For years researchers have struggled to create human blood stem cells in the lab. They have done it several times with animal models, but the human kind? Well, that’s proved a bit trickier. Now a CIRM-funded team at UC San Diego (UCSD) think they have cracked the code. And that would be great news for anyone who may ever need a bone marrow transplant.
Why are blood stem cells important? Well, they help create our red and white blood cells and platelets, critical elements in carrying oxygen to all our organs and fighting infections. They have also become one of the most important weapons we have to combat deadly diseases like leukemia and lymphoma. Unfortunately, today we depend on finding a perfect or near-perfect match to make bone marrow transplants as safe and effective as possible and without a perfect match many patients miss out. That’s why this news is so exciting.
Researchers at UCSD found that the process of creating new blood stem cells depends on the action of three molecules, not two as was previously thought.
Here’s where it gets
a bit complicated but stick with me. The team worked with zebrafish, which use
the same method to create blood stem cells as people do but also have the
advantage of being translucent, so you can watch what’s going on inside them as
it happens. They noticed that a molecule
called Wnt9a touches down on a receptor called Fzd9b and brings along with it
something called the epidermal growth factor receptor (EGFR). It’s the
interaction of these three together that turns a stem cell into a blood cell.
In a news release, Stephanie Grainger, the first author of the
study published in Nature Cell Biology, said this discovery could help lead to new
ways to grow the cells in the lab.
“Previous attempts to develop blood stem cells in a
laboratory dish have failed, and that may be in part because they didn’t take
the interaction between EGFR and Wnt into account.”
If this new approach helps the team generate blood stem cells in the lab these could be used to create off-the-shelf blood stem cells, instead of bone marrow transplants, to treat people battling leukemia and/or lymphoma.
When governments cut funding for scientific research the consequences can be swift, and painful. In Canada last week for example, the government of Ontario cut $5 million in annual funding for stem cell research, effectively ending a project developing a therapy to heal the damaged lungs of premature babies.
Here in the US the federal government is already placing restrictions on support for fetal tissue research and there is speculation embryonic stem cell research could be next. That’s why agencies like CIRM are so important. We don’t rely on a government giving us money every year. Instead, thanks to the voters of California, we have had a steady supply of funds to enable us to plan long-term and support multi-year projects.
But those funds
are due to run out soon. We anticipate funding our last new awards this year
and while we have enough money to continue supporting all the projects our
Board has already approved, we won’t be able to take on any new projects. That’s
bad news for the scientists and, ultimately, really bad for the patients who
are in need of new treatments for currently incurable diseases.
We are going to talk about that in two upcoming events.
The first is a
patient advocate event at UC San Diego
on Tuesday, May 28th from 12.30pm to 1.30pm. It’s free, there is parking and snacks and
refreshments will be available.
feature UC San Diego’s Dr. Catriona
Jamieson, CIRM’s President and CEO Dr.
Maria Millan and CIRM Board member and Patient Advocate for Parkinson’s
Disease, David Higgins PhD. The
three will talk about the exciting progress being made at UC San Diego and other
programs around California, but also the uncertain future and the impact that
could have for the field as a whole.
For all of you
who don’t live in the San Diego Area – or who do but can’t make it to the event
– we are holding a similar discussion online on a special Facebook Live: Ask the Stem Cell Team About the Future of Stem Cell
Research event on Thursday, May 30th
from noon till 1pm PDT.
features Dr. Millan and Dr. Higgins, but it also features UC Davis stem cell
scientist, CIRM-grantee and renowned blogger Paul Knoepfler PhD.
their own experience, expertise and perspective on the field and will discuss the
impact that a reduction in funding for stem cell research would have, not just
in the short term but in the long run.
Because we all
have a stake in what happens, both events – whether it’s in person or online – include
time for questions from you, the audience.
You can find our
Facebook Live: Ask the Stem Cell Team
About the Future of Stem Cell Research on our Facebook
page at noon on May 30th PDT
It’s not often you read the word “sensational” in a news release about stem cells. But this week researchers at the University of Copenhagen released findings that are overturning long-held ideas about the development of cells in our stomachs. So perhaps calling it “sensational” is not too big a stretch.
In the past it was believed that the development of immature cells in our stomachs, before a baby is born, was predetermined, that the cells had some kind of innate sense of what they were going to become and when. Turns out that’s not the case. The researchers say it’s the cells’ environment that determines what they will become and that all cells in the fetus’ gut have the potential to turn into stem cells.
In the “sensational” news
release lead author, Kim Jensen, says this
finding could help in the development of new therapies.
