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.

barbara_lee_official_photo

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

 

 

Saying goodbye to a good friend and a stem cell pioneer: Karl Trede

FrankTrede_B_0110_20161204120959_2016_12_04_CIRM_AnnualReport_KarlTrede_SanJose_Portraits_SeesTheDay

Sometimes even courage and determination are not enough. Karl Trede had courage and determination in droves as he fought a 12 year battle against cancer. He recently lost that battle. But he remains an inspiration for all who knew him.

I got to know Karl for our 2016 Annual Report. Karl had been diagnosed with throat cancer in 2006. He underwent surgery to remove his vocal cords and the cancer seemed to be in remission. But then it returned, this time having spread to his lungs. His doctors said they had pretty much run out of options but would Karl consider trying something new, something no one else had tried before; stem cells.

Karl told me he didn’t hesitate.

“I said “sure”. I don’t believe I knew at the time that I was going to be the first one but I thought I’d give it a whirl. It was an experience for me. It was eye opening. I wasn’t real concerned about being the first, I figured I was going to have to go someday so I guess if I was the first person and something really went wrong then they’d definitely learn something. So, to me, that was kind of worth my time.”

Happily nothing went wrong and the team behind the therapy (Forty Seven Inc.) definitely learned something, they learned a lot about the correct dosage for patients; invaluable information in treating future patients.

Karl’s cancer was held at bay and he was able to do the one thing that brought him more pleasure than anything else; spend time with his family, his wife Vita, their four sons and their families. He doted on his grand kids and got to see them grow, and they got to know him.

Recently the cancer returned and this time there was no holding it at bay. To the end Karl remained cheerful and positive.

KARL poster

In our office is a huge poster of Karl with the words “Every Moment Counts” at the bottom. It’s a reminder to us why we come to work every day, why the people at Forty Seven Inc. and all the other researchers we support work so hard for years and years; to try and give people like Karl a few extra moments with his family.

At the top of the poster the word “Courage” is emblazoned across it. Karl has a huge smile on his face. Karl was certainly courageous, a stem cell pioneer willing to try something no one else ever had. He was also very modest.

Here is Karl speaking to our governing Board in December 2016

When I spoke to him in 2016, despite all he had gone through in his fight against cancer, he said he had no regrets:

“I consider myself very fortunate. I’m a lucky guy.”

Those of us who got to spend just a little time with Karl know that we were the lucky ones.

Our hearts go out to his family and friends for their loss.

 

 

Research Targeting Prostate Cancer Gets Almost $4 Million Support from CIRM

Prostate cancer

A program hoping to supercharge a patient’s own immune system cells to attack and kill a treatment resistant form of prostate cancer was today awarded $3.99 million by the governing Board of the California Institute for Regenerative Medicine (CIRM)

In the U.S., prostate cancer is the second most common cause of cancer deaths in men.  An estimated 170,000 new cases are diagnosed each year and over 29,000 deaths are estimated in 2018.  Early stage prostate cancer is usually managed by surgery, radiation and/or hormone therapy. However, for men diagnosed with castrate-resistant metastatic prostate cancer (CRPC) these treatments often fail to work and the disease eventually proves fatal.

Poseida Therapeutics will be funded by CIRM to develop genetically engineered chimeric antigen receptor T cells (CAR-T) to treat metastatic CRPC. In cancer, there is a breakdown in the natural ability of immune T-cells to survey the body and recognize, bind to and kill cancerous cells. Poseida is engineering T cells and T memory stem cells to express a chimeric antigen receptor that arms these cells to more efficiently target, bind to and destroy the cancer cell. Millions of these cells are then grown in the laboratory and then re-infused into the patient. The CAR-T memory stem cells have the potential to persist long-term and kill residual cancer calls.

“This is a promising approach to an incurable disease where patients have few options,” says Maria T. Millan, M.D., President and CEO of CIRM. “The use of chimeric antigen receptor engineered T cells has led to impressive results in blood malignancies and a natural extension of this promising approach is to tackle currently untreatable solid malignancies, such as castrate resistant metastatic prostate cancer. CIRM is pleased to partner on this program and to add it to its portfolio that involves CAR T memory stem cells.”

Poseida Therapeutics plans to use the funding to complete the late-stage testing needed to apply to the Food and Drug Administration for the go-ahead to start a clinical trial in people.

