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

 

 

Starving stem cells of oxygen can help build stronger bones

Leach_Kent_BME.2012

J. Kent Leach: Photo courtesy UC Davis

We usually think that starving something of oxygen is going to make it weaker and maybe even kill it. But a new study by J. Kent Leach at UC Davis shows that instead of weakening bone defects, depriving them of oxygen might help boost their ability to create new bone or repair existing bone.

Leach says in the past the use of stem cells to repair damaged or defective bone had limited success because the stem cells often didn’t engraft in the bone or survive long if they did. That was because the cells were being placed in an environment that lacked oxygen (concentration levels in bone range from 3% to 8%) so the cells found it hard to survive.

However, studies in the lab had shown that if you preconditioned mesenchymal stem cells (MSCs), by exposing them to low oxygen levels before you placed them on the injury site, you helped prolong their viability. That was further enhanced by forming the MSCs into three dimensional clumps called spheroids.

Lightbulb goes off

In the  current study, published in Stem Cells, Leach says the earlier spheroid results  gave him an idea:

“We hypothesized that preconditioning MSCs in hypoxic (low oxygen) culture before spheroid formation would increase cell viability, proangiogenic potential (ability to create new blood vessels), and resultant bone repair compared with that of individual MSCs.”

So, the researchers placed one group of human MSCs, taken from bone marrow, in a dish with just 1% oxygen, and another identical group of MSCs in a dish with normal oxygen levels. After three days both groups were formed into spheroids and placed in an alginate hydrogel, a biopolymer derived from brown seaweed that is often used to build cellular cultures.

Seaweed

Brown seaweed

The team found that the oxygen-starved cells lasted longer than the ones left in normal oxygen, and the longer those cells were deprived of oxygen the better they did.

Theory is great, how does it work in practice?

Next was to see how those two groups did in actually repairing bones in rats. Leach says the results were encouraging:

“Once again, the oxygen-deprived, spheroid-containing gels induced significantly more bone healing than did gels containing either preconditioned individual MSCs or acellular gels.”

The team say this shows the use of these oxygen-starved cells could be an effective approach to repairing hard-to-heal bone injuries in people.

“Short‐term exposure to low oxygen primes MSCs for survival and initiates angiogenesis (the development of new blood vessels). Furthermore, these pathways are sustained through cell‐cell signaling following spheroid formation. Hypoxic (low oxygen) preconditioning of MSCs, in synergy with transplantation of cells as spheroids, should be considered for cell‐based therapies to promote cell survival, angiogenesis, and bone formation.”

CIRM & Dr. Leach

While CIRM did not fund this study we have invested more than $1.8 million in another study Dr. Leach is doing to develop a new kind of imaging technology that will help us see more clearly what is happening in bone and cartilage-targeted therapies.

In addition, back in March of 2012, Dr. Leach spoke to the CIRM Board about his work developing new approaches to growing bone.

 

The story behind the book about the Stem Cell Agency

DonReed_BookSigning2018-35

Don Reed at his book launch: Photo by Todd Dubnicoff

WHY I WROTE “CALIFORNIA CURES”  By Don C. Reed

It was Wednesday, June 13th, 2018, the launch day for my new book, “CALIFORNIA CURES: How the California Stem Cell Research Program is Fighting Your Incurable Disease!”

As I stood in front of the audience of scientists, CIRM staff members, patient advocates, I thought to myself, “these are the kind of people who built the California stem cell program.” Wheelchair warriors Karen Miner and Susan Rotchy, sitting in the front row, typified the determination and resolve typical of those who fought to get the program off the ground. Now I was about to ask them to do it one more time.

My first book about CIRM was “STEM CELL BATTLES: Proposition 71 and Beyond. It told the story of  how we got started: the initial struggles—and a hopeful look into the future.

Imagine being in a boat on the open sea and there was a patch of green on the horizon. You could be reasonably certain those were the tops of coconut trees, and that there was an island attached—but all you could see was a patch of green.

Today we can see the island. We are not on shore yet, but it is real.

“CALIFORNIA CURES” shows what is real and achieved: the progress the scientists have made– and why we absolutely must continue.

For instance, in the third row were three little girls, their parents and grandparents.

One of them was Evangelina “Evie” Vaccaro, age 5. She was alive today because of CIRM, who had funded the research and the doctor who saved her.

