CIRM-Funded Scientist is Developing a Stem Cell Therapy that Could Cure HIV

Photo Illustration by the Daily Beast

This week, UCLA scientist Scott Kitchen made the news for his efforts to develop a CIRM-funded stem cell gene therapy that could potentially cure patients infected with HIV. Kitchen’s work was profiled in the Daily Beast, which argued that his “research could significantly up survival rates from the virus.”

Scott Kitchen, UCLA Medicine

Kitchen and a team of scientists at the UCLA David Geffen School of Medicine are genetically modifying blood-forming, hematopoietic stem cells (HSCs) to express chimeric antigen receptors (CARs) that target HIV-infected cells. CARs are protein complexes on the surface of cells that are designed to recognize specific types of cells and are being developed as powerful immunotherapies to fight cancer and HIV infection.

These CAR-expressing HSCs can be transplanted into patients where they develop into immune cells called T cells and natural killer (NK) cells that will destroy cells harboring HIV. This strategy also aims to make patients resistant to HIV because the engineered immune cells will stick around to prevent further HIV infection.

By engineering a patient’s own blood-forming stem cells to produce an unlimited supply of HIV-resistant immune cells that can also eradicate HIV in other cells, Kitchen and his team are creating the possibility for a life-long, functional cure.

Dr. Kelly Shepard, Senior Science Officer of Discovery and Translation Research at CIRM, reflected on significance of Kitchen’s research in an interview:

Kelly Shepard

“This unique approach represents a two-pronged strategy whereby a patient’s own stem cells are engineered not only to be protected from new HIV infection, but also to produce HIV-specific CAR T cells that will seek out and destroy existing and new pools of HIV infection in that patient, ideally leading to a lifelong cure.”

Kitchen and his team are currently testing this stem cell-based CAR-T therapy against HIV in a large-animal model. Their latest findings, which were published recently in the journal PLOS Pathogens, showed that stem cell-derived human CAR T cells were effective at reducing the amount of HIV virus (called the viral load) in their animal-model. They also saw that the CAR T cells survived for more than two years without causing any toxic side effects. This work was funded by an earlier CIRM award led by another CIRM grantee, Dr. Jerome Zack, who is research collaborator of Kitchen’s.

In December 2017, Kitchen received a $1.7 million CIRM Discovery Stage Quest award so that the team can continue to optimize their stem cell CAR T therapy in animal models. Ultimately, they hope to gain insights into how this treatment could be further developed to treat patients with HIV.

Currently, there is no widely available cure for HIV and standard antiretroviral therapies are expensive, difficult for patients to manage and have serious side effects that reduce life expectancy. CIRM has awarded almost $75 million in funding to California scientists focused on developing novel stem cell-based therapies for HIV to address this unmet medical need. Three of these awards support early stage clinical trials, while the rest support earlier stage research projects like Kitchen’s.

CIRM Communications Director, Kevin McCormack, was quoted at the end Daily Beast article explaining CIRM’s strategy for tackling HIV:

“There are a lot of researchers working on developing stem cell therapies for HIV. We fund different approaches because at this stage we don’t know which approach will be most effective, and it may turn out that it’s ultimately a combination of these approaches, or others, that works.”

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

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

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

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

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

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


Novel regenerative drug for osteoarthritis entering clinical trialsThe Scripps Research Institute

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


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

Genetic ‘switches’ behind human brain evolutionScience Daily

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

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

UCLA scientists make sensory nerves from human stem cells for the first time

Being able to tell the difference between hot and cold or feeling the embrace of a loved one are experiences that many of us take for granted in our daily lives. But paralyzed patients who have lost their sense of touch don’t have this luxury.

Sensory nerves are cells in the spinal cord that send signals from outside of the body to the brain where they are translated into senses like touch, temperature and smell. When someone is paralyzed, their sensory nerves can be damaged, preventing these sensory signals from reaching the brain and leaving patients at risk for severe burns or not knowing when they’ve cut themselves because they can’t feel the pain.

A Journey to Restore Touch

A group of scientists led by Dr. Samantha Butler at the  Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA are on a research journey to restore the sense of touch in paralyzed patients and people with sensory neuron damage. In their earlier work, which we blogged about back in September, the team discovered that signaling proteins called BMPs played an important role in the development of sensory nerve cells in chicken embryos.