Quest Awards

The CIRM Board also voted to approve investing $10 million for eight projects under its 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.

Among those approved for funding are:

  • Eric Adler at UC San Diego is using genetically modified blood stem cells to treat Danon Disease, a rare and fatal condition that affects the heart
  • Li Gan at the Gladstone Institutes will use induced pluripotent stem cells to develop a therapy for a familial form of dementia
  • Saul Priceman at City of Hope will use CAR-T therapy to develop a treatment for recurrent ovarian cancer

Because the amount of funding for the recommended applications exceeded the money set aside, the Application Subcommittee voted to approve partial funding for two projects, DISC2-11192 and DISC2-11109 and to recommend, at the next full Board meeting in October, that the projects get the remainder of the funds needed to complete their research.

The successful applications are:

 

APPLICATION

 

TITLE

 

INSTITUTION

CIRM COMMITTED FUNDING
DISC2-11131 Genetically Modified Hematopoietic Stem Cells for the

Treatment of Danon Disease

 

 

U.C San Diego

 

$1,393,200

 

DISC2-11157 Preclinical Development of An HSC-Engineered Off-

The-Shelf iNKT Cell Therapy for Cancer

 

 

U.C. Los Angeles

 

$1,404,000

DISC2-11036 Non-viral reprogramming of the endogenous TCRα

locus to direct stem memory T cells against shared

neoantigens in malignant gliomas

 

 

U.C. San Francisco

 

$900,000

DISC2-11175 Therapeutic immune tolerant human islet-like

organoids (HILOs) for Type 1 Diabetes

 

 

Salk Institute

 

$1,637,209

DISC2-11107 Chimeric Antigen Receptor-Engineered Stem/Memory

T Cells for the Treatment of Recurrent Ovarian Cancer

 

 

City of Hope

 

$1,381,104

DISC2-11165 Develop iPSC-derived microglia to treat progranulin-

deficient Frontotemporal Dementia

 

 

Gladstone Institutes

 

$1,553,923

DISC2-11192 Mesenchymal stem cell extracellular vesicles as

therapy for pulmonary fibrosis

 

 

U.C. San Diego

 

$865,282

DISC2-11109 Regenerative Thymic Tissues as Curative Cell

Therapy for Patients with 22q11 Deletion Syndrome

 

 

Stanford University

 

$865,282

 

 

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

Lung cancer

Lung cancer: Photo courtesy Verywell

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

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

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

Translation Awards

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

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

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

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

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

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

 

 

Stanford University

 

$5,977,155

 

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

 

 

Children’s Hospital Oakland Research Institute

 

$1,721,606

 

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

MAX BioPharma Inc.

 

$1,689,855

 

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

 

 

UC Irvine

 

$4,769,039

 

Stanford Scientist Sergiu Pasca Receives Prestigious Vilcek Prize for Stem Cell Research on Neuropsychiatric Disorders

Sergiu Pasca, Stanford University

Last month, we blogged about Stanford neuroscientist Sergiu Pasca and his interesting research using stem cells to model the human brain in 3D. This month we bring you an exciting update about Dr. Pasca and his work.

On February 1st, Pasca was awarded one of the 2018 Vilcek Prizes for Creative Promise in Biomedical Science. The Vilcek Foundation is a non-profit organization dedicated to raising awareness of the important contributions made by immigrants to American arts and sciences.

Pasca was born in Romania and got his medical degree there before moving to the US to pursue research at Stanford University in 2009. He is now an assistant professor of psychiatry and behavioral sciences at Stanford and has dedicated his lab’s research to understanding human brain development and neuropsychiatric disorders using 3D brain organoid cultures derived from pluripotent stem cells.

The Vilcek Foundation produced a fascinating video (below) featuring Pasca’s life journey and his current CIRM-funded research on Timothy Syndrome – a rare form of autism. In the video, Pasca describes how his lab’s insights into this rare psychiatric disorder will hopefully shed light on other neurological diseases. He shares his hope that his research will yield something that translates to the clinic.

The Vilcek Prize for Creative Promise in Biomedical Science comes with a $50,000 cash award. Pasca along with the other prize winners will be honored at a gala event in New York City in April 2018.

You can read more about Pasca’s prize winning research on the Vilcek website and in past CIRM blogs below.


