Dashed Dreams and New Hope: A Quest to Cure Thymic Deficiency

By Kelly Shepard, PhD., CIRM’s Associate Director, Discovery & Translation

CIRM has previously blogged about advances in treating certain forms of  “bubble baby” disease”, where a person is born with a defect in their blood forming stem cells that results in a deficient immune system, rendering them vulnerable to lethal infections by all manner of bacteria, virus or germ.

If a suitable donor can be found, or if the patient’s own defective cells can be corrected through gene therapy approaches, it is now possible to treat or cure such disorders through a bone marrow transplant. In this procedure, healthy blood stem cells are infused into the patient, taking up residence in his or her bone marrow and dividing to give rise to functioning immune cells such as T cells and B cells.

Unfortunately, there is another type of “bubble baby” disease that cannot be treated by providing healthy blood stem cells, because the defective immune system is caused by a different culprit altogether- a missing or dysfunctional thymus.

Created for the National Cancer Institute, http://www.cancer.gov

T Cells Go to School

What is a thymus?  Most of us give little thought to this leaf-shaped organ, which is large and important in our early childhoods, but becomes small and inconspicuous as we age. This transformation belies the critical role a thymus plays in the development of our adaptive immune systems, which takes place in our youth: to prepare our bodies to fight infections for the rest of our lives.

One might think of the thymus as a “school”, where immature T cells go to “learn” how to recognize and attack foreign antigens (surface markers), such as those found on microorganisms or tissues from other individuals. The thymus also “teaches” our immune system to distinguish “self” from “other” by eliminating any T cells that attack our own tissues. Without this critical function, our immune system could inadvertently turn against us, causing serious autoimmune disorders such as ulcerative colitis and myasthenia gravis.

Many children with a severely deficient or absent thymus, referred to as athymia, have inherited a chromosome that is missing a key stretch of genes on a region called 22q11. Doctors believe perhaps 1/2000-1/4000 babies are born with some type of deletion in this region, which leads to a variable spectrum of disorders called 22q11 syndrome that can affect just about any part of the body, and can even cause learning disabilities and mental illness.

Individuals with one form of 22q11, called DiGeorge Syndrome, are particularly affected in the heart, thymus, and parathyroid glands. In the United States, about 20 infants are born per year with the “complete” and most severe form of DiGeorge Syndrome, who lack a thymus altogether, and have severely depressed numbers of T cells for fighting infections. Without medical intervention, this condition is usually fatal by 24 months of age.

Optimism and Setback                                                                  

Although there are no therapies approved by the Food and Drug Administration (FDA) for pediatric athymia, Dr. Mary Louise Markert at Duke University and Enzyvant, Inc. have been pioneering an experimental approach to treat children with complete DiGeorge syndrome.

In this procedure, discarded thymic tissues are collected from infants undergoing cardiac surgery, where some of the thymus needs to be removed in order for the surgeon to gain access to the heart. These tissues are processed to remove potentially harmful donor T cells and then transplanted into the thigh of an athymic DiGeorge patient.

Results from early clinical trials seemed promising, with more than 70% of patients surviving, including several who are now ten years post-transplant. Based on those results, in June of 2019 Enzyvant applied to the FDA for a Biologics License Application (BLA), which is needed to be able to sell the therapy in the US. Unfortunately, only a few months later, Enzyvant announced that the FDA had declined to approve the BLA due to manufacturing concerns.

While it may be possible to address these issues in time, the need to step back to the drawing board was a devastating blow to the DiGeorge Community, who have waited decades for a promising treatment to emerge on the horizon.

New Opportunities

Despite the setback, there is reason to hope. In early 2019, CIRM granted a “Quest” Award to team of investigators at Stanford University to develop a novel stem cell based approach for treating thymic deficiency. Co-led by Katja Weinacht, a pediatric hematologist/oncologist, and Vittorio Sebastiano, a stem cell expert and developmental biologist, the team’s strategy is to coax induced pluripotent stem cells (iPS) in the laboratory to differentiate into thymic tissue, which could then be transplanted into patients using the route pioneered by Duke and Enzyvant.