With the help of CIRM-funding, Butler and her team have made significant progress since this earlier study, and today, we bring you an exciting update on their latest findings published in the journal Stem Cell Reports.

Using a similar strategy to their previous study, Butler and her team attempted to make sensory nerve cells from human stem cells in a dish. They exposed human pluripotent stem cells to a specific BMP protein, BMP4, and a chemical called retinoic acid. This combination treatment created two types of sensory nerve cells: Dl1 cells, which allow you to sense your body’s position and movement, and Dl3 cells, which allow you to feel pressure.

Human embryonic stem cell-derived neurons (green) showing nuclei in blue. Left: with retinoic acid added. Right: with retinoic acid and BMP4 added, creating proprioceptive sensory nerve cells (pink). (Image source: UCLA Broad Stem Cell Research Center/Stem Cell Reports)

This is the first time that researchers have reported the ability to make sensory nerve cells from human stem cells. Another important finding was that the UCLA team was able to make sensory nerve cells from both human embryonic stem cells and human induced pluripotent stem cells (iPSCs), which are pluripotent stem cells derived from a patient’s own cells. The latter finding suggests a future where paralyzed patients can be treated with personalized cell-based therapies without the need for immune suppressing drugs.

Feeling the Future

This study, while still in its early stages, is an important step towards a future where paralyzed patients can regain feeling and their sense of touch. Restoring a patient’s ability to move their limbs or walk has dominated the field’s focus, but Butler argues in a UCLA news release that restoring touch is just as important:

Samantha Butler

“The field has for a long time focused on making people walk again. Making people feel again doesn’t have quite the same ring. But to walk, you need to be able to feel and to sense your body in space; the two processes really go hand in glove.”

 

Butler and her team are continuing on their journey to restore touch by transplanting the human sensory nerve cells into the spinal cords of mice to determine whether they can incorporate into the spine and function properly. If the transplanted cells show promise in animal models, the team will further develop this cell-based therapy for clinical trials.

Butler concluded,

“This is a long path. We haven’t solved how to restore touch but we’ve made a major first step by working out some of these protocols to create sensory interneurons.”

UCLA scientists on track to develop a stem cell replacement therapy for Duchenne Muscular Dystrophy

Muscle cells generated by April Pyle’s Lab at UCLA.

Last year, we wrote about a CIRM-funded team at UCLA that’s on a mission to develop a stem cell treatment for patients with Duchenne muscular dystrophy (DMD). Today, we bring you an exciting update on this research just in time for the holidays (Merry Christmas and Happy Hanukkah and Kwanza to our readers!).

DMD is a deadly muscle wasting disease that primarily affects young boys and young men. The UCLA team is trying to generate better methods for making skeletal muscle cells from pluripotent stem cells to regenerate the muscle tissue that is lost in patients with the condition. DMD is caused by genetic mutations in the dystrophin gene, which codes for a protein that is essential for skeletal muscle function. Without dystrophin protein, skeletal muscles become weak and waste away.

In their previous study, the UCLA team used CRISPR gene editing technology to remove dystrophin mutations in induced pluripotent stem cells (iPSCs) made from the skin cells of DMD patients. These corrected iPSCs were then matured into skeletal muscle cells that were transplanted into mice. The transplanted muscle cells successfully produced dystrophin protein – proving for the first time that DMD mutations can be corrected using human iPSCs.

A Step Forward

The team has advanced their research a step forward and published a method for making skeletal muscle cells, from DMD patient iPSCs, that look and function like real skeletal muscle tissue. Their findings, which were published today in the journal Nature Cell Biology, address a longstanding problem in the field: not being able to make stem cell-derived muscle cells that are mature enough to model DMD or to be used for cell replacement therapies.

Dr. April Pyle, senior author on the study and Associate Professor at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA explained in a news release:

April Pyle, UCLA.

“We have found that just because a skeletal muscle cell produced in the lab expresses muscle markers, doesn’t mean it is fully functional. For a stem cell therapy for Duchenne to move forward, we must have a better understanding of the cells we are generating from human pluripotent stem cells compared to the muscle stem cells found naturally in the human body and during the development process.”

By comparing the proteins expressed on the cell surface of human fetal and adult muscle cells, the team identified two proteins, ERBB3 and NGFR, that represented a regenerative population of skeletal muscle cells. They used these two markers to isolate these regenerative muscle cells, but found that the muscle fibers they created in a lab dish were smaller than those found in human muscle.