Don Reed and Evie and Alysia

Don Reed, Alysia Vaccaro and daughter Evie: Photo by Yimy Villa

Evie was born with Severe Combined Immunodeficiency (SCID) commonly called the “bubble baby” disease. It meant she could never go outside because her immune system could not protect her.  Her mom and dad had to wear hospital masks to get near her, even just to give her a hug.

But Dr. Donald Kohn of UCLA operated on the tiny girl, taking out some of her bone marrow, repairing the genetic defect that caused SCID, then putting the bone marrow back.

Today, “Evie” glowed with health, and was cheerfully oblivious to the fuss she raised.

I was actually a little intimidated by her, this tiny girl who so embodied the hopes and dreams of millions. What a delight to hear her mother Alysia speak, explaining  how she helped Evie understand her situation:  she had “unicorn blood” which could help other little children feel better too.

This was CIRM in action, fighting to save lives and ease suffering.

If people really knew what is happening at CIRM, they would absolutely have to support it. That’s why I write, to get the message out in bite-size chunks.

You might know the federal statistics—133 million children, women and men with one or more chronic diseases—at a cost of $2.9 trillion dollars last year.

But not enough people know California’s battle to defeat those diseases.

DonReed_BookSigning2018-22

Adrienne Shapiro at the book launch: Photo by Todd Dubnicoff

Champion patient advocate Adrienne Shapiro was with us, sharing a little of the stress a parent feels if her child has sickle cell anemia, and the science which gives us hope:  the CIRM-funded doctor who cured Evie is working on sickle cell now.

Because of CIRM, newly paralyzed people now have a realistic chance to recover function: a stem cell therapy begun long ago (pride compels me to mention it was started by the Roman Reed Spinal Cord Injury Research Act, named after my son), is using stem cells to re-insulate damaged nerves in the spine.  Six people were recently given the stem cell treatment pioneered by Hans Keirstead, (currently running for Congress!)  and all six experienced some level of recovery, in a few cases regaining some use of their arms hands.

Are you old enough to remember the late Annette Funicello and Richard Pryor?  These great entertainers were stricken by multiple sclerosis, a slow paralysis.  A cure did not come in time for them. But the international cooperation between California’s Craig Wallace and Australia’s Claude Bernard may help others: by  re-insulating MS-damaged nerves like what was done with spinal cord injury.

My brother David shattered his leg in a motorcycle accident. He endured multiple operations, had steel rods and plates inserted into his leg. Tomorrow’s accident recovery may be easier.  At Cedars-Sinai, Drs. Dan Gazit and Hyun Bae are working to use stem cells to regrow the needed bone.

My wife suffers arthritis in her knees. Her pain is so great she tries to make only one trip a day down and up the stairs of our home.  The cushion of cartilage in her knees is worn out, so it is bone on bone—but what if that living cushion could be restored? Dr. Denis Evseenko of UCLA is attempting just that.

As I spoke, on the wall behind me was a picture of a beautiful woman, Rosie Barrero, who had been left blind by retinitis pigmentosa. Rosie lost her sight when her twin children were born—and regained it when they were teenagers—seeing them for the first time, thanks to Dr. Henry Klassen, another scientist funded by CIRM.

What about cancer? That miserable condition has killed several of my family, and I was recently diagnosed with prostate cancer myself. I had everything available– surgery, radiation, hormone shots which felt like harpoons—hopefully I am fine, but who knows for sure?

Irv Weissman, the friendly bear genius of Stanford, may have the answer to cancer.  He recognized there were cancer stem cells involved. Nobody believed him for a while, but it is now increasingly accepted that these cancer stem cells have a coating of protein which makes them invisible to the body’s defenses. The Weissman procedure may peel off that “cloak of invisibility” so the immune system can find and kill them all—and thereby cure their owner.

What will happen when CIRM’s funding runs out next year?

If we do nothing, the greatest source of stem cell research funding will be gone. We need to renew CIRM. Patients all around the world are depending on us.

The California stem cell program was begun and led by Robert N. “Bob” Klein. He not only led the campaign, was its chief writer and number one donor, but he was also the first Chair of the Board, serving without pay for the first six years. It was an incredible burden; he worked beyond exhaustion routinely.

Would he be willing to try it again, this time to renew the funding of a successful program? When I asked him, he said:

“If California polls support the continuing efforts of CIRM—then I am fully committed to a 2020 initiative to renew the California Institute for Regenerative Medicine (CIRM).”

