CIRM invests in stem cell clinical trial targeting lung cancer and promising research into osteoporosis and incontinence

Lung cancer

Lung cancer: Photo courtesy Verywell

The five-year survival rate for people diagnosed with the most advanced stage of non-small cell lung cancer (NSCLC) is pretty grim, only between one and 10 percent. To address this devastating condition, the Board of the California Institute for Regenerative Medicine (CIRM) today voted to invest almost $12 million in a team from UCLA that is pioneering a combination therapy for NSCLC.

The team is using the patient’s own immune system where their dendritic cells – key cells in our immune system – are genetically modified to boost their ability to stimulate their native T cells – a type of white blood cell – to destroy cancer cells.  The investigators will combine this cell therapy with the FDA-approved therapy pembrolizumab (better known as Keytruda) a therapeutic that renders cancer cells more susceptible to clearance by the immune system.

“Lung cancer is a leading cause of cancer death for men and women, leading to 150,000 deaths each year and there is clearly a need for new and more effective treatments,” says Maria T. Millan, M.D., the President and CEO of CIRM. “We are pleased to support this program that is exploring a combination immunotherapy with gene modified cell and antibody for one of the most extreme forms of lung cancer.”

Translation Awards

The CIRM Board also approved investing $14.15 million in four projects under its Translation Research Program. The goal of these awards is to support promising stem cell research and help it move out of the laboratory and into clinical trials in people.

Researchers at Stanford were awarded almost $6 million to help develop a treatment for urinary incontinence (UI). Despite being one of the most common indications for surgery in women, one third of elderly women continue to suffer from debilitating urinary incontinence because they are not candidates for surgery or because surgery fails to address their condition.

The Stanford team is developing an approach using the patient’s own cells to create smooth muscle cells that can replace those lost in UI. If this approach is successful, it provides a proof of concept for replacement of smooth muscle cells that could potentially address other conditions in the urinary tract and in the digestive tract.

Max BioPharma Inc. was awarded almost $1.7 million to test a therapy that targets stem cells in the skeleton, creating new bone forming cells and blocking the destruction of bone cells caused by osteoporosis.

In its application the company stressed the benefit this could have for California’s diverse population stating: “Our program has the potential to have a significant positive impact on the lives of patients with osteoporosis, especially in California where its unique demographics make it particularly vulnerable. Latinos are 31% more likely to have osteoporosis than Caucasians, and California has the largest Latino population in the US, accounting for 39% of its population.”

Application Title Institution CIRM funding
TRAN1-10958 Autologous iPSC-derived smooth muscle cell therapy for treatment of urinary incontinence

 

 

Stanford University

 

$5,977,155

 

TRAN2-10990 Development of a noninvasive prenatal test for beta-hemoglobinopathies for earlier stem cell therapeutic interventions

 

 

Children’s Hospital Oakland Research Institute

 

$1,721,606

 

TRAN1-10937 Therapeutic development of an oxysterol with bone anabolic and anti-resorptive properties for intervention in osteoporosis  

MAX BioPharma Inc.

 

$1,689,855

 

TRAN1-10995 Morphological and functional integration of stem cell derived retina organoid sheets into degenerating retina models

 

 

UC Irvine

 

$4,769,039

 

Say Hello to CIRM’s New Active Awards Portfolio Dashboard (Video Included!)

It takes a lot of time, money and effort to develop a promising stem cell research idea into an effective treatment that can help patients. Oftentimes, you don’t hear about the early-stage research that goes into developing a particular treatment until it reaches the clinic.

CIRM recognizes the importance of investing in all stages of stem cell research and has an impressive portfolio of over 160 active projects spanning discovery, translation, and clinical-stage research.

To help you understand the breadth of our funding efforts, and to highlight our expanding research pipeline, we’ve created the Active Awards Portfolio Dashboard on our website. This interactive tool makes it easy to search through the active research projects that we’re currently funding, and filter these projects by disease focus, technology type or stage of research.

Watch the short video below to learn more about our new Dashboard and how to use it.