Related Links:

Hey, what’s the big idea? CIRM Board is putting up more than $16.4 million to find out

Higgins

David Higgins, CIRM Board member and Patient Advocate for Parkinson’s disease; Photo courtesy San Diego Union Tribune

When you have a life-changing, life-threatening disease, medical research never moves as quickly as you want to find a new treatment. Sometimes, as in the case of Parkinson’s disease, it doesn’t seem to move at all.

At our Board meeting last week David Higgins, our Board member and Patient Advocate for Parkinson’s disease, made that point as he championed one project that is taking a new approach to finding treatments for the condition. As he said in a news release:

“I’m a fourth generation Parkinson’s patient and I’m taking the same medicines that my grandmother took. They work but not for everyone and not for long. People with Parkinson’s need new treatment options and we need them now. That’s why this project is worth supporting. It has the potential to identify some promising candidates that might one day lead to new treatments.”

The project is from Zenobia Therapeutics. They were awarded $150,000 as part of our Discovery Inception program, which targets great new ideas that could have a big impact on the field of stem cell research but need some funding to help test those ideas and see if they work.

Zenobia’s idea is to generate induced pluripotent stem cells (iPSCs) that have been turned into dopaminergic neurons – the kind of brain cell that is dysfunctional in Parkinson’s disease. These iPSCs will then be used to screen hundreds of different compounds to see if any hold potential as a therapy for Parkinson’s disease. Being able to test compounds against real human brain cells, as opposed to animal models, could increase the odds of finding something effective.

Discovering a new way

The Zenobia project was one of 14 programs approved for the Discovery Inception award. You can see the others on our news release. They cover a broad array of ideas targeting a wide range of diseases from generating human airway stem cells for new approaches to respiratory disease treatments, to developing a novel drug that targets cancer stem cells.

Dr. Maria Millan, CIRM’s President and CEO, said the Stem Cell Agency supports this kind of work because we never know where the next great idea is going to come from:

“This research is critically important in advancing our knowledge of stem cells and are the foundation for future therapeutic candidates and treatments. Exploring and testing new ideas increases the chances of finding treatments for patients with unmet medical needs. Without CIRM’s support many of these projects might never get off the ground. That’s why our ability to fund research, particularly at the earliest stage, is so important to the field as a whole.”

The CIRM Board also agreed to invest $13.4 million in three projects at the Translation stage. These are programs that have shown promise in early stage research and need funding to do the work to advance to the next level of development.

  • $5.56 million to Anthony Oro at Stanford to test a stem cell therapy to help people with a form of Epidermolysis bullosa, a painful, blistering skin disease that leaves patients with wounds that won’t heal.
  • $5.15 million to Dan Kaufman at UC San Diego to produce natural killer (NK) cells from embryonic stem cells and see if they can help people with acute myelogenous leukemia (AML) who are not responding to treatment.
  • $2.7 million to Catriona Jamieson at UC San Diego to test a novel therapeutic approach targeting cancer stem cells in AML. These cells are believed to be the cause of the high relapse rate in AML and other cancers.

At CIRM we are trying to create a pipeline of projects, ones that hold out the promise of one day being able to help patients in need. That’s why we fund research from the earliest Discovery level, through Translation and ultimately, we hope into clinical trials.

The writer Victor Hugo once said:

“There is one thing stronger than all the armies in the world, and that is an idea whose time has come.”

We are in the business of finding those ideas whose time has come, and then doing all we can to help them get there.

 

 

 

Stem Cell Stories That Caught Our Eye: Halting Brain Cancer, Parkinson’s disease and Stem Cell Awareness Day

Stopping brain cancer in its tracks.

Experiments by a team of NIH-funded scientists suggests a potential method for halting the expansion of certain brain tumors.Michelle Monje, M.D., Ph.D., Stanford University.

Scientists at Stanford Medicine discovered that you can halt aggressive brain cancers called high-grade gliomas by cutting off their supply of a signaling protein called neuroligin-3. Their research, which was funded by CIRM and the NIH, was published this week in the journal Nature. 

The Stanford team, led by senior author Michelle Monje, had previously discovered that neuroligin-3 dramatically spurred the growth of glioma cells in the brains of mice. In their new study, the team found that removing neuroligin-3 from the brains of mice that were transplanted with human glioma cells prevented the cancer cells from spreading.

Monje explained in a Stanford news release,

“We thought that when we put glioma cells into a mouse brain that was neuroligin-3 deficient, that might decrease tumor growth to some measurable extent. What we found was really startling to us: For several months, these brain tumors simply didn’t grow.”