Katja Weinacht: Photo courtesy Stanford Children’s Health

The beauty of this new approach is that pluripotent stem cells are essentially immortal in culture, providing an inexhaustible supply of fresh thymic cells for transplant, thereby allowing greater control over the quality and consistency of donor tissues. A second major advantage is the possibility of using pluripotent cells from the patient him/herself as the source, which should be perfectly immune-matched and alleviate the risk of rejection and autoimmunity that comes with use of donated tissues.

Vittorio Sebastiano: Photo courtesy Stanford

Sounds easy, so what are the challenges? As with many regenerative medicine approaches, the key is getting a pluripotent stem cell to differentiate into the right type of cells in the lab, which is a very different environment than what cells experience naturally when they develop in the context of an embryo and womb, where many cells are interacting and providing complex, instructive cues to one another. The precise factors and timing all need to be worked out and in most cases, this is done with an incomplete knowledge of human development.

A second challenge relates to using cells from DiGeorge patients to produce thymic tissue, which are missing several genes on their 22nd chromosome and will likely require sophisticated genetic engineering to restore this ability.

Fortunately, Drs. Weinacht and Sebastiano are up to the challenge, and have already made progress in differentiating human induced pluripotent stem cells (iPS) into thymic lineage intermediates that appear to be expressing the right proteins at the right time. They plan to combine these cells with engineered materials to create a three-dimensional (3D) tissue that more closely resembles an authentic organ, and which can be tested for functionality in athymic mice.

There is more work to be done, but these advances, along with continued technological improvements and renewed efforts from Enzyvant, could forge a path to the clinic and  lead to a brighter future for patients suffering from congenital athymia and other forms of thymic dysfunction.

 

CIRM supported study of gene silencer blocks ALS degeneration, saves motor function

Dr. Martin Marsala, UC San Diego

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a neurodegenerative disease that destroys the nerve cells in the brain and spinal cord. As a result of ALS, the motor neurons that enable bodily movement and muscle control are harmed, which can make it difficult to move, speak, eat, and breathe. This condition usually affects people from age 40 to 70, but individuals in their 20s and 30s have also been known to develop ALS. Unfortunately there is no cure for this condition.

However, a study supported by CIRM and conducted by Dr. Martin Marsala at UC San Diego is using a mouse model to look at an approach that uses a gene silencer to protect motor neurons before or shortly after ALS symptoms start to develop.

The gene silencer works by turning off a targeted gene and is delivered via injection. In the case of ALS, previous research suggests that mutations in a gene called SOD1 may cause motor neuronal cell death, resulting in ALS. For this study, Dr. Marsala and his team injected the gene silencer at two sites in the spinal cord in adult mice expressing an ALS-causing mutation of the SOD1 gene. The mice injected did not yet display symptoms of ALS or had only begun showing symptoms.

In mice not yet showing ALS symptoms, they displayed normal neurological function with no onset ALS symptoms after treatment. Additionally, near complete protection of motor neurons and other cells was observed. In mice that had just began showing ALS symptoms, the injection blocked further disease progression as well as further harm to remaining motor neurons. Both of these groups of mice lived without negative side effects for the duration of the study.

In a news release, Dr. Marsala talks about what these results mean for the study of ALS.

“At present, this therapeutic approach provides the most potent therapy ever demonstrated in mouse models of mutated SOD1 gene-linked ALS.”

The next steps for this research would be to conduct additional safety studies with a larger animal model in order to determine an optimal, safe dose for the treatment.

The full results of this study were published in Nature Medicine.

In addition to supporting this research for ALS, CIRM has funded two clinical trials in the field as well. One of these trials is being conducted by BrainStorm Cell Therapeutics and the other trial is being by Cedars-Sinai Medical Center.

Brain wave of an idea is picked as one of the top science stories of the year

Dr. Alysson Muotri: Photo courtesy UC San Diego

It’s always gratifying when one of the projects you have funded starts to show promising results. It says your faith in the research and the researcher were well founded. But it’s also fun when the project you fund turns up some really cool findings and is picked as a top science story of the year.