The Active Awards Dashboard reflects our Agency’s commitment to investing in the full range of stem cell research and to helping the most promising research projects advance to the next level.

For those of you interested in learning more about the 45 active clinical trials we’re funding, be sure to check out the companion Clinical Trials Dashboard on our website, featured previously on the Stem Cellar blog.

Harnessing the body’s immune system to tackle cancer

Often on the Stem Cellar we write about work that is in a clinical trial. But getting research to that stage takes years and years of dedicated work. Over the next few months, we are profiling some of the scientists we fund who are doing Discovery (early stage) and Translational (pre-clinical) research, to highlight the importance of this work in developing the treatments that could ultimately save lives. 

This second profile in the series is by Ross Okamura, Ph.D., a science officer in CIRM’s Discovery & Translation Program.

Your immune system is your body’s main protection against disease; harnessing this powerful defense system to target a given disorder is known as immunotherapy.  There are different types of immunotherapies that have been developed over the years. These include vaccines to help generate antibodies against viruses, drugs to direct immune cell function and most recently, the engineering of immune cells to fight cancer.

Understanding How Immunotherapies Work

One of the more recent immunotherapy approaches to fight cancer that has seen rapid development is equipping a subset of immune cells (T cells) with a chimeric antigen receptor (CAR). In brief, CAR T ceIls are first removed from the patient and then engineered to recognize a specific feature of the targeted cancer cells.  This direct targeting of T cells to the cancer allows for an effective anti-cancer therapy made from your own immune system.

Simplified explanation of how CAR T cell therapies fight cancer. (Memorial Sloan Kettering)

For the first time this fall, two therapeutics employing CAR T cells targeting different types of blood cancers were approved for use by the US Food and Drug Administration (FDA) based on remarkable results found during the clinical trials. Specifically, Kymriah (developed by Novartis) was approved for treatment of acute lymphoblastic leukemia and Yescarta (developed by Kite Pharma) was approved for treatment of non-Hodgkin lymphoma.

There are drawbacks to the CAR T approach, however. Revving up the immune system to attack tumors can cause dangerous side effects. When CAR T cells enter the body, they trigger the release of proteins called cytokines, which join in the attack on the tumors. But this can also create what’s referred to as a cytokine storm or cytokine release syndrome (CRS), which can lead to a range of responses, from a mild fever to multi-organ failure and death. Balancing treatments to resolve CRS after it’s detected while still maintaining the treatment’s cancer-killing abilities is a significant challenge that remains to be overcome.  A second issue is that cancer cells can evade the immune system by no longer producing the target that the CAR-T therapy was designed to recognize. When this happens, the patient subsequently experiences a cancer relapse that is no longer treatable by the same cell therapy.

Natural Killer (NK) T cells represent another type of anti-cancer immunotherapy that is also being tested in clinical trials. NK cells are part of the innate immune system responsible for defending your body against both infection and tumor formation.  NK cells target stressed cells by releasing cell-penetrating proteins that poke holes in the cells leading to induced cell death.  As an immunotherapy, NK cells have the potential to avoid both the issues of CRS and cancer cell immune evasion as they release a more limited array of cytokines and do not rely on a specific single target to recognize tumors.  NK cells instead selectively target tumor cells due to the presence of stress-induced proteins on the cancer cells. In addition, the cancer cells lack other proteins that would normally send out a “I’m a healthy cell you can ignore me” message to NK cells. Without that message, NK cells target and kill those cancer cells.

Developing new immunotherapies against cancer

Dan Kaufman, UCSD

Dr. Dan Kaufman of the University of California at San Diego is a physician-scientist whose research group developed a method to produce functional NK cells from human pluripotent stem cells (PSC).  In order to overcome a major hurdle in the use of NK cells as an anti-cancer therapeutic, Dr. Kaufman is exploring using stem cells as a limitless source to produce a scalable, standardized, off-the-shelf product that could treat thousands of patients.  CIRM is currently funding Dr. Kaufman’s work under both a Discovery Quest award and a just recently funded Translational research award in order to try to advance this candidate approach.