“We used to believe that a cell’s
potential for becoming a stem cell was predetermined, but our new results show
that all immature cells have the same probability for becoming stem cells in
the fully developed organ. In principle, it is simply a matter of being in the
right place at the right time. Here signals from the cells’ surroundings
determine their fate. If we are able to identify the signals that are necessary
for the immature cell to develop into a stem cell, it will be easier for us to
manipulate cells in the wanted direction’.
It’s long been known that some lizards and other mammals can
regrow severed limbs, but it hasn’t been clear how. Now scientists at the
University of Cambridge in the UK have figured out what’s going on.
genomics the scientists were able to track which genes are turned on and
off at particular times, allowing them to watch what happens inside the tail of
the African clawed frog tadpole as it regenerates the damaged limb.
They found that the response was orchestrated by a group of
skin cells they called Regeneration-Organizing
Cells, or ROCs. Can Aztekin, one of the lead authors of the study in the
journal Science, says seeing how ROCs work could lead
to new ideas on how to stimulate similar regeneration in other mammals.
“It’s an astonishing process to
watch unfold. After tail amputation, ROCs migrate from the body to the wound
and secrete a cocktail of growth factors that coordinate the response of tissue
precursor cells. These cells then work together to regenerate a tail of the
right size, pattern and cell composition.”
Orphan Drug Designation for CIRM-funded
Poseida Therapeutics got some good news recently about their CIRM-funded therapy for multiple myeloma. The US Food and Drug Administration (FDA) granted them orphan drug designation.
drug designation is given to therapies targeting rare diseases or disorders
that affect fewer than 200,000 people in the U.S. It means the company may be
eligible for grant funding toward clinical trial costs, tax
advantages, FDA user-fee benefits and seven years of market
exclusivity in the United States following marketing approval by
is seeking to destroy these cancerous myeloma cells with an immunotherapy
approach that uses the patient’s own engineered immune system T cells to seek
and destroy the myeloma cells.”
CEO, Eric Ostertag, said the designation is an important milestone for the
company therapy which “has
demonstrated outstanding potency, with strikingly low rates of toxicity in our
phase 1 clinical trial. In fact, the FDA has approved fully outpatient dosing
in our Phase 2 trial starting in the second quarter of 2019.”
Understanding the basic biology of how a cell functions can be crucial to being able to better understand a disease and unlock a potential approach for a treatment. Stem cells are unique in that they give scientists the opportunity to create a controlled environment of cells that might be otherwise difficult to study. Dr. Eva Hedlund and a team of researchers at the Karolinska Institute in Sweden utilize a stem cell model approach to uncover findings related to Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s Disease.
ALS is a progressive neurodegenerative disease that destroys motor neurons, a type of nerve cell, that are important for voluntary muscle movement. When motor neurons can no longer send signals to the muscles, the muscles begin to deteriorate, a process formally known as atrophy. The progressive atrophy leads to muscle paralysis, including those in the legs and feet, arms and hands, and those that control swallowing and breathing. It affects about 30,000 people in the United States alone, with 5,000 new cases diagnosed each year. There is currently no cure.
In a previous study, researchers at the Karolinska Institute were able to successfully create oculomotor neurons from embryonic stem cells. For reasons not yet fully understood, oculomotor neurons are “ALS resilient” and can survive all stages of the disease.
In the current study, published in Stem Cell Reports, Dr. Hedlund and her team found that the oculomotor neurons they generated appeared more resilient to ALS-like degeneration when compared to spinal cord motor neurons, something commonly observed in humans. Furthermore, they discovered that their “ALS resilient” neurons generated from stem cells activate a survival-enhancing signal known as Akt, which is common in oculomotor neurons in humans and could explain their resilience. These results could potentially aid in identifying genetic targets for treatments protecting sensitive neurons from the disease.
Age-related macular degeneration (AMD) is the leading cause of vision loss in people over 60. It affects 10 million Americans. That’s more than cataracts and glaucoma combined. The causes of AMD are not known but are believed to involve a mixture of hereditary and environmental factors. There is no treatment for it.
Now, in a
CIRM-funded study, researchers at UC San Diego (UCSD) have used stem cells to
help identify genetic elements that could provide some clues as to the cause,
and maybe give some ideas on how to treat it.
Before we get into what the researchers did let’s take a look at what AMD does. At a basic level it attacks the retina, the thin layer of tissue that lines the back of the eye. The retina receives light, turns it into electrical signals and sends it to the brain which turns it into a visual image.
The disease destroys the macula, the part of the retina that controls our central vision. At first, sight becomes blurred or fuzzy but over time it progresses to the point where central vision is almost completely destroyed.