Shakespeare said it best in his famous “to be or not to be” speech, asking if it is “nobler …to endure the slings and arrows of outrageous fortune, or to take arms against a sea of troubles—and by opposing, end them”.

Should we passively endure chronic disease and disability—or fight for cures?

California’s answer was the stem cell program CIRM—and continuing CIRM is the reason I wrote this book.

Don C. Reed is the author of “CALIFORNIA CURES: How the California Stem Cell Program is Fighting Your Incurable Disease!”, from World Scientific Publishing, Inc., publisher of the late Professor Stephen Hawking.

For more information, visit the author’s website: www.stemcellbattles.com

 

CIRM funded study results in the first ever in utero stem cell transplant to treat alpha thalassemia

Mackenzie

Dr. Tippi MacKenzie (left) of UCSF Benioff Children’s Hospital San Francisco, visits with newborn Elianna and parents Nichelle Obar and Chris Constantino. Photo by Noah Berger

Imagine being able to cure a genetic disorder before a baby is even born. Thanks to a CIRM funded study, what would have been a mere dream a couple of years ago has become a reality.

Drs. Tippi MacKenzie and Juan Gonzalez Velez of the University of California San Francisco (UCSF) have successfully treated alpha thalassemia in Elianna Constantino, using stem cells from her mother’s bone marrow. Alpha thalassemia is part of a group of blood disorders that impairs the body’s ability to produce hemoglobin, the molecule that is responsible for transporting oxygen throughout the body on red blood cells. Present in approximately 5% of the population, alpha thalassemia is particularly prevalent among individuals of Asian heritage. Treatment options for this disease are severely limited, generally requiring multiple rounds of blood transfusions or a bone marrow transplant which requires immunosuppressive therapy. Normally, fetuses die in the womb or the pregnancy is aborted because of the poor prognosis.

The revolutionary treatment pioneered at UCSF involved isolating blood stem cells (cells that are capable of turning into all blood cell types) from the mother’s bone marrow and injecting these cells into Elianna’s bloodstream via the umbilical vein. The doctors were able to observe the development of healthy blood cells in the baby’s blood stream, allowing for efficient oxygen transport throughout the baby’s body. Because the cells were transplanted at the fetal stage, a time when the immune system is not fully developed, there was low risk of rejection and the transplant occurred without aggressive immunosuppressive therapy.

The baby was born healthy earlier this year and has been allowed to return home. While it is still too early to tell how effective this treatment will be in the long term, it is very encouraging that both the mother and baby have endured the treatment thus far.

In a press release, Dr. MacKenzie states:

“Her healthy birth suggests that fetal therapy is a viable option to offer to families with this diagnosis.”

The in utero stem cell transplant was performed as part of a clinical trial conducted at the UCSF Benioff Children’s Hospitals in San Francisco and Oakland. The trial is currently enrolling 10 pregnant women to test the safety and effectiveness of this treatment over a wider population.

If successful, this type of treatment is particularly exciting because it could be expanded to other types of hereditary blood disorders such as sickle cell anemia and hemophilia.

 

 

 

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

 

Coming up with a stem cell FIX for a life-threatening blood disorder

Hemophilia

A promising new treatment option for hemophiliacs is in the works at the Salk Institute for Biological Sciences. Patients with Hemophilia B experience uncontrolled, and sometimes life threatening, bleeding due to loss or improper function of Factor IX (FIX), a protein involved in blood clotting. There is no cure for the disease and patients rely on routine infusions of FIX to prevent excessive blood loss. As you can imagine, this treatment regimen is both time consuming and expensive, while also becoming less effective over time.

Salk researchers, partially funded by CIRM, aimed to develop a more long-term solution for this devastating disease by using the body’s own cells to fix the problem.

In the study, published in the journal Cell Reports, They harvested blood cells from hemophiliacs and turned them into iPSCs (induced pluripotent stem cells), which are able to turn into any cell type. Using gene editing, they repaired the iPSCs so they could produce FIX and then turned the iPSCs into liver cells, the cell type that naturally produces FIX in healthy individuals.

