Stem Cell Agency Invests in New Immunotherapy Approach to HIV, Plus Promising Projects Targeting Blindness and Leukemia

HIV AIDS

While we have made great progress in developing therapies that control the AIDS virus, HIV/AIDS remains a chronic condition and HIV medicines themselves can give rise to a new set of medical issues. That’s why the Board of the California Institute for Regenerative Medicine (CIRM) has awarded $3.8 million to a team from City of Hope to develop an HIV immunotherapy.

The City of Hope team, led by Xiuli Wang, is developing a chimeric antigen receptor T cell or CAR-T that will enable them to target and kill HIV Infection. These CAR-T cells are designed to respond to a vaccine to expand on demand to battle residual HIV as required.

Jeff Sheehy

CIRM Board member Jeff Sheehy

Jeff Sheehy, a CIRM Board member and patient advocate for HIV/AIDS, says there is a real need for a new approach.

“With 37 million people worldwide living with HIV, including one million Americans, a single treatment that cures is desperately needed.  An exciting feature of this approach is the way it is combined with the cytomegalovirus (CMV) vaccine. Making CAR T therapies safer and more efficient would not only help produce a new HIV treatment but would help with CAR T cancer therapies and could facilitate CAR T therapies for other diseases.”

This is a late stage pre-clinical program with a goal of developing the cell therapy and getting the data needed to apply to the Food and Drug Administration (FDA) for permission to start a clinical trial.

The Board also approved three projects under its Translation Research Program, this is promising research that is building on basic scientific studies to hopefully create new therapies.

  • $5.068 million to University of California at Los Angeles’ Steven Schwartz to use a patient’s own adult cells to develop a treatment for diseases of the retina that can lead to blindness
  • $4.17 million to Karin Gaensler at the University of California at San Francisco to use a leukemia patient’s own cells to develop a vaccine that will stimulate their immune system to attack and destroy leukemia stem cells
  • Almost $4.24 million to Stanford’s Ted Leng to develop an off-the-shelf treatment for age-related macular degeneration (AMD), the leading cause of vision loss in the elderly.

The Board also approved funding for seven projects in the Discovery Quest Program. The Quest program promotes the discovery of promising new stem cell-based technologies that will be ready to move to the next level, the translational category, within two years, with an ultimate goal of improving patient care.

Application Title Institution CIRM Committed Funding
DISC2-10979 Universal Pluripotent Liver Failure Therapy (UPLiFT)

 

Children’s Hospital of Los Angeles $1,297,512

 

DISC2-11105 Pluripotent stem cell-derived bladder epithelial progenitors for definitive cell replacement therapy of bladder cancer

 

Stanford $1,415,016
DISC2-10973 Small Molecule Proteostasis Regulators to Treat Photoreceptor Diseases

 

U.C. San Diego $1,160,648
DISC2-11070 Drug Development for Autism Spectrum Disorder Using Human Patient iPSCs

 

Scripps $1,827,576
DISC2-11183 A screen for drugs to protect against chemotherapy-induced hearing loss, using sensory hair cells derived by direct lineage reprogramming from hiPSCs

 

University of Southern California $833,971
DISC2-11199 Modulation of the Wnt pathway to restore inner ear function

 

Stanford $1,394,870
DISC2-11109 Regenerative Thymic Tissues as Curative Cell Therapy for Patients with 22q11 Deletion Syndrome

 

Stanford $1,415,016

Finally, the Board approved the Agency’s 2019 research budget. Given CIRM’s new partnership with the National Heart, Lung, Blood Institute (NHLBI) to accelerate promising therapies that could help people with Sickle Cell Disease (SCD) the Agency is proposing to set aside $30 million in funding for this program.