To try and
understand why this happens the team at UCSD took skin samples from six people
with AMD and, using the iPSC method, turned those cells into the kinds of cell found in the retina. Because
these cells came from people who had AMD they now displayed the same
characteristics as AMD-affected retinal cells. This allowed the researchers to
create what is called a “disease-in-a-dish” model that allowed them to see, in
real time, what is happening in AMD.
They were able to
identify a genetic variant that reduces production of a protein called VEGFA,
which is known to promote the growth of new blood vessels.
In a news release Kelly Frazer, director of the Institute for Genomic Medicine at UCSD and the lead author of the study, said the results were unexpected.
“We didn’t start with the VEGFA gene when we went looking for genetic causes of AMD. But we
were surprised to find that with samples from just six people, this genetic
variation clearly emerged as a causal factor.”
Frazer says this
discovery, published in the journal Stem
Cell Reports, could
ultimately lead to new approaches to developing new treatments for AMD.
When CIRM was created in 2004 the field of stem cell research was still very much in its infancy. Fast forward 15 years and it’s moving ahead at a rapid pace, probably faster than most scientists would have predicted. How fast? Find out for yourself at a free public event at UC San Diego on May 28th from 12.30 to 1.30p.
In the last 15 years CIRM has funded 53 clinical
trials in everything from heart disease and stroke, to spinal cord injury,
vision loss, sickle cell disease and HIV/AIDS.
Clearly progress is being made. But the field is also facing some challenges. Funding at the federal level for stem cell research is under threat, and CIRM is entering what could be its final phase. We have enough money left to fund new projects through this year (and these are multi-year projects so they will run into 2021 or 2022) but unless there is a new round of funding we will slowly disappear. And with us, may also disappear the hopes of some of the most promising projects underway.
If CIRM goes, then projects that we have supported and nurtured through different phases of research may struggle to make it into a clinical trial because they can’t get the necessary funding.
Clearly this is a pivotal time in the field.
We will discuss all this, the past, the present and the uncertain future of stem cell research at the meeting at UC San Diego on May 28th. The doors will open at noon for registration (snacks and light refreshments will also be available) and the program runs from 12.30p to 1.30p.
The speakers are:
Jamieson, Director of the UC San Diego Health CIRM Alpha Stem Cell Clinic
and Sanford Stem Cell Clinical Center.
Millan, President and CEO of CIRM
Higgins, CIRM Board member and Patient Advocate for Parkinson’s Disease.
And of course, we want to hear from you, so we’ll leave
plenty of time for questions.
The beginning of a clinical trial, particularly the first time a new therapy is being tested in people, is often a time of equal parts anticipation and nervousness. Anticipation, because you have been working to this point for many years. Nervousness, because you have never tested this in people before and even though you have done years of study to show it is probably safe, until you try it in people you never really know.
That’s why the latest results from the CIRM-funded SCiStar Study, a clinical trial for spinal cord injury, are so encouraging. The results show that, one year after being treated, all the patients are doing well, none have experienced any serious side effects, and most have experienced impressive gains in movement, mobility and strength.
In a news release Ed Wirth, BioTIme’s Chief Medical Officer, said they were encouraged by what they saw:
“We believe the primary goals of the SCiStar Study, which
were to observe the safety of OPC1 in cervical spinal cord injury patients as
well as other important metrics including related to the optimal timing of OPC1
injection, tolerability of the immunosuppression regimen, engraftment of OPC1
cells, and rates of motor recovery observed among different study
subpopulations, have all been successfully achieved.”
The study involved
transplanting what the researchers called AST-OPC1
cells into patients who have suffered recent injuries that have left them
paralyzed from the neck down. AST-OPC1 are oligodendrocyte progenitor
cells, which develop into cells that support and protect nerve cells in the
central nervous system, the area damaged in spinal cord injury. It’s hoped the
treatment will restore connections at the injury site, allowing patients to
regain some movement and feeling.
Altogether 25 patients were involved. Three, in Cohort 1, were given injections of just two million OPC1 cells. This was to ensure the approach was safe and wouldn’t endanger patients. The remaining 22, in Cohorts 2-5, were given between 10 and 20 million cells. One year after the last patient was treated the results show:
MRI scans show no evidence of adverse changes in any of the 25 SCiStar study subjects.
No SCiStar study subjects had worsening of neurological function post-injection
At 12 months, 95% (21/22) of patients in Cohorts 2-5 recovered at least one motor level on at least one side and 32% (7/22) of these subjects recovered two or more motor levels on at least one side.