One step therapy

To test whether these FIX-producing liver cells were able to reduce excess blood loss, the scientists injected the repaired human cells into a hemophiliac mouse. The results were very encouraging; they saw a greater than two-fold increase in clotting efficiency in the mice, reaching about a quarter of normal activity. This is particularly promising because other studies showed that increasing FIX activity to this level in hemophiliac humans significantly reduces bleeding rates. On top of that they also observed that these cells were able to survive and produce FIX for up to a year in the mice.

In a news release Suvasini Ramaswamy, the first author of the paper, said this method could eliminate the need for multiple treatments, as well as avoiding the immunosuppressive therapy that would be required for a whole liver transplant.

“The appeal of a cell-based approach is that you minimize the number of treatments that a patient needs. Rather than constant injections, you can do this in one shot.”

While these results provide an exciting new avenue in hemophilia treatment, there is still much more work that needs to be done before this type of treatment can be used in humans. This approach, however, is particularly exciting because it provides an important proof of principle that combining stem cell reprogramming with genetic engineering can lead to life-changing breakthroughs for treating genetic diseases that are not currently curable.

 

 

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

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

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

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

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

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


Novel regenerative drug for osteoarthritis entering clinical trialsThe Scripps Research Institute

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


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

Genetic ‘switches’ behind human brain evolutionScience Daily

180111115351_1_540x360

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

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

Stem Cell Roundup: Gene therapy for diabetes, alcohol is bad for your stem cells and hairy skin

The start of a new year is the perfect opportunity to turn a new leaf. I myself have embraced 2018 with open arms and decided to join my fellow millennials who live and die by the acronym YOLO.

How am I doing this? Well, so far, I got a new haircut, I started doing squats at the gym, and I’m changing up how we blog on the Stem Cellar!

On Fridays, we always share the stem cell stories that “caught our eye” that week. Usually we pick three stories and write short blogs about each of them. Over time, these mini-blogs have slowly grown in size to the point where sometimes we (and I’m sure our readers) wonder why we’re trying to pass off three blogs as one.

Our time-honored tradition of telling the week’s most exciting stem cell stories on Friday will endure, but we’re going to change up our style and give you a more succinct, and comprehensive roundup of stem cell news that you be on your radar.

To prove that I’m not all talk, I’m starting off our new Roundup today. Actually, you’re reading it right now. But don’t worry, the next one we do won’t have this rambling intro 😉.

So here you go, this week’s eye-catching stem cell stories in brief:


Gene therapy helps mice with type 1 diabetesEurekAlert!

A study in Cell Stem Cell found that gene therapy can be used to restore normal blood sugar levels in mice with type 1 diabetes. The scientists used a virus to deliver two genes, PDX1 and MAFA, into non-insulin producing pancreatic cells. The expression of these two proteins, reprogrammed the cells into insulin-producing beta cells that stabilized the blood sugar levels of the mice for 4 months. While the curative effects of the gene therapy weren’t permanent, the scientists noted that the reprogrammed beta cells didn’t trigger an immune response, indicating that the cells acted like normal beta cells. The researchers will next test this treatment in primates and if it works and is safe, they will move onto clinical trials in diabetic patients.


Alcohol increases cancer risk in mice by damaging stem cell DNA – GenBio

*Fair warning for beer or wine lovers: you might not want to read story.

Cambridge scientists published a study in Nature that suggests a byproduct of alcohol called acetaldehyde is toxic to stem cells. They gave watered-down alcohol to mice lacking an essential enzyme that breaks down alcohol in the liver. They found that the DNA in the blood-forming stem cells of the mice lacking this enzyme were four times more damaged than the DNA of normal mice. Excessive DNA damage creates instability in the genetic material of cells, which, over time, can lead to cancer. While many things can cause cancer, individuals who aren’t able to process alcohol effectively should take this study into consideration.


Stem cell therapy success for sclerodoma patientsThe Niche

For those of you unfamiliar with sclerodoma, it’s an autoimmune disease that can affect the skin, blood vessels, muscle tissue and organs in the body. Rather than recreate the wheel, here’s an overview of this study by UC Davis Professor Paul Knoepfler in his blog called The Niche:

Paul Knoepfler

A new NIH-funded study reported in the New England Journal of Medicine (NEJM) gives some hope for the use of a combination of a specific type of myeloablation [a form of chemotherapy] and a transplant of hematopoietic stem cells. This approach yields improved long-term outcomes for patients with a severe form of scleroderma called systemic sclerosis. While survival rates for systemic sclerosis have improved it remains a very challenging condition with a significant mortality rate.”