The team is now exploring whether targeting neuroligin-3 will be an effective therapeutic treatment for gliomas. They tested two inhibitors of neuroligin-3 secretion and saw that both were effective in stunting glioma growth in mice.

Because blocking neuroligin-3 doesn’t kill glioma cells and gliomas eventually find ways to grow even in the absence of neuroligin-3, Monje is now hoping to develop a combination therapy with neuroligin-3 inhibitors that will cure patients of high-grade gliomas.

“We have a really clear path forward for therapy; we are in the process of working with the company that owns the clinically characterized compound in an effort to bring it to a clinical trial for brain tumor patients. We will have to attack these tumors from many different angles to cure them. Any measurable extension of life and improvement of quality of life is a real win for these patients.”

Parkinson’s Institute CIRM Research Featured on KTVU News.

The Bay Area Parkinson’s Institute and Clinical Center located in Sunnyvale, California, was recently featured on the local KTVU news station. The five-minute video below features patients who attend the clinic at the Parkinson’s Institute as well as scientists who are doing cutting edge research into Parkinson’s disease (PD).

Parkinson’s disease in a dish. Dopaminergic neurons made from PD induced pluripotent stem cells. (Image courtesy of Birgitt Schuele).

One of these scientists is Dr. Birgitt Schuele, who recently was awarded a discovery research grant from CIRM to study a new potential therapy for Parkinson’s using human induced pluripotent stem cells (iPSCs) derived from PD patients. Schuele explains that the goal of her team’s research is to “generate a model for Parkinson’s disease in a dish, or making a brain in a dish.”

It’s worth watching the video in its entirety to learn how this unique institute is attempting to find new ways to help the growing number of patients being diagnosed with this degenerative brain disease.

Click on photo to view video.

Mark your calendars for Stem Cell Awareness Day!

Every year on the second Wednesday of October is Stem Cell Awareness Day (SCAD). This is a day that our agency started back in 2009, with a proclamation by former California Mayor Gavin Newsom, to honor the important accomplishments made in the field of stem cell research by scientists, doctors and institutes around the world.

This year, SCAD is on October 11th. Our Agency will be celebrating this day with a special patient advocate event on Tuesday October 10th at the UC Davis MIND Institute in Sacramento California. CIRM grantees Dr. Jan Nolta, the Director of UC Davis Institute for Regenerative Cures, and Dr. Diana Farmer, Chair of the UC Davis Department of Surgery, will be talking about their CIRM-funded research developing stem cell models and potential therapies for Huntington’s disease and spina bifida (a birth defect where the spinal cord fails to fully develop). You’ll also hear an update on  CIRM’s progress from our President and CEO (Interim), Maria Millan, MD, and Chairman of the Board, Jonathan Thomas, PhD, JD. If you’re interested in attending this event, you can RSVP on our Eventbrite Page.

Be sure to check out a list of other Stem Cell Awareness Day events during the month of October on our website. You can also follow the hashtag #StemCellAwarenessDay on Twitter to join in on the celebration!

One last thing. October is an especially fun month because we also get to celebrate Pluripotency Day on October 4th. OCT4 is an important gene that maintains stem cell pluripotency – the ability of a stem cell to become any cell type in the body – in embryonic and induced pluripotent stem cells. Because not all stem cells are pluripotent (there are adult stem cells in your tissues and organs) it makes sense to celebrate these days separately. And who doesn’t love having more reasons to celebrate science?

Have scientists discovered a natural way to boost muscle regeneration?

Painkillers like ibuprofen and aspirin are often a part of an athlete’s post-exercise regimen after intense workouts. Sore muscles, aches and stiffness can be more manageable by taking these drugs – collectively called non-steroidal anti-inflammatory drugs, or NSAIDS – to reduce inflammation and pain. But research suggests that the anti-inflammatory effects of these painkillers might cause more harm than good by preventing muscle repair and regeneration after injury or exercise.

A new study out of Stanford Medicine supports these findings and proposes that a component of the inflammatory process is necessary to promote muscle regeneration. Their study was funded in part by a CIRM grant and was published this week in the Proceedings of the National Academy of Sciences.

