patients are given stem cell transplants rather than shots to manage their diabetes. In the 90s, Melton’s son was diagnosed with type 1 diabetes. Motivated by his son’s diagnosis, Melton dedicated the focus of his research on understanding how beta cells develop from stem cells in the body and also in a cell culture dish.

Almost 30 years later, Melton has made huge strides towards understanding the biology of beta cell development and has generated methods to “reprogram” or coax pluripotent stem cells into human beta cells.

Melton was honored for his important contributions to stem cell and diabetes research at the second annual Ogawa-Yamanaka Stem Cell Prize ceremony last week at the Gladstone Institutes. This award recognizes outstanding scientists that are translating stem cell research from the lab to clinical trials in patients.

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Deepak Srivastava, director of the Gladstone Institute of Cardiovascular Disease, explained why Melton was selected as this year’s prize winner:

Deepak Srivastava, Gladstone Institutes

Deepak Srivastava, Gladstone Institutes

“Doug’s research on genetic markers expressed during pancreas development have led to a reliable way to reprogram stem cells into human beta cells. His work provides the foundation for the ultimate goal of transplantable, patient-specific beta cells.”

 

Making Beta Cells for Patients

During the awards ceremony, Melton discussed his latest work on generating beta cells from human stem cells and how this technology could transform the way insulin-dependent patients are treated.

Douglas Melton, Harvard University.

Douglas Melton, Harvard University.

“I don’t mean to say that this [insulin treatment] isn’t a good idea. That’s keeping these people alive and in good health,” said Melton during his lecture. “What I want to talk about is a different approach. Rather than making more and better insulins and providing them by different medical devices, why not go back to nature’s solution which is the beta cells that makes the insulin?”

Melton first described his initial research on making pancreatic beta cells from embryonic and induced pluripotent stem cells in a culture dish. He described the power of this system for not only modeling diabetes, but also screening for potential drugs, and testing new therapies in animal models.

He also mentioned how he and his colleagues are developing methods to manufacture large amounts of human beta cells derived from pluripotent stem cells for use in patients. They are able to culture stem cells in large spinning flasks that accelerate the growth and development of pluripotent stem cells into billions of human beta cells.

Challenges and Future of Stem-Cell Derived Diabetes Treatments

Melton expressed a positive outlook for the future of stem cell-derived treatments for insulin-dependent diabetes, but he also mentioned two major challenges. The first is the need for better control over the methods that make beta cells from stem cells. These methods could be more efficient and generate higher numbers of beta cells (beta cells make up 16% of stem cell-derived cells using their current culturing methods). The second is preventing an autoimmune attack after transplanting the stem-cell derived beta cells into patients.

Melton and other scientists are already working on improving techniques to make more beta cells from stem cells. As for preventing transplanted beta cells from being attacked by the patient’s immune system, Melton described two possibilities: using an encapsulation device or biological protection to mask the transplanted cells from an attack.

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He mentioned a CIRM-funded clinical trial by ViaCyte, which is testing an encapsulation device that is placed under the skin. The device contains embryonic stem cell-derived pancreatic progenitor cells that develop into beta cells that secrete insulin into the blood stream. The device also prevents the immune system from attacking and killing the beta cells.

Melton also discussed a biological approach to protecting transplanted beta cells. In collaboration with Dan Anderson at MIT, they coated stem cell-derived beta cells in a biomaterial called alginate, which comes from seaweed. They injected alginate microcapsule-containing beta cells into diabetic mice and were able control their blood sugar levels.

At the end of his talk, Melton concluded that he believes that beta cell transplantation in an immunoprotective device containing stem cell-derived cells will have the most benefit for diabetes patients.

Gladstone Youtube video of Douglas Melton’s lecture at the Ogawa-Yamanaka Prize lecture.


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Another way to dial back stem cell hype (but not hope): Put a dollar figure on it

In an effort to reign in the hype surrounding stem cell research that has led to a proliferation of unapproved and potentially dangerous stem cell therapies, the International Society for Stem Cell Research (ISSCR) recently released updated guidelines outlining conduct for stem cell researchers that,  for the first time, included communications activities.  At only 1.5 pages in the 37-page document, the statements around communications asked researchers, communications professionals, institutions and the media to be more proactive in combatting stem cell hype by ensuring accuracy and balance in communications activities.

Stock Image

Stock Image

It’s too early to know what the full impact of the guidelines will be, however, the communications recommendations did generate a good deal of interest and some media, at least, have taken steps to address the issue.

Whether directly influenced by the guidelines or not, in the final plenary session of the ISSCR annual meeting last week, Professor Roger Barker, a research-clinician at the University of Cambridge, provided a candid portrayal of some of the challenges of preclinical and early clinical research.

Though he may have poked a small hole in some of the optimism that characterized the four-day conference, in providing a rare glimpse of the real costs of research, Dr. Barker might also have given us a new way to frame research to downplay hype.