Phase III stem cell trial for osteoarthritis starts in JapanEurekAlert!

Scientists in Japan have developed a stem cell-based therapy they hope will help patients with osteoarthritis – a degenerative joint disease that causes the breakdown of cartilage. The therapy consists of donor mesenchymal stem cells from a commercial stem cell bank. The team is now testing this therapy in a Phase III clinical trial to assess the therapy’s safety and effectiveness. As a side note, CIRM recently funded a clinical trial for osteoarthritis run by a company called CALIBR. You can read more about it here.


Cool Stem Cell Photo of the Week

I’ll leave you with this rad photo of hairy skin made from mouse pluripotent stem cells. You can read about the study that produced these hairy skin organoids here.

In this artwork, hair follicles grow radially out of spherical skin organoids, which contain concentric epidermal and dermal layers (central structure). Skin organoids self-assemble and spontaneously generate many of the progenitor cells observed during normal development, including cells expressing the protein GATA3 in the hair follicles and epidermis (red). Credit: Jiyoon Lee and Karl R. Koehler

Stories that caught our eye: How dying cells could help save lives; could modified blood stem cells reverse diabetes?; and FDA has good news for patients, bad news for rogue clinics

Gunsmoke

Growing up I loved watching old cowboy movies. Invariably the hero, even though mortally wounded, would manage to save the day and rescue the heroine and/or the town.

Now it seems some stem cells perform the same function, dying in order to save the lives of others.

Researchers at Kings College in London were trying to better understand Graft vs Host Disease (GvHD), a potentially fatal complication that can occur when a patient receives a blood stem cell transplant. In cases of GvHD, the transplanted donor cells turn on the patient and attack their healthy cells and tissues.

Some previous research had found that using bone marrow cells called mesenchymal stem cells (MSCs) had some success in combating GvHD. But it was unpredictable who it helped and why.

Working with mice, the Kings College team found that the MSCs were only effective if they died after being transplanted. It appears that it is only as they are dying that the MSCs engage with the individual’s immune system, telling it to stop attacking healthy tissues. The team also found that if they kill the MSCs just before transplanting them into mice, they were just as effective.

In a news article on HealthCanal, lead researcher Professor Francesco Dazzi, said the next step is to see if this will apply to, and help, people:

“The side effects of a stem cell transplant can be fatal and this factor is a serious consideration in deciding whether some people are suitable to undergo one. If we can be more confident that we can control these lethal complications in all patients, more people will be able to receive this life saving procedure. The next step will be to introduce clinical trials for patients with GvHD, either using the procedure only in patients with immune systems capable of killing mesenchymal stem cells, or killing these cells before they are infused into the patient, to see if this does indeed improve the success of treatment.”

The study is published in Science Translational Medicine.

Genetically modified blood stem cells reverse diabetes in mice (Todd Dubnicoff)

When functioning properly, the T cells of our immune system keep us healthy by detecting and killing off infected, damaged or cancerous cells in our body. But in the case of type 1 diabetes, a person’s own T cells turn against the body by mistakenly targeting and destroying perfectly normal islet cells in the pancreas, which are responsible for producing insulin. As a result, the insulin-dependent delivery of blood sugar to the energy-hungry organs is disrupted leading to many serious complications. Blood stem cell transplants have been performed to treat the disease by attempting to restart the immune system. The results have failed to provide a cure.

Now a new study, published in Science Translational Medicine, appears to explain why those previous attempts failed and how some genetic rejiggering could lead to a successful treatment for type 1 diabetes.

An analysis of the gene activity inside the blood stem cells of diabetic mice and humans reveals that these cells lack a protein called PD-L1. This protein is known to play an important role in putting the brakes on T cell activity. Because T cells are potent cell killers, it’s important for proteins like PD-L1 to keep the activated T cells in check.

Cell based image for t 1 diabetes

Credit: Andrea Panigada/Nancy Fliesler

Researchers from Boston Children’s Hospital hypothesized that adding back PD-L1 may prevent T cells from the indiscriminate killing of the body’s own insulin-producing cells. To test this idea, the research team genetically engineered mouse blood stem cells to produce the PD-L1 protein. Experiments with the cells in a petri dish showed that the addition of PD-L1 did indeed block the attack-on-self activity. And when these blood stem cells were transplanted into a diabetic mouse strain, the disease was reversed in most of the animals over the short term while a third of the mice had long-lasting benefits.