Muscle stem cells are scattered throughout skeletal muscle tissue and remain inactive until they are stimulated to divide. When muscles are damaged or injured, an inflammatory response involving a cascade of immune cells, molecules and growth factors activates these stem cells, prompting them to regenerate muscle tissue.

Andrew Ho, Helen Blau and Adelaida Palla led a study that found drugs like aspirin and ibuprofen can inhibit the ability of muscle tissue to repair itself in mice. (Image credit: Scott Reiff)

The Stanford team discovered that a molecule called Prostaglandin E2 or PGE2 is released during the inflammatory response and stimulates muscle repair by directly targeting the EP4 receptor on the surface of muscle stem cells. The interaction between PGE2 and EP4 causes muscle stem cells to divide and robustly regenerate muscle tissue.

Senior author on the study, Dr. Helen Blau, explained her team’s interest in PGE2-mediated muscle repair in a news release,

“Traditionally, inflammation has been considered a natural, but sometimes harmful, response to injury. But we wondered whether there might be a component in the pro-inflammatory signaling cascade that also stimulated muscle repair. We found that a single exposure to prostaglandin E2 has a profound effect on the proliferation of muscle stem cells in living animals. We postulated that we could enhance muscle regeneration by simply augmenting this natural physiological process in existing stem cells already located along the muscle fiber.”

Further studies in mice revealed that injury increased PGE2 levels in muscle tissue and increased expression of the EP4 receptor on muscle stem cells. This gave the authors the idea that treating mice with a pulse of PGE2 could stimulate their muscle stem cells to regenerate muscle tissue.

Their hunch turned out to be right. Co-first author Dr. Adelaida Palla explained,

“When we gave mice a single shot of PGE2 directly to the muscle, it robustly affected muscle regeneration and even increased strength. Conversely, if we inhibited the ability of the muscle stem cells to respond to naturally produced PGE2 by blocking the expression of EP4 or by giving them a single dose of a nonsteroidal anti-inflammatory drug to suppress PGE2 production, the acquisition of strength was impeded.”

Their research not only adds more evidence against the using NSAID painkillers like ibuprofen and aspirin to treat sore muscles, but also suggests that PGE2 could be a natural therapeutic strategy to boost muscle regeneration.

This cross-section of regenerated muscle shows muscle stem cells (red) in their niche along the muscle fibers (green). (Photo courtesy of Blau lab)

PGE2 is already approved by the US Food and Drug Administration (FDA) to induce labor in pregnant women, and Dr. Blau hopes that further research in her lab will pave the way for repurposing PGE2 to treat muscle injury and other conditions.

“Our goal has always been to find regulators of human muscle stem cells that can be useful in regenerative medicine. It might be possible to repurpose this already FDA-approved drug for use in muscle. This could be a novel way to target existing stem cells in their native environment to help people with muscle injury or trauma, or even to combat natural aging.”

Stanford scientists devise an algorithm that identifies gene pairs associated with cancer

Using data from human tumor samples, Stanford scientists have developed a new computer algorithm to identify pairs of genes that cause cancer. Their research aims to identify alternative ways to target cancer-causing mutations that have thus far evaded effective clinical treatment.

The study, which was published this week in Nature Communications, was led by senior authors Dr. Ravi Majeti and Dr. David Dill and included two CIRM Bridges interns Damoun Torabi and David Cruz Hernandez.

Identifying Partners in Crime

Cancer cells are notorious for acquiring genetic mutations due to the instability of their genomes and errors in the machinery that repairs DNA. Sometimes these errors create what are called synthetic lethal genes. These are pairs of genes that can cause a cell to die if both genes are defective due to acquired mutations, but a defect in only one of the genes allows a cell to live.

Cancer cells rely on pairs of genes with similar functions for their survival. If one gene is mutated, then the cancer cell depends on the other functional gene, aka its “partner in crime”, to keep it doing its mischief. Scientist are interested in targeting this second partner gene in synthetic lethal pairs in the hopes of developing less toxic cancer therapies that only kill cancer cells instead of healthy ones too.

The Stanford team went on the hunt for synthetic lethal partner genes in data from 12 different human cancers using an algorithm they developed called Mining Synthetic Lethals (MiSL). David Dill explained their strategy in a Stanford Medicine news release:

“We were looking for situations in which, if gene A is mutated, gene Y is amplified to compensate for the loss of function of gene A. Conversely, gene Y is only ever deleted in cells in which gene A is not mutated.”