That’s what happened with UC San Diego researcher Alysson Muotri’s work on growing brain organoids (tiny clumps of brain cells, created in a dish, that can mimic some of the properties of a real brain). His work, funded by yours truly, was chosen by Discover Magazine as one of the Top Ten Science stories of 2019.

You can read about that here.

Or you can watch a video about the work.

Alysson has done some extraordinary work in the past and we look forward to seeing even more extraordinary science from him in 2020.

Four CIRM Funded Trials Release Results at 2019 ASH Meeting

With more than 17,000 members from nearly 100 countries, the American Society of Hematology (ASH) is an organization composed of clinicians and scientists around the world working to conquer various blood diseases. Currently, they are having their 61st Annual ASH Meeting to highlight some of the exciting work going on in the field. Four of our CIRM funded trials have released promising results at this conference and we wanted to take the opportunity to highlight them below.

Sangamo Therapeutics

Sangamo Therapeutics is conducting a CIRM-funded clinical trial for beta-thalassemia, a severe form of anemia caused by mutations in the hemoglobin gene. The therapy Sangamo is testing takes a patient’s own blood stem cells and, using a gene-editing technology called zinc finger nuclease (ZFN), provides a functional copy of the hemoglobin gene. These modified cells are then given back to the patient. The company announced preliminary results from their first three patients treated. in the clinical trials at the ASH 2019 Conference as well.

Some of the highlights are the following:

  • The first three patients experienced prompt hematopoietic reconstitution, meaning that their supply of blood stem cells was restored.
  • The first three patients experienced no clonal hematopoiesis, meaning that the blood stem cells did not create cells with mutations in the DNA
  • Additional study results are expected in late 2020 once enrollment is complete and all six patients have longer follow-up

You can read more detailed results regarding the first three patients in the press release.

Forty Seven, Inc.

In another CIRM funded trial, Forty Seven, Inc. is testing a treatment for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The treatment involves an antibody called magrolimab in combination with the chemotherapy drug azacitidine. Cancer cells express a signal that send a “don’t eat me” message to white blood cells that are part of the immune system designed to “eat” and destroy unhealthy cells. Magrolimab works by blocking the signal, enabling the body’s own immune system to detect these evasive cancer cells. The goal is to use both magrolimab and azacitidine to make the cancer stem cells vulnerable to being attacked and destroyed by the immune system.

Of the 46 patients evaluated, 24 patients had untreated higher-risk MDS and 22 patients had untreated AML. None of the patients were eligible for treatment with chemotherapy.

In higher-risk MDS, the overall response rate (ORR), which is the proportion of patients in a trial whose tumor is destroyed or significantly reduced by a treatment, was 92%.

Within this group of patients with an ORR, the following was observed:

  • 12 patients (50%) achieved a complete response (CR), meaning that they experienced a disappearance of all signs of cancer in response to treatment.
  • Two patients (8%) achieved hematologic (blood) improvement. 
  • Additionally, two patients (8%) achieved stable disease, meaning the cancer is neither increasing nor decreasing in extent or severity.

In untreated AML, the ORR was 64% and the following was observed within this group patients with an ORR:

  • Nine patients (41%) achieved a CR
  • Three patients (14%) achieved a CR with an incomplete blood count recovery (CRi)
  • One patient (5%) achieved a morphologic leukemia-free state (MLFS), which is defined as the disappearance of all cells with morphologic characteristics of leukemia, accompanied by bone marrow recovery, in response to treatment.
  • Seven patients (32%) achieved stable disease (SD)

The median time to response among MDS and AML patients treated with the combination was 1.9 months.

More details regarding these results are available via the news release.

Oncternal Therapeutics

Onceternal Therapeutics, which is conducting a CIRM-funded trial for a treatment for lymphoma and leukemia, presented results at the 2019 ASH Meeting. The treatment involves an antibody called cirmtuzumab (named after yours truly) being used with a cancer fighting drug called ibrutinib. The antibody recognizes and attaches to a protein on the surface of cancer stem cells. This attachment disables the protein, which slows the growth of the leukemia and makes it more vulnerable to anti-cancer drugs.