The researchers hope this targeting of PD-L1 production – which the researchers could also stimulate with pharmacological drugs – will contribute to a cure for type 1 diabetes.

FDA’s new guidelines for stem cell treatments

Gottlieb

FDA Commissioner Scott Gottlieb

Yesterday Scott Gottlieb, the Commissioner at the US Food and Drug Administration (FDA), laid out some new guidelines for the way the agency regulates stem cells and regenerative medicine. The news was good for patients, not so good for clinics offering unproven treatments.

First the good. Gottlieb announced new guidelines encouraging innovation in the development of stem cell therapies, and faster pathways for therapies, that show they are both safe and effective, to reach the patient.

At the same time, he detailed new rules that provide greater clarity about what clinics can do with stem cells without incurring the wrath of the FDA. Those guidelines detail the limits on the kinds of procedures clinics can offer and what ways they can “manipulate” those cells. Clinics that go beyond those limits could be in trouble.

In making the announcement Gottlieb said:

“To be clear, we remain committed to ensuring that patients have access to safe and effective regenerative medicine products as efficiently as possible. We are also committed to making sure we take action against products being unlawfully marketed that pose a potential significant risk to their safety. The framework we’re announcing today gives us the solid platform we need to continue to take enforcement action against a small number of clearly unscrupulous actors.”

Many of the details in the announcement match what CIRM has been pushing for some years. Randy Mills, our previous President and CEO, called for many of these changes in an Op Ed he co-wrote with former US Senator Bill Frist.

Our hope now is that the FDA continues to follow this promising path and turns these draft proposals into hard policy.

 

The life of a sleeping muscle stem cell is very busy

For biological processes, knowing when to slow down is as important as knowing when to step on the accelerator. Take for example muscle stem cells. In a healthy state, these cells mostly lay quiet and rarely divide but upon injury, they bolt into action by dividing and specializing into new muscle cells to help repair damaged muscle tissue. Once that mission is accomplished, the small pool of muscle stem cells is replenished through self-renewal before going back into a dormant, or quiescent, state.

muscle stem cell

Muscle stem cell (pink with green outline) sits along a muscle fiber. Image: Michael Rudnicki/OIRM

“Dormant” may not be the best way to describe it because a lot of activity is going on within the cells to maintain its sleepy state. And a better understanding of the processes at play in a dormant state could reveal insights about treating aging or diseased muscles which often suffer from a depletion of muscle stem cells. One way to analyze cellular activity is by examining RNA transcripts which are created when a gene is turned “on”. These transcripts are the messenger molecules that provide a gene’s instructions for making a particular protein.

By observing something, you change it
In order to carry out the RNA transcript analyses in animal studies, researchers must isolate and purify the stem cells from muscle tissue. The worry here is that all of the necessary poking of prodding of the cells during the isolation method will alter the RNA transcripts leading to a misinterpretation of what is actually happening in the native muscle tissue. To overcome this challenge, Dr. Thomas Rando and his team at Stanford University applied a recently developed technique that allowed them to tag and track the RNA transcripts within living mice.

The CIRM-funded study reported today in Cell Reports found that there are indeed significant differences in results when comparing the standard in vitro lab method to the newer in vivo method. As science writer Krista Conger summarized in a Stanford Medical School press release, those differences led to some unexpected results that hadn’t been observed previously:

“The researchers were particularly surprised to learn that many of the RNAs made by the muscle stem cells in vivo are either degraded before they are made into proteins, or they are made into proteins that are then rapidly destroyed — a seemingly shocking waste of energy for cells that spend most of their lives just cooling their heels along the muscle fiber.”

It takes a lot of energy to stay ready
Dr. Rando thinks that these curious observations do not point to an inefficient use of a cell’s resources but instead, “it’s possible that this is one way the cells stay ready to undergo a rapid transformation, either by blocking degradation of RNA or proteins or by swiftly initiating translation of already existing RNA transcripts.”

The new method provides Rando’s team a whole new perceptive on understanding what’s happening behind the scenes during a muscle stem cell’s “dormant” state. And Rando thinks the technique has applications well beyond this study:

Rando

Thomas Rando

“It’s so important to know what we are and are not modeling about the state of these cells in vivo. This study will have a big impact on how researchers in the field think about understanding the characteristics of stem cells as they exist in their native state in the tissue.”