In the CIRM Translational award, Dr. Kaufman is looking to cure acute myelogenous leukemia (AML) which in the US has a 5-year survival rate of 27% (National Cancer Institute, 2017) and is estimated to kill over 10,000 individuals this year (American Cancer Society, 2017).  He has previously shown that his stem cell-derived NK cells can kill human cancer cells in a dish and in mouse models, and his goals are to perform preliminary safety studies and to develop a process to scale his production of NK cells to support a clinical trial in people.  Since NK cells don’t require the patient and the donor to be a genetic match to be effective, a bank of PSC-derived NK cells derived from a single donor could potentially treat thousands of patients.

Looking forward, CIRM is also providing Discovery funding to Dr. Kaufman to explore ways to improve his existing approach against leukemia as well as expand the potential of his stem cell-derived NK cell therapeutic by engineering his cells to directly target solid tumors like ovarian cancer.

The field of pluripotent stem cell-based immunotherapies is full of game-changing potential and important innovations like Dr. Kaufman’s are still in the early stages.  CIRM recognizes the importance of supporting early stage research and is currently investing $27.9 million to fund 8 active Discovery and Translation awards in the cancer immunotherapy area.

Budgeting for the future of the stem cell agency

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The CIRM Board discusses the future of the Stem Cell Agency

Budgets are very rarely exciting things; but they are important. For example, it’s useful for a family to know when they go shopping exactly how much money they have so they know how much they can afford to spend. Stem cell agencies face the same constraints; you can’t spend more than you have. Last week the CIRM Board looked at what we have in the bank, and set us on a course to be able to do as many of the things we want to, with the money we have left.

First some context. Last year CIRM spent a shade over $306 million on a wide range of research from Discovery, the earliest stage, through Translational and into Clinical trials. We estimate that is going to leave us with approximately $335 million to spend in the coming years.

A couple of years ago our Board approved a 5 year Strategic Plan that laid out some pretty ambitious goals for us to achieve – such as funding 50 new clinical trials. At the time, that many clinical trials definitely felt like a stretch and we questioned if it would be possible. We’re proving that it is. In just two years we have funded 26 new clinical trials, so we are halfway to our goal, which is terrific. But it also means we are in danger of using up all our money faster than anticipated, and not having the time to meet all our goals.

Doing the math

So, for the last couple of months our Leadership Team has been crunching the numbers and looking for ways to use the money in the most effective and efficient way. Last week they presented their plan to the Board.

It boiled down to a few options.

  • Keep funding at the current rate and run out of money by 2019
  • Limit funding just to clinical trials, which would mean we could hit our 50 clinical trial goal by 2020 but would not have enough to fund Discovery and Translational level research
  • Place caps on how much we fund each clinical trial, enabling us to fund more clinical trials while having enough left over for Discovery and Translational awards

The Board went for the third option for some good reasons. The plan is consistent with the goals laid out in our Strategic Plan and it supports Discovery and Translational research, which are important elements in our drive to develop new therapies for patients.

Finding the right size cap

Here’s a look at the size of the caps on clinical trial funding. You’ll see that in the case of late stage pre-clinical work and Phase 1 clinical trials, the caps are still larger than the average amount we funded those stages last year. For Phase 2 the cap is almost the same as the average. For Phase 3 the cap is half the amount from last year, but we think at this stage Phase 3 trials should be better able to attract funding from other sources, such as industry or private investors.

cap awards

Another important reason why the Board chose option three – and here you’ll have to forgive me for being rather selfish – is that it means the Administration Budget (which pays the salaries of the CIRM team, including yours truly) will be enough to cover the cost of running this research plan until 2020.

The bottom line is that for 2018 we’ll be able to spend $130 million on clinical stage research, $30 million for Translational stage, and $10 million for Discovery. The impact the new funding caps will have on clinical stage projects is likely to be small (you can see the whole presentation and details of our plan here) but the freedom it gives us to support the broad range of our work is huge.

And here is where to go if you are interested in seeing the different funding opportunities at CIRM.

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.


Related Links:

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

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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

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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.