Some of the results presented are summarized as follows:

  • Twenty-nine of the 34 patients achieved a response, for an overall best objective response rate of 85%.
  • One patient achieved a complete response (CR) and remained in remission six months after completion of the trial and discontinuation of all anti-CLL therapy. In addition, three patients met radiographic and hematologic response criteria for Clinical CR.
  • Five patients had stable disease.
  • The total clinical benefit rate was 100%.
  • None of the patients died or saw their disease progress.
  • Patients achieved responses rapidly, with 68% of patients achieving a clinical response by three months on the combination therapy.
  • The rise in leukemic cell counts that is typically seen in the first six months with ibrutinib by itself was blunted with the addition of cirmtuzumab, and leukemic cell counts returned toward baseline and normal levels rapidly.

You can read more about these results in the official press release.

Rocket Pharmaceuticals

Last, but not least, Rocket Pharmaceuticals presented results at the 2019 ASH Conference related to a CIRM-funded trial for Leukocyte Adhesion Deficiency-I (LAD-I), a rare pediatric disease caused by a mutation in a specific gene that affects the body’s ability to combat infections. As a result, there is low expression of neutrophil (CD18). The company is testing a treatment that uses a patient’s own blood stem cells and inserts a functional version of the gene.  These modified stem cells are then reintroduced back into the patient. The goal is to establish functional immune cells, enabling the body to combat infections.  

Here are some of the highlights from the presentation:

  • Initial results from the first pediatric patient treated demonstrate early evidence of safety and potential effectiveness. 
  • The patient exhibited early signs of engraftment
  •  The patient also displayed visible improvement of multiple disease-related skin lesions after receiving therapy
  •  No safety issues related to administration have been identified

More detailed results on this trial are available via the news release.

Researchers create a better way to grow blood stem cells

UCLA’s Dr. Hanna Mikkola and Vincenzo Calvanese, lead scientists on the study. Photo courtesy UCLA

Blood stem cells are a vital part of us. They create all the other kinds of blood cells in our body and are used in bone marrow transplants to help people battling leukemia or other blood cancers. The problem is growing these blood stem cells outside the body has always proved challenging. Up till now.

Researchers at UCLA, with CIRM funding, have identified a protein that seems to play a key role in helping blood stem cells renew themselves in the lab. Why is this important? Because being able to create a big supply of these cells could help researchers develop new approaches to treating a wide array of life-threatening diseases.

One of the most important elements that a stem cell has is its ability to self-renew itself over long periods of time. The problem with blood stem cells has been that when they are removed from the body they quickly lose their ability to self-renew and die off.

To discover why this is the case the team at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA analyzed blood stem cells to see which genes turn on and off as those cells turn into other kinds of blood cells – red, white and platelets. They identified one gene, called MLLT3, which seemed to play a key role in helping blood stem cells self-renew.

To test this finding, the researchers took blood stem cells and, in the lab, inserted copies of the MLLT3 gene into them. The modified cells were then able to self-renew at least 12 times; a number far greater than in the past.

Dr. Hanna Mikkola, a senior author of the study says this finding could help advance the field:

“If we think about the amount of blood stem cells needed to treat a patient, that’s a significant number. But we’re not just focusing on quantity; we also need to ensure that the lab-created blood stem cells can continue to function properly by making all blood cell types when transplanted.”

Happily, that seemed to be the case. When they subjected the MLLT3-enhanced blood stem cells to further analysis they found that they appeared to self-renew at a safe rate and didn’t multiply too much or mutate in ways that could lead to leukemia or other blood cancers.

The next steps are to find more efficient and effective ways of keeping the MLLT3 gene active in blood stem cells, so they can develop ways of using this finding in a clinical setting with patients.

Their findings are published in the journal Nature.