First author, Michael Hicks, discovered that using a drug to block a human developmental signaling pathway called TGF Beta pushed these ERBB3/NGFR cells past this intermediate stage and allowed them to mature into functional skeletal muscle cells similar to those found in human muscle.

Putting It All Together

In their final experiments, the team combined the new stem cell techniques developed in the current study with their previous work using CRISPR gene editing technology. First, they removed the dystrophin mutations in DMD patient iPSCs using CRISPR. Then, they coaxed the iPSCs into skeletal muscle cells in a dish and isolated the regenerative cells that expressed ERBB3 and NGFR. Mice that lacked the dystrophin protein were then transplanted with these cells and were simultaneously given an injection of a TGF Beta blocking drug.

The results were exciting. The transplanted cells were able to produce human dystrophin and restore the expression of this protein in the Duchenne mice.

Skeletal muscle cells isolated using the ERBB3 and NGFR surface markers (right) restore human dystrophin (green) after transplantation significantly greater than previous methods (left). (Image courtesy of UCLA)

Dr. Pyle concluded,

“The results were exactly what we’d hoped. This is the first study to demonstrate that functional muscle cells can be created in a laboratory and restore dystrophin in animal models of Duchenne using the human development process as a guide.”

In the long term, the UCLA team hopes to translate this research into a patient-specific stem cell therapy for DMD patients. In the meantime, the team will use funding from a recent CIRM Quest award to make skeletal muscle cells that can regenerate long-term in response to chronic injury in hopes of developing a more permanent treatment for DMD.

The UCLA study discussed in this blog received funding from Discovery stage CIRM awards, which you can read more about here and here.

Progress to a Cure for Bubble Baby Disease

Welcome back to our “Throwback Thursday” series on the Stem Cellar. Over the years, we’ve accumulated an arsenal of exciting stem cell stories about advances towards stem cell-based cures for serious diseases. Today we’re featuring stories about the progress of CIRM-funded clinical trials for the treatment of a devastating, usually fatal, primary immune disease that strikes newborn babies.

evangelina in a bubble

Evie, a former “bubble baby” enjoying life by playing inside a giant plastic bubble

‘Bubble baby disease’ will one day be a thing of the past. That’s a bold statement, but I say it with confidence because of the recent advancements in stem cell gene therapies that are curing infants of this life-threatening immune disease.

The scientific name for ‘bubble baby disease’ is severe combined immunodeficiency (SCID). It prevents the proper development of important immune cells called B and T cells, leaving newborns without a functioning immune system. Because of this, SCID babies are highly susceptible to deadly infections, and without treatment, most of these babies do not live past their first year. Even a simple cold virus can be fatal.

Scientists are working hard to develop stem cell-based gene therapies that will cure SCID babies in their first months of life before they succumb to infections. The technology involves taking blood stem cells from a patient’s bone marrow and genetically correcting the SCID mutation in the DNA of these cells. The corrected stem cells are then transplanted back into the patient where they can grow and regenerate a healthy immune system. Early-stage clinical trials testing these stem cell gene therapies are showing very encouraging results. We’ll share a few of these stories with you below.

CIRM-funded trials for SCID

CIRM is funding three clinical trials, one from UCLA, one at Stanford and one from UCSF & St. Jude Children’s Research Hospital, that are treating different forms of SCID using stem cell gene therapies.

Adenosine Deaminase-Deficient SCID

The first trial is targeting a form of the disease called adenosine deaminase-deficient SCID or ADA-SCID. Patients with ADA-SCID are unable to make an enzyme that is essential for the function of infection-fighting immune cells called lymphocytes. Without working lymphocytes, infants eventually are diagnosed with SCID at 6 months. ADA-SCID occurs in approximately 1 in 200,000 newborns and makes up 15% of SCID cases.

CIRM is funding a Phase 2 trial for ADA-SCID that is testing a stem cell gene therapy called OTL-101 developed by Dr. Don Kohn and his team at UCLA and a company called Orchard Therapeutics. 10 patients were treated in the trial, and amazingly, nine of these patients were cured of their disease. The 10th patient was a teenager who received the treatment knowing that it might not work as it does in infants. You can read more about this trial in our blog from earlier this year.