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Congresswoman Barbara Lee (D-CA 13th District)

“I am deeply grateful for organizations like CIRM and NHLBI that do vital work every day to help people struggling with Sickle Cell Disease,” said Congresswoman Barbara Lee (D-CA 13th District). “As a member of the House Appropriations Subcommittee on Labor, Health and Human Services, and Education, I know well the importance of this work. This innovative partnership between CIRM and NHLBI is an encouraging sign of progress, and I applaud both organizations for their tireless work to cure Sickle Cell Disease.”

Under the agreement CIRM and the NHLBI will coordinate efforts to identify and co-fund promising therapies targeting SCD.  Programs that are ready to start an IND-enabling or clinical trial project for sickle cell can apply to CIRM for funding from both agencies. CIRM will share application information with the NHLBI and CIRM’s Grants Working Group (GWG) – an independent panel of experts which reviews the scientific merits of applications – will review the applications and make recommendations. The NHLBI will then quickly decide if it wants to partner with CIRM on co-funding the project and if the CIRM governing Board approves the project for funding, the two organizations will agree on a cost-sharing partnership for the clinical trial. CIRM will then set the milestones and manage the single CIRM award and all monitoring of the project.

“This is an extraordinary opportunity to create a first-of-its-kind partnership with the NHLBI to accelerate the development of curative cell and gene treatments for patients suffering with Sickle Cell Disease” says Maria T. Millan, MD, President & CEO of CIRM. “This allows us to multiply the impact each dollar has to find relief for children and adults who battle with this life-threatening, disabling condition that results in a dramatically shortened lifespan.  We are pleased to be able to leverage CIRM’s acceleration model, expertise and infrastructure to partner with the NHLBI to find a cure for this condition that afflicts 100,000 Americans and millions around the globe.”

The budget for 2019 is:

Program type 2019
CLIN1 & 2

CLIN1& 2 Sickle Cell Disease

$93 million

$30 million

TRANSLATIONAL $20 million
DISCOVER $0
EDUCATION $600K

 

 

Stem Cell Roundup: New infertility tools, helping the 3 blind mice hear and cow ESCs

Cool Stem Cell Image of the Week

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Human egg grown from immature cells in ovarian tissue. (credit: David Albertini)

This week’s Cool Stem Cell Image of the Week comes to us from the lab of reproductive biologist Evelyn Telfer at the University of Edinburgh. Telfer and her team successfully grew human eggs cells from immature ovarian tissue.

This technology could revolutionize the way doctors approach infertility. For instance, when girls and young women undergo chemotherapy for cancer, their eggs are often damaged. By preserving a small piece of ovarian tissue before the cancer treatments, this method could be used to generate eggs later in life for in vitro fertilization. Much more work is necessary to figure out if these eggs are healthy and safe to use to help infertile women.

The study was recently published in Molecular Human Reproduction and was picked up this Science writer Kelly Servick.

Forget 3 blind mice, iPS cells could help 3 deaf mice hear again (Kevin McCormack)
For years scientists have been trying to use stem cells to restore hearing to people who are deaf or hearing impaired. Now a group of researchers in Japan may have found a way.

The team used human iPS cells to create inner ear cells, the kind damaged in one of the most common forms of hereditary deafness. They then transplanted them into the inner ears of mice developing in the womb that are suffering from a congenital form of hearing loss. The cells appeared to engraft and produce a protein, Connexin 30, known to be critical in hearing development.

The research, published in the journal Scientific Reports, could be an important step towards developing a therapy for congenital hearing loss in people.

UC Davis team isolates cow embryonic stem cells for the first time

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An early stage cow embryo. Inner cell mass (red) is source of embryonic stem cells. (Credit: Pablo Ross/UC Davis) 

Although human embryonic stem cells (ESCs) were isolated way back in ’98, researchers haven’t had similar luck with embryonic stem cells from cows. Until this week, that is.  A UC Davis team just published a report in PNAS showing that they not only can isolate cow ESCs but their method works almost 100% of the time.