What to be thankful for this Thanksgiving: scientists hard at work

Biomedical technician Louis Pinedo feeds stem cells their special diet. Photo by Cedars-Sinai.

With Thanksgiving and Black Friday approaching in the next couple of days, we wanted to give thanks to all the scientists hard at work during this holiday weekend. Science does not sleep–the groundbreaking research and experiments that are being conducted do not take days off. There are tasks in the laboratory that need to be done daily otherwise months, even years, of important work can be lost in an instant.

Below is a story from Cedars-Sinai Medical Center that talks about one of these scientists, Louis Pinedo, that will be working during this holiday weekend.

Stem Cells Don’t Take the Day Off on Thanksgiving

Inside a Cedars-Sinai Laboratory, Where a Scientist Will be Busy Feeding Stem Cells During the Holiday

While most of us are stuffing ourselves with turkey and pumpkin pie at home on Thanksgiving Day, the staff at one Cedars-Sinai laboratory will be on the job, feeding stem cells.

“Stem cells do not observe national holidays,” says Loren Ornelas-Menendez, the manager of a lab that converts samples of adult skin and blood cells into stem cells—the amazing “factories” our bodies use to make our cells. These special cells help medical scientists learn how diseases develop and how they might be cured.

Stem cells are living creatures that must be hand-fed a special formula each day, monitored for defects and maintained at just the right temperature. And that means the cell lab is staffed every day, 52 weeks a year.

These cells are so needy that Ornelas-Menendez jokes: “Many people have dogs. We have stem cells.”

Millions of living stem cells are stored in the David and Janet Polak Foundation Stem Cell Core Laboratory at the Cedars-Sinai Board of Governors Regenerative Medicine Institute. Derived from hundreds of healthy donors and patients, they represent a catalogue of human ills, including diabetes, breast cancer, Alzheimer’s disease, Parkinson’s disease and Crohn’s disease.

Cedars-Sinai scientists rely on stem cells for many tasks: to make important discoveries about how our brains develop; to grow tiny versions of human tissues for research; and to create experimental treatments for blindness and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) that they are testing in clinical trials.

The lab’s main collection consists of induced pluripotent stem cells, or iPSCs, which mimic the all-powerful stem cells we all had as embryos. These ingenious cells, which Cedars-Sinai scientists genetically engineer from adult cells, can make any type of cell in the body—each one matching the DNA of the donor. Other types of stem cells in the lab make only one or two kinds of cells, such as brain or intestinal cells.

Handy and versatile as they are, stem cells are high-maintenance. A few types, such as those that make connective tissue cells for wound healing, can be fed as infrequently as every few days. But iPSCs require a daily meal to stay alive, plus daily culling to weed out cells that have started to turn into cells of the gut, brain, breast or other unwanted tissues.

So each day, lab staff suit up and remove trays of stem cells from incubators that are set at a cozy 98.6 degrees. Peering through microscopes, they carefully remove the “bad” cells to ensure the purity of the iPSCs they will provide to researchers at Cedars-Sinai and around the world.

While the cells get sorted, a special feeding formula is defrosting in a dozen bottles spread around a lab bench. The formula incudes sodium, glucose, vitamins and proteins. Using pipettes, employees squeeze the liquid into food wells inside little compartments that contain the iPSCs. Afterward, they return the cells to their incubators.

The lab’s 10 employees are on a rotating schedule that ensures the lab is staffed on weekends and holidays, not just weekdays. On Thanksgiving Day this year, biomedical technician Louis Pinedo expects to make a 100-mile round trip from his home in Oxnard, California, to spend several hours at work, filling nearly 600 feeding wells. On both Christmas and New Year’s Day, two employees are expected to staff the lab.

All this ceaseless effort helps make Cedars-Sinai one of the world’s top providers of iPSCs, renowned for consistency and quality. Among the lab’s many clients are major universities and the global Answer ALS project, which is using the cells in its search for a cure for this devastating disease.

That’s why the lab’s director, Dhruv Sareen, PhD, suggests that before you sit down to your Thanksgiving feast, why not lift a glass to these hard-working lab employees?