In a recent news release, Orchard Therapeutics announced that the US Food and Drug Administration (FDA) has awarded Rare Pediatric Disease Designation to OTL-101, meaning that the company will qualify for priority review for drug approval by the FDA. You can read more about what this designation means in this blog.

X-linked SCID

The second SCID trial CIRM is funding is treating patients with X-linked SCID. These patients have a genetic mutation on a gene located on the X-chromosome that causes the disease. Because of this, the disease usually affects boys who have inherited the mutation from their mothers. X-linked SCID is the most common form of SCID and appears in 1 in 60,000 infants.

UCSF and St. Jude Children’s Research Hospital are conducting a Phase 1/2 trial for X-linked SCID. The trial, led by Dr. Brian Sorrentino, is transplanting a patient’s own genetically modified blood stem cells back into their body to give them a healthy new immune system. Patients do receive chemotherapy to remove their diseased bone marrow, but doctors at UCSF are optimizing low doses of chemotherapy for each patient to minimize any long-term effects. According to a UCSF news release, the trial is planning to treat 15 children over the next five years. Some of these patients have already been treated and we will likely get updates on their progress next year.

CIRM is also funding a third clinical trial out of Stanford University that is hoping to make bone marrow transplants safer for X-linked SCID patients. The team, led by Dr. Judy Shizuru, is developing a therapy that will remove unhealthy blood stem cells from SCID patients to improve the survival and engraftment of healthy bone marrow transplants. You can read more about this trial on our clinical trials page.

SCID Patients Cured by Stem Cells

These clinical trial results are definitely exciting, but what is more exciting are the patient stories that we have to share. We’ve spoken with a few of the families whose children participated in the UCLA and UCSF/St. Jude trials, and we asked them to share their stories so that other families can know that there is hope. They are truly inspiring stories of heartbreak and joyful celebration.

Evie is a now six-year-old girl who was diagnosed with ADA-SCID when she was just a few months old. She is now cured thanks to Don Kohn and the UCLA trial. Her mom gave a very moving presentation about Evie’s journey at the CIRM Bridges Trainee Annual Meeting this past July.  You can watch the 20-minute talk below:

Ronnie’s story

Ronnie SCID kid

Ronnie: Photo courtesy Pawash Priyank

Ronnie, who is still less than a year old, was diagnosed with X-linked SCID just days after he was born. Luckily doctors told his parents about the UCSF/St. Jude trial and Ronnie was given the life-saving stem cell gene therapy before he was six months old. Now Ronnie is building a healthy immune system and is doing well back at home with his family. Ronnie’s dad Pawash shared his families moving story at our September Board meeting and you can watch it here.

Our mission at CIRM is to accelerate stem cell treatments to patients with unmet medical needs. We hope that by funding promising clinical trials like the ones mentioned in this blog, that one day soon there will be approved stem cell therapies for patients with SCID and other life-threatening diseases.

The Alpha Stem Cell Clinics: Innovation for Breakthrough Stem Cell Treatments

During this third week of the Month of CIRM, we are focusing on CIRM’s Infrastructure programs which are all focused on helping to accelerate stem cell treatments to patients with unmet medical needs.

So here is the question of the day: What is the world’s largest network of medical centers dedicated to providing stem cell treatments to patients?

The answer is the CIRM Alpha Stem Cell Clinics Network.

The CIRM Alpha Stem Cell Clinics Network consists of leading medical institutions throughout California.

The ASCC Network consists of six leading medical centers throughout California. In 2015, the Network was launched in southern California at the City of Hope, UC Irvine, UC Los Angeles, and UC San Diego. In September 2017, CIRM awarded funding to UC Davis and UC San Francisco to enable the Network to better serve patients throughout the state. Forty stem cell clinical trials have been conducted within the Network with hundreds of patients being treat for a variety of conditions, including:

  • Cancers of the blood, brain, lung and other sites
  • Organ diseases of the heart and kidney
  • Pediatric diseases
  • Traumatic injury to the brain and spine

A complete list of clinical trials may be found on our website.

The Alpha Clinics at UC Los Angeles and San Francisco are working collaboratively on breakthrough treatments for serious childhood diseases. This video highlights a CIRM-funded clinical trial at the UCLA Alpha Clinic that is designed to restore the immune system of patients with life-threatening immune deficiencies. A similar breakthrough treatment is also being used at the UCLA Alpha Clinic to treat sickle cell disease. A video describing this treatment is below.