Dr. Roger Barker

Dr. Roger Barker

Dr. Barker is one of many researchers across the globe working on a potential cell-based treatment for Parkinson’s Disease. Parkinson’s is a rather straightforward disease to tackle in this way, because its cause is known: the death of cells that produce the chemical dopamine. Even so, the challenges in developing a treatment are many. Apart from the design of a clinical study (which includes, for example, careful selection of the Parkinson’s patients to include; as Barker pointed out, there are two main types of Parkinson progression and one type may respond to a treatment while the other may not. This is a real concern for Barker, who commented that “a lack of rigour in selecting patients has dogged the field for the past 25 years.”), there are several other factors that need to be addressed in the pre-clinical work, such as identifying the best type of cells to use, how to scale them up and make them both GMP-compliant and standardized for reproducibility.

Such work, Barker estimated, costs between £2 and £3 million (or roughly $3-5 million, valued at pre-Brexit currency rates, one would assume). And, having invested so much to this point, you don’t even have something that can be published yet.

Running the actual clinical phase 1 study, with roughly 20 patients, will cost millions more. If it doesn’t work, you’re back to lab and in search of more pre-clinical funding.

But, assuming the study nets the desired results, it’s still only looking at safety, not efficacy. Getting it to phases 2 and 3 costs several orders of magnitude more. Put in this light, the $3 billion USD given to the California Institute for Regenerative Medicine seems like not nearly enough. The Ontario Institute for Regenerative Medicine’s $25 million CAD is nothing at all. Not that we aren’t grateful — we do what we can to maximize impact and make even a small investment worthwhile. Every step counts.

Another point to consider is whether the final therapy will be more cost-effective than existing, approved medical interventions. If it’s not, there is little incentive in pursuing it. This is the notion of headroom that I’ve heard discussed more directly at commercialization-based conferences (and is very well explained here) but is one that will become increasingly relevant to research as more basic and translational work finds its way into the clinic.

Talking about money with regard to health can be seen as tedious and even crass. The three short talks given by patient advocates at the ISSCR meeting served to emphasize this – each outlined personal tragedy connected to illness or disease: congestive heart failure at 11 years of age, four generations of a family with sickle cell disease, retinitis pigmentosa that derailed a young woman’s budding career. You simply can’t put a price on a person’s life, happiness and well-being. Each of these patients, and millions more, have hope that research will find an answer. It’s a lofty goal, one that is sometimes hard to remember in the lab trenches when a grant doesn’t materialize or a negative result sends the work back to ground zero.

And therein lies some of the tension that can easily lead to hype. We do want to fly high. We do want to deliver cures and therapies. We need to be reminded, by interactions with the patient community, of what’s at stake and what we can gain for humanity. The field should and will continue to strive to achieve these goals.

But not without responsibility. And a dose of realism.


This post appears simultaneously on OIRM Expression and appears here with permission by the author Lisa Willemse.

Spotlight on CIRM Grantee Joe Wu: Clinical Trials for Heart Disease in a Dish?

It’s always exciting to read a science article featuring a talented scientist who is breaking boundaries in the field of regenerative medicine. It’s especially exciting to us at CIRM when the scientist is a CIRM grantee.

Last week, OZY published a fun and inspiring piece on Stanford scientist Joe Wu. Dr. Wu is the Director of the Stanford Cardiovascular Institute and his lab studies how stem cells (both adult and pluripotent) function and how they can be used to model heart diseases and screen for new drug therapies. He also is a CIRM grantee and has a Disease Team Therapy Development grant that aims to clinically test human embryonic stem cell-derived cardiomyocytes (heart cells) in end stage heart failure patients.

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

The OZY piece does a great job of highlighting Dr. Wu’s recent efforts to use human induced pluripotent stem cells (iPS cells) to make heart tissue in a dish and model cardiovascular disease. And without getting too technical, the article explains Dr. Wu’s larger mission to combine precision medicine and stem cell research to identify drugs that would be best suited for specific patient populations.

The article commented,

“He envisions treatments based on an individual’s own iPS cells. For example, a popular breast cancer drug has an 8 percent chance of giving patients heart failure. In Wu’s world, we’d test the drug on stem cells first, and if a patient lands in that 8 percent, begin treatment for the side effects preemptively or avoiding the drug totally and avoiding heart failure, too.”

Basically, Dr. Wu sees the future of clinical trials in a dish using human stem cells. “His goal is to take these stem cells from thousands of patients to create a genetically diverse enough bank that will allow for “clinical trials in a dish” — Wu’s go-to phrase.”

Instead of following the traditional drug development paradigm that takes more than 10 years, billions of dollars, and unfortunately usually ends in failure, Dr. Wu wants to follow an accelerated path where stem cells are used for drug toxicity and efficacy testing.

This alternative path could improve overall drug development and approval by the FDA. The article explained,

“Testing drugs on stem cells will give big pharma and the FDA vastly improved heads up for toxic complications. Stem cells are “absolutely” the best avenue going forward, says Norman Stockbridge, director of the division of cardiovascular and renal products at the FDA’s Center for Drug Evaluation and Research.”