“One day the cells they tend could lead to treatments for diseases that have plagued humankind for centuries,” he says. “And that’s something to be truly thankful for.”

Machine learning used to pattern stem cells – a vital step in organ modeling

Gladstone researchers discovered a method to control the patterns stem cells form in a dish. The work was led by Senior Investigator Todd McDevitt (left) and his team, including (pictured) David Joy and Ashley Libby.

When someone thinks of machine learning, the first thing that comes to mind might be the technology used by Netflix or Hulu to suggest new shows based on their viewing history. But what if this technology could be applied towards advancing the field of regenerative medicine?

Thanks to a CIRM funded study, a team of scientists lead by Dr. Todd McDevitt at the Gladstone Institutes have found a way to to use machine learning to control the spacial organization of stem cells, a key process that plays a vital role in organ development. This new understanding of how stem cells organize themselves in 3D is an important step towards being able to create functional and/or personalized organs for research or organ transplants.

“We’ve shown how we can leverage the intrinsic ability of stem cells to organize,” said Dr. McDevitt in a news release from Gladstone Institutes. “This gives us a new way of engineering tissues, rather than a printing approach where you try to physically force cells into a specific configuration.”

In their normal environment, stem cells are able to form patterns as they mature and over time morph into the tissues seen in an adult organism. One type of stem cell, called an induced pluripotent stem cell (iPSC), can become nearly every cell type of the body. In fact, researchers have already found ways to direct iPSCs to become various cell types such as those in the heart or brain.

Unfortunately, attempting to replicate the pattern formation of stem cells as they mature has been challenging. Some have used 3D printing to lay out stem cells in a desired shape, but the cells often migrated away from their initial locations.

In the same news release mentioned above, Ashley Libby, a graduate student at Gladstone and co-first author of this study, said that,

“Despite the importance of organization for functioning tissues, we as scientists have had difficulty creating tissues in a dish with stem cells. Instead of an organized tissue, we often get a disorganized mix of different cell types.”

To solve this problem, the scientists used a computational model to learn how to influence stem cells into forming new arrangements, such as those that might be useful in generating personalized organs.

Previous studies conducted by Dr. McDevitt showed that blocking the expression of two genes, called ROCK1 and CDH1, affected the layout of iPS cells grown in a petri dish.

In this current study, the scientists used CRISPR/Cas9 gene editing (you can read about this technology in more detail here) to block expression of ROCK1 and CDH1 at any time by adding a drug to the iPSCs. This was done to see if they could predict stem cell arrangement based on the alterations made to ROCK1 and CDH1 at different drug doses and time periods.

The team carried out various experiments with different doses and timing. Then, the data was input into a machine-learning program designed to identify patterns, something that could take a human months to identify.

(Left) video showing simulated interactions between different stem cell populations. (Right) image of stem cells grown in conditions dictated by the machine-learning program generate a colony that forms a bull’s-eye pattern, as predicted.

The machine-learning program used the data to predict ways that ROCK1 and CDH1 affect iPSC organization. The scientists then began to see whether the program could compute how to make entirely new patterns, like a bull’s-eye or an island of cells. The team says the results were little short of astounding. Machine learning was able to accurately predict conditions that will cause stem cell colonies to form desired patterns.

The full study was published in the journal Cell Systems.

What is IPEX syndrome? A deeper dive into a CIRM funded award

Brian Lookofsky (left) and his son Taylor Lookofsky (right) at the CIRM Board meeting on October 31, 2019. Taylor is living with IPEX syndrome.

Last week we shared a powerful story of patient advocate Taylor Lookofsky, a young man with IPEX syndrome. In his speech, he talked about the impact the condition has had on his life. Taylor shared this speech a few weeks ago right after the CIRM Board awarded $5.53 million to Dr. Rosa Bacchetta for her work related to IPEX syndrome.

But this begs the question, what exactly is IPEX syndrome? What is the approach that Dr. Bacchetta is working on? For those of you interested in the deeper scientific dive, we will elaborate on this complex disease and promising approach.