No patient saw decreased motor function following administration of OPC1 and all either retained for 12 months the motor function recovery seen through 6 months or experienced further motor function recovery from 6 to 12 months.
All three subjects in Cohort 1 and 95% (21/22) of those in Cohorts 2 to 5 have MRI scans at 12 months consistent with the formation of a tissue matrix at the injury site. This is encouraging evidence the OPC1 cells have engrafted at the injury site and helped to prevent cavitation, a destructive process that occurs within the spinal cord following spinal cord injuries, and typically results in permanent loss of motor and sensory function.
“We appreciate the support of the California Institute for
Regenerative Medicine, the world’s largest institution dedicated to bringing
the future of cellular medicine closer to reality, whose generous grant funding
to date of $14.3 million has helped advance the clinical development of our
OPC1 program and generate these encouraging clinical results in patients with
traumatic spinal cord injuries.”
is now planning to meet with the Food and Drug Administration (FDA) later this
year to discuss next steps for the therapy. Soon as we know the outcome of
those talks, we’ll share them with you.
governing Board of the California Institute for Regenerative Medicine (CIRM) awarded
two grants totaling $11.15 million to carry out two new clinical trials. These latest additions bring the total number
of CIRM funded clinical trials to 53.
$6.56 Million was awarded to Rocket Pharmaceuticals, Inc. to conduct a clinical trial for
treatment of infants with Leukocyte Adhesion Deficiency-I (LAD-I)
LAD-I is a rare pediatric disease caused a mutation in a specific gene that
affects the body’s ability to combat infections. As a result, infants with
severe LAD-I are often affected immediately after birth. During infancy, they
suffer from recurrent life-threatening bacterial and fungal infections that
respond poorly to antibiotics and require frequent hospitalizations. Those that survive infancy experience
recurrent severe infections, with mortality rates for severe LAD-I at 60-75%
prior to the age of two and survival very rare beyond the age of five.
Rocket Pharmaceuticals, Inc. will test a treatment that uses a patient’s own blood stem cells and inserts a functional version of the gene. These modified stem cells are then reintroduced back into the patient that would give rise to functional immune cells, thereby enabling the body to combat infections.
The award is in
the form of a CLIN2 grant, with the goal of conducting a clinical trial to
assess the safety and effectiveness of this treatment in patients with LAD-I.
utilizes a gene therapy approach, similar to that of three other clinical
trials funded by CIRM and conducted at UCLA by Dr. Don Kohn, for X-linked
Chronic Granulomatous Disease, an inherited immune deficiency “bubble baby”
disease known as ADA-SCID, and Sickle Cell Disease.
An additional $4.59 million was awarded to Dr.
Theodore Nowicki at UCLA to conduct a clinical trial for treatment of patients
with sarcomas and other advanced solid tumors. In 2018 alone, an
estimated 13,040 people were diagnosed with soft tissue sarcoma (STS) in the
United States, with approximately 5,150 deaths.
Standard of care treatment for sarcomas typically consists of surgery,
radiation, and chemotherapy, but patients with late stage or recurring tumor
growth have few options.
Dr. Nowicki and his team will genetically modify peripheral blood stem cells (PBSCs) and peripheral blood monocular cells (PBMCs) to target these solid tumors. The gene modified stem cells, which have the ability to self-renew, provide the potential for a durable effect.
This award is
also in the form of a CLIN2 grant, with the goal of conducting a clinical trial
to assess the safety of this rare solid tumor treatment.
“CIRM has funded 23 clinical stage programs utilizing cell and gene medicine approaches” says Maria T. Millan, M.D., the President and CEO of CIRM. “The addition of these two programs, one in immunodeficiency and the other for the treatment of malignancy, broaden the scope of unmet medical need we can impact with cell and gene therapeutic approaches.”
From Day One CIRM’s goal has been to advance stem cell research in California. We don’t do that just by funding the most promising research -though the 51 clinical trials we have funded to date clearly shows we do that rather well – but also by trying to bring the best minds in the field together to overcome problems.
Over the years we
have held conferences, workshops and symposiums on everything from Parkinson’s
palsy and tissue
engineering. Each one attracted the key players and stakeholders in the
field, brainstorming ideas to get past obstacles and to explore new ways of
developing therapies. It’s an attempt to get scientists, who would normally be
rivals or competitors, to collaborate and partner together in finding the best
It’s not easy to do,
and the results are not always obvious right away, but it is essential if we
hope to live up to our mission of accelerating stem cell therapies to patients
with unmet medical needs.
For example. This
past week we helped organize two big events and were participants in another.