Not everyone is on the same page with Dr. Wu’s bold vision of the future of precision medicine, stem cells, and treatments for heart disease. Some believe he is overly ambitious, however top scientists in the stem cell field have praised Dr. Wu’s “systematic approach” to research and how he doesn’t stop at data discovery, he focuses on the big picture and how his work can ultimately help patients.

You can read more about Dr. Wu’s research on his lab website and I highly encourage you to check out the OZY article which is a great example of science communication for the general public.


Related Links:

Get your BIO on: Sneak Peak of the June 2016 BIO Convention in SF

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Summer is almost here and for scientists around the world, that means it’s time to flock to one of the world’s biggest biotech meetings, the BIO International Convention.

This year, BIO is hosted in the lovely city of San Francisco. From June 6-9th, over 15,000 biotechnology and pharma leaders, as well as other professionals, academics, and patients will congregate to learn, educate, and network.

There’s something for everyone at this convention. If you check out the BIO agenda, you’ll find a plethora of talks, events, education sessions, and fire side chats on almost any topic related to science and biotechnology that you can imagine. The hard part will be deciding what to attend in only four short days.

For those going to BIO this year, make sure to check out the myBIO event planning tool that’s free for attendees and allows you to browse events and create a personalized agenda. You can also set up a professional profile that will share your background and networking interests with others at BIO. With this nifty tool, you can search for scientists, companies, and speakers you might want to connect with during the convention. Think of all the potential networking opportunities right at your fingertips!

Will Smith (source)

Will Smith (source)

For those who can’t make it to BIO, don’t worry, we have you covered. CIRM will be at the convention blogging and live tweeting. Because our mission is to bring stem cell treatments to patients with unmet medical needs, the majority of our coverage will be on talks and sessions related to regenerative medicine and patient advocacy. However, there are definitely some sessions outside these areas that we won’t want to miss such as the Tuesday Keynote talk by Dr. Bennet Omalu – who helped reveal the extent of brain damage in the NFL – and actor Will Smith – who plays Dr. Omalu in the movie ‘Concussion’. Their join talk is called “Knowledge Precipitates Evolution.”

Here’s a sneak peak of some of the other talks and events that we think will be especially interesting:


Monday June 6th

Education Sessions on Brain Health and Mitochondrial Disease

Moving Out of Stealth Mode: Biotech Journalists Offer Real-World Advice on Working with Media to Tell Your Story

“In this interactive panel discussion, well-known biotech reporters from print and online outlets will share their insights on how to successfully work with the media. Session attendees will learn critical needs of the media from what makes a story newsworthy to how to “pitch” a reporter to strategies for translating complicated science into a story for a broad audience.”

The Bioethics of Drug Development: You Decide

A discussion of the critical bioethical issues innovative manufacturers face in today’s healthcare ecosystem. Panelists will provide insights from a diverse set of perspectives, including investors, the patient advocacy community, bioethicists and federal regulators.”


Tuesday June 7th

Fireside Chat with Robert Califf, Commissioner of the US Food and Drug Administration (FDA)

Fireside Chat with Janet Napolitano, President of the University of California

Casting a Wider Net in Alzheimer’s Research: The Diversity of Today’s Approaches and Signs of Progress

Hear clinical researchers, biotech CEOs, and patient advocates explain how the field is pivoting from the failures of past approaches to make use of the latest generation of beta-amyloid research results as well as pursue alternative therapeutic angles to improve brain health.”

From Ebola to Zika: How Can We Go Faster in a Global Emergency?

This interactive panel of public health and industry leaders will discuss what has been learned through our global response to Ebola and what is and is not applicable to Zika or other pathogens of pandemic potential.”


Wednesday June 8th

Curative Therapies: Aligning Policy with Science to Ensure Patient Access

“The promise of curative treatments creates an urgent need to ensure access for patients, promote an environment conducive to developing new treatments, and manage the concentration of healthcare expenses in a sustainable manner.  A diverse set of panelists will tackle the tough questions around curative therapies and discern what changes are necessary for our health care delivery system to meet the challenges they pose.”

An Evolving Paradigm: Advancing the Science of Patient Input in the Drug Development and Regulatory Processes

This panel will explore advances in the field of assessing patient views and perspectives, and highlight how the patient voice is being incorporated into development programs and informing FDA review and approval decisions.”

A Media Perspective

“Any press is good press or so they say. You want your story known at the right time and in the right light, but how do you get industry journalist to notice you? What peaks their interest and how do they go about story discovery? What will they be looking to write about in the next 3 to 12 months? Three top journalists will discuss their approaches to keeping current and what makes a story newsworthy.”
Patient Advocacy Meetup

Over 40 patient advocacy organizations will be discussing their latest partnerships and developments in the areas of advancing disease research and drug development.


Thursday June 9th

Novel Advances in Cancer R&D: Meeting the Needs of the Patient

This panel will feature the views of patients and advocates, regulators, and companies who are working to change the way in which we diagnose and evaluate patients with cancer by better understanding the underlying biology of their disease.”


 To follow our coverage of BIO, visit our Stem Cellar Blog or follow us on Twitter at @CIRMNews.