IPEX syndrome is a rare disease that primarily affects males and is caused by a genetic mutation that leads to a lack of specialized immune cells called regulatory T cells (Tregs).

Without the presence of Tregs, a patient’s own immune cells attack the body’s own tissues and organs, a phenomenon known as autoimmunity.  This affects many different areas such as the intestines, skin, and hormone-producing glands and can be fatal in early childhood. 

Current treatment options include a bone marrow transplant and immune suppressing drugs.  However, immune suppression is only partially effective and can cause severe side effects while bone marrow transplants are limited due to lack of matching donors.

Dr. Rosa Bacchetta and her team at Stanford will take a patient’s own blood in order to obtain CD4+ T cells.  Then, using gene therapy, they will insert a normal version of the mutated gene into the CD4+ T cells, allowing them to function like normal Treg cells.  These Treg-like cells would then be reintroduced back into the patient, hopefully creating an IPEX-free blood supply and correcting the problem.

Furthermore, if successful, this treatment could be adapted for treatment of other autoimmune conditions where Treg cells are underlying problem.

The goal of this work is to complete the work necessary to conduct a clinical trial for IPEX syndrome.

Transplanted stem cells used to grow fully functional lungs in mice

Illustration of a human lung

According to organ donation statistics from the Health Resources & Services Administration, over 113,000 men, women, and children are on the national transplant waiting list as of July 2019. Another person is added to the waiting list every 10 minutes and 20 people die each day waiting for a transplant.

As these statistics highlight, there is a tremendous need for obtaining viable organs for people that are in need of a transplant. It is because of this, that scientists and researchers are exploring ways of using stem cells to potentially grow fully functional organs.

Dr. Hiromitsu Nakauchi, Stanford University

In a CIRM-supported study, Dr. Hiromitsu Nakauchi at Stanford University, in collaboration with Dr. Wellington Cardoso at Columbia University, were able to grow fully functional lungs in mouse embryos using transplanted stem cells. The full study, published in Nature Medicine, suggests that it may be possible to grow human lungs in animals and use them for patients in dire need of transplants or to study new lung treatments.

In the study, the researchers took stem cells and implanted them into modified mouse embryos that either lacked the stem cells necessary to form a lung or were not able to produce enough cells to make a lung. It was found that the implanted stem cells formed fully functional lungs that allowed the mice to live well into adulthood. Additionally, there were no signs of the mouse’s body rejecting the lung tissue composed of donor stem cells.

In a press release, Dr. Cardoso expressed optimism for the study and the potential the results hold:

“Millions of people worldwide who suffer from incurable lung diseases die without treatment due to the limited supply of donor lungs for transplantation. Our study shows that it may eventually be possible to develop new strategies for generating human lungs in animals for transplantation as an alternative to waiting for donor lungs.”

CIRM Board Awards $15.8 Million to Four Translational Research Projects

Last week, the CIRM Board approved $32.92 million in awards directed towards four new clinical trials in vision related diseases and Parkinson’s Disease.

In addition to these awards, the Board also approved investing $15.80 million in four awards in the Translational Research program. The goal of this program is to help promising projects complete the testing needed to begin talking to the US Food and Drug Administration (FDA) about holding a clinical trial.

Before we go into more specific details of each one of these awards, here is a table summarizing these four new projects:

ApplicationTitleInstitutionAward Amount
TRAN1 11536Ex Vivo Gene Editing of Human Hematopoietic Stem Cells for the Treatment of X-Linked Hyper IgM Syndrome  UCLA $4,896,628
TRAN1 11555BCMA/CS1 Bispecific CAR-T Cell Therapy to Prevent Antigen Escape in Multiple Myeloma  UCLA $3,176,805
TRAN1 11544 Neural Stem cell-mediated oncolytic immunotherapy for ovarian cancer  City of Hope $2,873,262
TRAN1 11611Development of a human stem cell-derived inhibitory neuron therapeutic for the treatment of chronic focal epilepsyNeurona Therapeutics$4,848,750
Dr. Caroline Kuo, UCLA

$4.89 million was awarded to Dr. Caroline Kuo at UCLA to pursue a gene therapy approach for X-Linked Hyper IgM Syndrome (X-HIM).