Why do we need a specialized Network for stem cell clinical trials?

Stem cell treatments are unique in many ways. First, they consist of cells or cell products that frequently require specialized processing. For example, the breakthrough treatments for children, described above, requires the bone marrow to be genetically modified to correct defects. This “gene therapy” is performed in the Alpha Clinic laboratories, which are specifically designed to implement cutting edge gene therapy techniques on the patient’s stem cells.

Many of the cancer clinical trials also take the patient’s own cells and then process them in a laboratory. This processing is designed to enhance the patient’s ability to fight cancer using their own immune cells. Each Alpha Clinic has specialized laboratories to process cells, and the sites at City of Hope and UC Davis have world-class facilities for stem cell manufacturing. The City of Hope and Davis facilities produce high quality therapeutic products for commercial and academic clinical trial sponsors. Because of this ability, the Network has become a prime location internationally for clinical trials requiring processing and manufacturing services.

Another unique feature of the Network is its partnership with CIRM, whose mission is to accelerate stem cell treatments for patients with unmet medical needs. Often, this means developing treatments for rare diseases in which the patient population is comparatively small. For example, there about 40-100 immune deficient children born each year in the United States. We are funding clinical trials to help treat those children. The Network is also treating rare brain and blood cancers.

To find patients that may benefit from these treatments, the Network has developed the capacity to confidentially query over 20 million California patient records. If a good match is found, there is a procedure in place, that is reviewed by an ethics committee, where the patient’s doctor can be notified of the trial and pass that information to the patient. For patients that are interested in learning more, each Alpha Clinic has a Patient Care Coordinator with the job of coordinating the process of educating patients about the trial and assisting them if they choose to participate.

How Can I Learn More?

If you are a patient or a family member and would like to learn more about the CIRM Alpha Clinics, click here. There is contact information for each clinic so you can learn more about specific trials, or you can visit our Alpha Clinics Trials page for a complete list of trials ongoing in the Network.

If you are a patient or a trial sponsor interested in learning more about the services offered through our Alpha Clinics Network, visit our website.

Caught our eye: new Americans 4 Cures video, better mini-brains reveal Zika insights and iPSC recipes go head-to-head

How stem cell research gives patients hope (Karen Ring).
You can learn about the latest stem cell research for a given disease in seconds with a quick google search. You’ll find countless publications, news releases and blogs detailing the latest advancements that are bringing scientists and clinicians closer to understanding why diseases happen and how to treat or cure them.

But one thing these forms of communications lack is the personal aspect. A typical science article explains the research behind the study at the beginning and ends with a concluding statement usually saying how the research could one day lead to a treatment for X disease. It’s interesting, but not always the most inspirational way to learn about science when the formula doesn’t change.

However, I’ve started to notice that more and more, institutes and organizations are creating videos that feature the scientists/doctors that are developing these treatments AND the patients that the treatments could one day help. This is an excellent way to communicate with the public! When you watch and listen to a patient talk about their struggles with their disease and how there aren’t effective treatments at the moment, it becomes clear why funding and advancing research is important.

We have a great example of a patient-focused stem cell video to share with you today thanks to our friends at Americans for Cures, a non-profit organization that advocates for stem cell research. They posted a new video this week in honor of Stem Cell Awareness Day featuring patients and patient advocates responding to the question, “What does stem cell research give you hope for?”. Many of these patients and advocates are CIRM Stem Cell Champions that we’ve featured on our website, blog, and YouTube channel.

Americans for Cures is encouraging viewers to take their own stab at answering this important question by sharing a short message (on their website) or recording a video that they will share with the stem cell community. We hope that you are up for the challenge!

Mini-brains help uncover some of Zika’s secrets (Kevin McCormack).
One of the hardest things about trying to understand how a virus like Zika can damage the brain is that it’s hard to see what’s going on inside a living brain. That’s not surprising. It’s not considered polite to do an autopsy of someone’s brain while they are still using it.

Human organoid_800x533

Microscopic image of a mini brain organoid, showing layered neural tissue and different groups of neural stem cells (in blue, red and magenta) giving rise to neurons (green). Image: Novitch laboratory/UCLA

But now researchers at UCLA have come up with a way to mimic human brains, and that is enabling them to better understand how Zika inflicts damage on a developing fetus.