The first event we
pulled together, in partnership with Cedars-Sinai Medical Center, was a
workshop called “Brainstorm Neurodegeneration”. It brought together leaders in stem
cell research, genomics, big data, patient advocacy and the Food and Drug
Administration (FDA) to tackle some of the issues that have hampered progress
in finding treatments for things like Parkinson’s, Alzheimer’s, ALS and
ambitiously subtitled the workshop “a cutting-edge meeting to disrupt the field”
and while the two days of discussions didn’t resolve all the problems facing us
it did produce some fascinating ideas and some tantalizing glimpses at ways to
advance the field.
Two days later we partnered with UC San Francisco to host the Fourth Annual CIRM Alpha Stem Cell Clinics Network Symposium. This brought together the scientists who develop therapies, the doctors and nurses who deliver them, and the patients who are in need of them. The theme was “The Past, Present & Future of Regenerative Medicine” and included both a look at the initial discoveries in gene therapy that led us to where we are now as well as a look to the future when cellular therapies, we believe, will become a routine option for patients.
different groups together is important for us. We feel each has a key role to
play in moving these projects and out of the lab and into clinical trials and
that it is only by working together that they can succeed in producing the
treatments and cures patients so desperately need.
As always it was the patients who surprised us. One, Cierra Danielle Jackson, talked about what it was like to be cured of her sickle cell disease. I think it’s fair to say that most in the audience expected Cierra to talk about her delight at no longer having the crippling and life-threatening condition. And she did. But she also talked about how hard it was adjusting to this new reality.
Cierra said sickle
cell disease had been a part of her life for all her life, it shaped her daily
life and her relationships with her family and many others. So, to suddenly
have that no longer be a part of her caused a kind of identity crisis. Who was
she now that she was no longer someone with sickle cell disease?
She talked about how
people with most diseases were normal before they got sick, and will be normal
after they are cured. But for people with sickle cell, being sick is all they
have known. That was their normal. And now they have to adjust to a new normal.
It was a powerful
reminder to everyone that in developing new treatments we have to consider the
whole person, their psychological and emotional sides as well as the physical.
And so on to the third event we were part of, the Stanford Drug Discovery Symposium. This was a high level, invitation-only scientific meeting that included some heavy hitters – such as Nobel Prize winners Paul Berg and Randy Schekman, former FDA Commissioner Robert Califf. Over the course of two days they examined the role that philanthropy plays in advancing research, the increasingly important role of immunotherapy in battling diseases like cancer and how tools such as artificial intelligence and big data are shaping the future.
CIRM’s President and CEO, Dr. Maria Millan, was one of those invited to speak and she talked about how California’s investment in stem cell research is delivering Something Better than Hope – which by a happy coincidence is the title of our 2018 Annual Report. She highlighted some of the 51 clinical trials we have funded, and the lives that have been changed and saved by this research.
The presentations at
these conferences and workshops are important, but so too are the conversations
that happen outside the auditorium, over lunch or at coffee. Many great
collaborations have happened when scientists get a chance to share ideas, or
when researchers talk to patients about their ideas for a successful clinical
It’s amazing what happens when you bring people together who might otherwise never have met. The ideas they come up with can change the world.
At CIRM we are very cautious about using the “c” word. Saying someone has been “cured” is a powerful statement but one that loses its meaning when over used or used inappropriately. However, in the case of a new study from U.C. San Francisco and St. Jude Children’s Research Hospital in Memphis, saying “cure” is not just accurate, it’s a celebration of something that would have seemed impossible just a few years ago.
The research focuses on children with a specific form of Severe Combined Immunodeficiency (SCID) called X-Linked SCID. It’s also known as “bubble baby” disease because children born with this condition lack a functioning immune system, so even a simple infection could be fatal and in the past they were kept inside sterile plastic bubbles to protect them.
In this study, published in the New England Journal of Medicine, researchers took blood stem
cells from the child and, in the lab, genetically re-engineered them to correct
the defective gene, and then infused them back into the child. Over time they
multiplied and created a new blood supply, one free of the defect, which helped
repair the immune system.
In a news
release Dr. Ewelina Mamcarz, the lead author of the study, announced that
ten children have been treated with this method.
“These patients are toddlers now, who are responding to
vaccinations and have immune systems to make all immune cells they need for
protection from infections as they explore the world and live normal lives.
This is a first for patients with SCID-X1.”
The ten children were treated at both St. Jude and at UCSF
funded the UCSF arm of the clinical trial.
The story, not surprisingly, got a lot of attention in the
media including this fine
piece by CNN.