 

Genetic engineering of these cow stem cells could have huge implications for the cattle industry. Senior author Pablo Ross mentioned in a press release how this breakthrough could help speed up the process of generating superior cows that produce more milk, release less methane and are more resistant to disease:

“In two and a half years, you could have a cow that would have taken you about 25 years to achieve. It will be like the cow of the future. It’s why we’re so excited about this.”

These cow ESCs may also lead to better models of human disease. Because of their small size, rat and mouse models are not always a good representation of how potential therapies or drugs will affect humans. Creating stem cell models from larger animals may provide a better representation.

Stem cell stories that caught our eye: better ovarian cancer drugs, creating inner ear tissue, small fish big splash

Two drugs are better than one for ovarian cancer (Karen Ring). Earlier this week, scientists from UCLA reported that a combination drug therapy could be an effective treatment for 50% of aggressive ovarian cancers. The study was published in the journal Precision Oncology and was led by Dr. Sanaz Memarzadeh.

Women with high-grade ovarian tumors have an 85% chance of tumor recurrence after treatment with a common chemotherapy drug called carboplatin. The UCLA team found in a previous study that ovarian cancer stem cells are to blame because they are resistant to carboplatin. It’s because these stem cells have an abundance of proteins called cIAPs, which prevent cell death from chemotherapy.

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Ovarian cancer cells (blue) expressing cIAP protein (red) on the left are more sensitive to a combination therapy than cancer cells that don’t express the protein on the right. (UCLA Broad Stem Cell Research Center/Precision Oncology)

Memarzadeh discovered that an experimental drug called birinapant made some ovarian cancer tumors more sensitive to chemotherapy treatment by breaking down cIAPs. This gave her the idea that combining the two drugs, birinapant and carboplatin, might be a more effective strategy for treating aggressive ovarian tumors.

By treating with the two drugs simultaneously, the scientists improved the survival rate of mice with ovarian cancer. They also tested this combo drug treatment on 23 ovarian cancer cell lines derived from women with highly aggressive tumors. The treatment killed off half of the cell lines indicating that some forms of this cancer are resistant to the combination treatment.

When they measured the levels of cIAPs in the human ovarian cancer cell lines, they found that high levels of the proteins were associated with ovarian tumor cells that responded well to the combination treatment. This is exciting because it means that clinicians can analyze tumor biopsies for cIAP levels to determine whether certain ovarian tumors would respond well to combination therapy.

Memarzadeh shared her plans for future research in a UCLA news release,

“I believe that our research potentially points to a new treatment option. In the near future, I hope to initiate a phase 1/2 clinical trial for women with ovarian cancer tumors predicted to benefit from this combination therapy.”

In a first, researchers create inner ear tissue. From heart muscle to brain cells to insulin-producing cells, researchers have figured out how to make a long list of different human cell types using induced pluripotent stem cells (iPSCs) – cells taken from the body and reprogrammed into a stem cell-like state.

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Human inner ear organoid with sensory hair cells (cyan) and sensory neurons (yellow). An antibody for the protein CTBP2 reveals cell nuclei as well as synapses between hair cells and neurons (magenta). | Photo: Karl Koehler

This week, a research group at the Indiana University School of Medicine successfully added inner ear cells to that list. This feat, published in Nature Biotechnology, is especially important given the fact that the inner ear is one of the few parts of the body that cannot be biopsied for further examination. With these cells in hands, new insights into the causes of hearing loss and balance disorders may be on the horizon.

The inner ear contains 75,000 sensory hair cells that convert sound waves into electrical signals to the brain. Loud noises, drug toxicity, and genetic mutations can permanently damage the hair cells leading to hearing loss and dizziness. Over 15%  of the U.S. population have some form of hearing loss and that number swells to 67% for people over 75.

Due to the complex shape of the inner ear, the team grew the iPSCs into three dimensional balls of cells rather than growing them as a flat layer of cells on a petri dish. With educated guesses sprinkled in with some trial and error, the scientists, for the time, identified a recipe of proteins that stimulated the iPSCs to transform into inner ear tissue. And like any great recipe, it wasn’t so much the ingredient list but the timing that was key:

“If you apply these signals at the wrong time you can potentially generate a brain instead of an inner ear,” first author Dr. Karl Koehler said in an interview with Gizmodo. “The real breakthrough is that we figured out the exact timing to do each one of these [protein] treatments.”