For years researchers have been using stem cells to help create “mini brain organoids”, essentially clusters of some of the cells found in the brain. They were helpful in studying some aspects of brain behavior but limited because they were very small and didn’t reflect the layered complexity of the brain.

In a study, published in the journal Cell Reports, UCLA researchers showed how they developed a new method of creating mini-brain organoids that better reflected a real brain. For example, the organoids had many of the cells found in the human cortex, the part of the brain that controls thought, speech and decision making. They also found that the different cells could communicate with each other, the way they do in a real brain.

They used these organoids to see how the Zika virus attacks the brain, damaging cells during the earliest stages of brain development.

In a news release, Momoko Watanabe, the study’s first author, says these new organoids can open up a whole new way of looking at the brain:

“While our organoids are in no way close to being fully functional human brains, they mimic the human brain structure much more consistently than other models. Other scientists can use our methods to improve brain research because the data will be more accurate and consistent from experiment to experiment and more comparable to the real human brain.”

iPSC recipes go head-to-head: which one is best?
In the ten years since the induced pluripotent stem cell (iPSC) technique was first reported, many different protocols, or recipes, for reprogramming adult cells, like skin, into iPSCs have been developed. These variations bring up the question of which reprogramming recipe is best. This question isn’t the easiest to answer given the many variables that one needs to test. Due to the cost and complexity of the methods, comparisons of iPSCs generated in different labs are often performed. But one analysis found significant lab-to-lab variability which can really muck up the ability to make a fair comparison.

A Stanford University research team, led by Dr. Joseph Wu, sought to eliminate these confounding variables so that any differences found could be attributed specifically to the recipe. So, they tested six different reprogramming methods in the same lab, using cells from the same female donor. And in turn, these cells were compared to a female source of embryonic stem cells, the gold standard of pluripotent stem cells. They reported their findings this week in Nature Biomedical Engineering.

Previous studies had hinted that the reprogramming protocol could affect the ability to fully specialize iPSCs into a particular cell type. But based on their comparisons, the protocol chosen did not have a significant impact on how well iPSCs can be matured. Differences in gene activity are a key way that researchers do side-by-side comparisons of iPSCs and embryonic stem cells. And based on the results in this study, the reprogramming method itself can influence the differences. A gene activity comparison of all the iPSCs with the embryonic stem cells found the polycomb repressive complex – a set of genes that play an important role in embryonic development and are implicated in cancer – had the biggest difference.

In a “Behind the Paper” report to the journal, first author Jared Churko, says that based on these findings, their lab now mostly uses one reprogramming protocol – which uses the Sendai virus to deliver the reprogramming genes to the cells:

“The majority of our hiPSC lines are now generated using Sendai virus. This is due to the ease in generating hiPSCs using this method as well as the little to no chance of transgene integration [a case in which a reprogramming gene inserts into the cells’ DNA which could lead to cancerous growth].”

Still, he adds a caveat that the virus does tend to linger in the cells which suggests that:

“cell source or reprogramming method utilized, each hiPSC line still requires robust characterization prior to them being used for downstream experimentation or clinical use.”

 

CIRM-Funded Clinical Trials Targeting Blood and Immune Disorders

This blog is part of our Month of CIRM series, which features our Agency’s progress towards achieving our mission to accelerate stem cell treatments to patients with unmet medical needs.

This week, we’re highlighting CIRM-funded clinical trials to address the growing interest in our rapidly expanding clinical portfolio. Today we are featuring trials in our blood and immune disorders portfolio, specifically focusing on sickle cell disease, HIV/AIDS, severe combined immunodeficiency (SCID, also known as bubble baby disease) and rare disease called chronic granulomatous disease (CGD).

CIRM has funded a total of eight trials targeting these disease areas, all of which are currently active. Check out the infographic below for a list of those trials.

For more details about all CIRM-funded clinical trials, visit our clinical trials page and read our clinical trials brochure which provides brief overviews of each trial.

CIRM-Funded Clinical Trials Targeting Cancers

Welcome to the Month of CIRM!

As we mentioned in last Thursday’s blog, during the month of October we’ll be looking back at what CIRM has done since the agency was created by the people of California back in 2004. To start things off, we’ll be focusing on CIRM-funded clinical trials this week. Supporting clinical trials through our funding and partnership is a critical cornerstone to achieving our mission: to accelerate stem cell treatments to patients with unmet medical needs.