X-HIM is a hereditary immune disorder observed predominantly in males in which there are abnormal levels of different types of antibodies in the body.  Antibodies are also known as Immunoglobulin (Ig) and they combat infections by attaching to germs and other foreign substances, marking them for destruction.  In infants with X-HIM, there are normal or high levels of antibody IgM but low levels of antibodies IgG, IgA, and IgE.  The low level of these antibodies make it difficult to fight off infection, resulting in frequent pneumonia, sinus infections, ear infections, and parasitic infections.  Additionally, these infants have an increased risk of cancerous growths. 

The gene therapy approach Dr. Kuo is continuing to develop involves using CRISPR/Cas9 technology to modify human blood stem cells with a functional version of the gene necessary for normal levels of antibody production.  The ultimate goal would be to take a patient’s own blood stem cells, modify them with the corrected gene, and reintroduce them back into the patient.

CIRM has previously funded Dr. Kuo’s earlier work related to developing this gene therapy approach for XHIM.

Dr. Yvonne Chen, UCLA

$3.17 million was awarded to Dr. Yvonne Chen at UCLA to develop a CAR-T cell therapy for multiple myeloma (MM).

MM is a type of blood cancer that forms in the plasma cell, a type of white blood cell that is found in the bone marrow.  An estimated 32,110 people in the United States will be diagnosed with MM in 2019 alone.  Several treatment options are available to patients with MM, but there is no curative therapy.

The therapy that Dr. Chen is developing will consist of a genetically-modified version of the patient’s own T cells, which are an immune system cell that can destroy foreign or abnormal cells.  The T cells will be modified with a protein called a chimeric antigen receptor (CAR) that will recognize BCMA and CS1, two different markers found on the surface of MM cells.  These modified T cells (CAR-T cells) are then infused into the patient, where they are expected to detect and destroy BCMA and CS1 expressing MM cells.

Dr. Chen is using CAR-T cells that can detect two different markers in a separate clinical trial that you can read about in a previous blog post.

Dr. Karen Aboody, City of Hope

$2.87 million was awarded to Dr. Karen Aboody at City of Hope to develop an immunotherapy delivered via neural stem cells (NSCs) for treatment of ovarian cancer.

Ovarian cancer affects approximately 22,000 women per year in the United States alone.  Most ovarian cancer patients eventually develop resistance to chemotherapy, leading to cancer progression and death, highlighting the need for treatment of recurring ovarian cancer.

The therapy that Dr. Aboody is developing will use an established line of NSCs to deliver a virus that specifically targets these tumor cells.  Once the virus has entered the tumor cell, it will continuously replicate until the cell is destroyed.  The additional copies of the virus will then go on to target neighboring tumor cells.  This process could potentially stimulate the body’s own immune response to fight off the cancer cells as well.

Dr. Cory Nicholas, Neurona Therapeutics

$4.85 million was awarded to Dr. Cory Nicholas at Neurona Therapeutics to develop a treatment for epilepsy.

Epilepsy affects more than 3 million people in the United States with about 150,000 newly diagnosed cases in the US every year. It results in persistent, difficult to manage, or uncontrollable seizures that can be disabling and significantly impair quality of life. Unfortunately, anti-epileptic drugs fail to manage the disease in a large portion of people with epilepsy. Approximately one-third of epilepsy patients are considered to be drug-resistant, meaning that they do not adequately respond to at least two anti-epileptic drugs.

The therapy that Dr. Nicholas is developing will derive interneurons from human embryonic stem cells (hESCs). These newly derived interneurons would then be delivered to the brain via injection whereby the new cells are able to help regulate aberrant brain activity and potentially eliminate or significantly reduce the occurrence of seizures.

CIRM has previously funded the early stage development of this approach via a comprehensive grant and discovery grant.