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Senior author, Eri Hashino, Ph.D., and first author, Karl R. Koehler, Ph.D. Photo: Indiana University

Careful examination shows that the tissue, referred to as organoids, not only contained the sensory hair cells of the inner ear cell but also nerve cells, or neurons, that are responsible for relaying the sound waves to the brain. Koehler explained the importance of this result in a press release:

“We also found neurons, like those that transmit signals from the ear to the brain, forming connections with sensory cells. This is an exciting feature of these organoids because both cell types are critical for proper hearing and balance.”

Though it’s still early days, these iPSC-derived inner ear organoids are a key step toward the ultimate goal of repairing hearing loss. Senior author, Dr. Eri Hashino, talked about the team’s approach to reach that goal:

“Up until now, potential drugs or therapies have been tested on animal cells, which often behave differently from human cells. We hope to discover new drugs capable of helping regenerate the sound-sending hair cells in the inner ear of those who have severe hearing problems.”

This man’s research is no fish tale
And finally, we leave you this week with a cool article and video by STAT. It features Dr. Leonard Zon of Harvard University and his many, many tanks full of zebrafish. This little fish has made a huge splash in understanding human development and disease. But don’t take my word for it, watch the video!

Listen Up: A stem cell-based solution for hearing loss

Can you hear me now?

If you’re old enough, you probably recognize this phrase from an early 2000’s Verizon Wireless commercial where the company claims to be “the nation’s largest, most reliable wireless network”. However, no matter how hard wireless companies like Verizon try, there are still dead zones where cell phone reception is zilch and you can’t in fact hear me now.

This cell phone coverage is a good analogy for the 5% of the world population, or 360 million people, that suffer from hearing loss. There are many causes for hearing loss including genetic predispositions, birth defects, constant exposure to loud noises, infectious diseases, certain drugs, ear infections and aging. There is no cure that fully restores hearing, but patients can benefit from hearing aids, cochlear implants and other hearing devices.

But listen to this. A new stem cell-based technique developed by the Massachusetts Eye and Ear Infirmary may restore hearing in patients with hearing loss. The team discovered that stem cells in the inner ear can be manipulated in a culture dish to expand and develop into large quantities of cochlear hair cells, which make it possible for your brain to detect sound. Their work was published this week in the journal Cell Reports.

In a previous study, the Boston team found that stem cells in the inner ears of mice could be directly converted into cochlear hair cells, but they weren’t able to generate enough hair cells to fully restore hearing in these mice. Building on this work, the team isolated these stem cells, which express a protein called LGR5, and developed an augmentation technique consisting of drugs and growth factors to expand these stem cells and then specialize them into larger populations of hair cells.

A new technique converts stems cells into hair cells. Image credit Will McLean, Albert Edge, Massachusetts Eye and Ear

A new technique converts stems cells into hair cells. Image credit Will McLean, Albert Edge, Massachusetts Eye and Ear.

From a single mouse cochlea, they made more than 11,500 hair cells using their new augmentation method, which is more than 50 times the number of hair cells they made using a more basic method.

In a news release, senior author on the study, Dr. Albert Edge, explained the importance of their findings for patients with hearing loss:

Albert Edge

Albert Edge

“We have shown that we can expand Lgr5-expressing cells to differentiate into hair cells in high yield, which opens the door for drug discovery for hearing. We hope that by stimulating these cells to divide and differentiate that we will improve on our previous results in restoring hearing. With this knowledge, we can make better shots on goal, which is critical for repairing damaged ears. We have identified the cells of interest and have identified the pathways and drugs to target to improve on previous results. These clues may lead us closer to finding drugs that could treat hearing loss in adults.”