Over the next four days, we will post infographics that summarize CIRM-funded trials focused on therapies for cancer, neurologic disorders, heart and metabolic disease, and blood disorders. Today, we review the nine CIRM-funded clinical trial projects that target cancer. The therapeutic strategies are as varied as the types of cancers the researchers are trying to eradicate. But the common element is developing cutting edge methods to outsmart the cancer cell’s ability to evade standard treatment.

For more details about all CIRM-funded clinical trials, visit our clinical trials page and read our clinical trials brochure which provides brief overviews of each trial.

UCLA scientists begin a journey to restore the sense of touch in paralyzed patients

Yesterday, CIRM-funded scientists at UCLA published an interesting study that sheds light on the development of sensory neurons, a type of nerve cell that is damaged in patients with spinal cord injury. Their early-stage findings could potentially, down the road, lead to the development of stem cell-based treatments that rebuild the sensory nervous system in paralyzed people that have lost their sense of touch.

Dr. Samantha Butler, a CIRM grantee and professor at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, led the study, which was published in the journal eLife.

Restoring sensation

Butler and her team were interested in understanding the basic development of sensory interneurons in the spinal cord. These are nerve cells in the spinal cord that receive sensory signals from the environment outside the body (like heat, pain and touch) and relay these signals to the brain where the senses are then perceived.

Developing spinal cord injury treatments often focus on the loss of movement caused by damage to the motor neurons in the spine that control our muscles. However, the damage caused to sensory neurons in the spine can be just as debilitating to people with paralysis. Without being able to feel whether a surface is hot or cold, paralyzed patients can sustain serious burn injuries.

Butler commented in a UCLA news release that attempting to restoring sensation in paralyzed patients is just as important as restoring movement:

Samantha Butler

“The understanding of sensory interneuron development has lagged far behind that of another class of neurons—called motor neurons—which control the body’s ability to move. This lack in understanding belies the importance of sensation: it is at the core of human experience. Some patients faced with the reality of paralysis place the recovery of the sense of touch above movement.”

BMPs are important for sensory neuron development

To restore sensation in paralyzed patients, scientists need to replace the sensory neurons that are damaged in the spine. To create these neurons, Butler looked to proteins involved in the early development of the spinal cord called bone morphogenetic proteins or BMPs.

BMPs are an important family of signaling proteins that influence development of the embryo. Their signaling can determine the fate or identity of cells including cells that make up the developing spinal cord.

It was previously thought that the concentration of BMPs determined what type of sensory neuron a stem cell would develop into, but Butler’s team found the opposite in their research. By studying developing chick embryos, they discovered that the type, not the concentration, of BMP matters when determining what subtype of sensory neuron is produced. Increasing the amount of a particular BMP in the chick spinal cord only produced more of the same type of sensory interneuron rather than creating a different type.

Increasing the concentration of a certain type of BMP increases the production of the same categories of sensory interneurons (red and green). (Image credit: UCLA)

The scientists confirmed these findings using mouse embryonic stem cells grown in the lab. Interestingly a different set of BMPs were responsible for deciding sensory neuron fate in the mouse stem cell model compared to the chick embryo. But the finding that different BMPs determine sensory neuron identity was consistent.

So what and what’s next?

While this research is still in its early stages, the findings are important because they offer a better understanding of sensory neuron development in the spinal cord. This research also hints at the potential for stem cell-based therapies that replace or restore the function of sensory neurons in paralyzed patients.

Madeline Andrews, the first author of the study, concluded:

“Central nervous system injuries and diseases are particularly devastating because the brain and spinal cord are unable to regenerate. Replacing damaged tissue with sensory interneurons derived from stem cells is a promising therapeutic strategy. Our research, which provides key insights into how sensory interneurons naturally develop, gets us one step closer to that goal.”

The next stop on the team’s research journey is to understand how BMPs influence sensory neuron development in a human stem cell model. The UCLA news release gave a sneak preview of their plans in the coming years.

“Butler’s team now plans to apply their findings to human stem cells as well as drug testing platforms that target diseased sensory interneurons. They also hope to investigate the feasibility of using sensory interneurons in cellular replacement therapies that may one day restore sensation to paralyzed patients.”