David Dill. (Credit: L.A. Cicero/Stanford News Service)

They identified a total of 3,120 cancer-causing mutations and over 145,000 potential synthetic lethal partner genes associated with these mutations. Some of these partnerships were identified in other studies, validating MiSL as an effective tool for their purposes, while other partnerships were novel.

Targeting Partners in Crime

One of the new partnerships they discovered was between a mutation in the IDH1 gene, which is associated with acute myeloid leukemia, and a gene called ACACA. The team validated this pair with experiments in the lab proving that defects in both IDH1 and ACACA blocked leukemia cell growth. MiSL identified 89 potential synthetic lethal partners for the leukemia-causing IDH1 mutation, 17 of which they believe could be targeted by existing cancer drugs.

The authors concluded that using computer algorithms to sift through mountains of biological data is a powerful strategy for identifying genetic relationships leveraged by tumors and could advance drug development for different types of cancers.

Ravi Majeti concluded,

“We’re entering a new era of precision health. Using data from real human tumors gives us important, fundamental advantages over using cancer cell lines that often don’t display the same mutation profiles. We’ve found that, although many known cancer-associated mutations are difficult to target clinically, their synthetic lethal partners may be much more druggable.”

Ravi Majeti (Credit: Steve Fisch)

Keeping intestinal stem cells in their prime

Gut stem cells (green) in the small intestine of a mouse.

The average length of the human gut is 25 feet long. That’s equivalent to four really tall people or five really short people lined up head to toe. Intestinal stem cells have the fun job of regenerating and replacing ALL the cells that line the gut. Therefore, it’s important for these stem cells to be able to self-renew, a process that replenishes the stem cell population. If this important biological process is disrupted, the intestine is at risk for diseases like inflammatory bowel disease and cancer.

This week, Stanford Medicine researchers published new findings about the biological processes responsible for regulating the regenerative capacity of intestinal stem cells. Their work, which was partially funded by CIRM, was published in the journal Nature.

Priming gut stem cells to self-renew

Scientists know that the self-renewal of intestinal stem cells is very important for a happy, functioning gut, but the nuances of what molecules and signaling pathways regulate this process have yet to be figured out. The Stanford team, led by senior author and Stanford Professor Dr. Calvin Kuo, studied two signaling pathways, Wnt and R-Spondin, that are involved in the self-renewal of intestinal stem cells in mice.

Dr. Calvin Kuo, Stanford Medicine.

“The cascade of events comprising the Wnt signaling pathway is crucial to stem cell self-renewal,” Dr. Kuo explained in an email exchange. “The Wnt pathway can be induced by either hormones classified as “Wnts” or “R-spondins”.  However, it is not known if Wnts or R-spondins cooperate to induce Wnt signaling, and if these Wnts and R-spondins have distinct functions or if they can mutually substitute for each other.   We explored how Wnts and R-spondins might cooperate to regulate intestinal stem cells – which are extremely active and regenerate the 25-foot lining of the human intestine every week.”

The team used different reagents to activate or block Wnt or R-spondin signaling and monitored the effects on intestinal stem cells. They found that both were important for the self-renewal of intestinal stem cells, but that they played different roles.

“Our work revealed that Wnts and R-spondins are not equivalent and that they have very distinct functions even though they both trigger the Wnt signaling cascade,” said Dr. Kuo. “Both Wnts and R-spondins are required to maintain intestinal stem cells.  However, Wnts perform more of a subservient “priming” function, where they prepare intestinal stem cells for the action of R-spondin, which is the active catalyst for inducing intestinal stem cells to divide.”

The authors believe that this multi-step regulation, involving priming and self-renewal factors could apply to stem cell systems in other organs and tissues in the body. Some of the researchers on this study including Dr. Kuo are pursuing this idea through a new company called Surrozen, which produces artificial bioengineered Wnt molecules that don’t require activation like natural Wnt molecules. These Wnt molecules were used in the current study and are explained in more detail in a separate Nature article published at the same time.

The company believes that artificial Wnts will be useful for understanding stem cell biology and potentially for therapeutic applications. Dr. Kuo explained,

“The new surrogate Wnts are easily produced and can circulate in the bloodstream, unlike natural Wnts.  There may be medical applications of these bioengineered Wnt surrogates in stimulating various stem cell compartments of the body, given the wide range of stem cells that are governed by natural Wnts.”