Chemotherapy and radiation are two of the front-line weapons in treating cancer. They can be effective, even life-saving, but they can also be brutal, taking a toll on the body that lasts for months. Now a team at UCLA has developed a therapy that might enable the body to bounce back faster after chemo and radiation, and even make treatments like bone marrow transplants easier on patients.
First a little
background. Some cancer treatments use chemotherapy and radiation to kill the
cancer, but they can also damage other cells, including those in the bone
marrow responsible for making blood stem cells. Those cells eventually recover
but it can take weeks or months, and during that time the patient may feel
fatigue and be more susceptible to infections and other problems.
In a CIRM-supported study, UCLA’s Dr. John Chute and his team developed a drug that speeds up the process of regenerating a new blood supply. The research is published in the journal Nature Communications.
They focused their
attention on a protein called PTP-sigma that is found in blood stem cells and
acts as a kind of brake on the regeneration of those cells. Previous studies by
Dr. Chute showed that, after undergoing radiation, mice that have less
PTP-sigma were able to regenerate their blood stem cells faster than mice that
had normal levels of the protein.
So they set out to
identify something that could help reduce levels of PTP-sigma without affecting
other cells. They first identified an organic compound with the charming name
of 6545075 (Chembridge) that was reported to be effective against PTP-sigma.
Then they searched a library of 80,000 different small molecules to find
something similar to 6545075 (and this is why science takes so long).
From that group they
developed more than 100 different drug candidates to see which, if any, were
effective against PTP-sigma. Finally, they found a promising candidate, called DJ009.
In laboratory tests DJ009 proved itself effective in blocking PTP-sigma in
human blood stem cells.
They then tested
DJ009 in mice that were given high doses of radiation. In a news
release Dr. Chute said the results were very encouraging:
“The potency of this compound in animal models was very
high. It accelerated the recovery of blood stem cells, white blood cells and
other components of the blood system necessary for survival. If found to be
safe in humans, it could lessen infections and allow people to be discharged
from the hospital earlier.”
Of the radiated mice, most that were given DJ009
survived. In comparison, those that didn’t get DJ009 died within three weeks.
They saw similar benefits in mice given chemotherapy.
Mice with DJ009 saw their white blood cells – key components of the immune
system – return to normal within two weeks. The untreated mice had dangerously
low levels of those cells at the same point.
It’s encouraging work and the team are already getting
ready for more research so they can validate their findings and hopefully take
the next step towards testing this in people in clinical trials.
At CIRM we are privileged to work with many remarkable people who combine brilliance, compassion and commitment to their search for new therapies to help people in need. One of those who certainly fits that description is UC Davis’ Jan Nolta.
This week the UC Davis Newsroom posted a great interview with Jan. Rather than try and summarize what she says I thought it would be better to let her talk for herself.
Talking research, unscrupulous clinics, and sustaining the momentum
In 2007, Jan Nolta
returned to Northern California from St. Louis to lead what was at the
time UC Davis’ brand-new stem cell program. As director of the UC Davis Stem Cell Program
and the Institute for Regenerative Cures, she has overseen the opening
of the institute, more than $140 million in research grants, and dozens
upon dozens of research studies. She recently sat down to answer some
questions about regenerative medicine and all the work taking place at UC Davis Health.
Q: Turning stem cells into cures has been your mission and mantra since you founded the program. Can you give us some examples of the most promising research?
I am so excited about our research. We have about 20 different disease-focused teams.
That includes physicians, nurses, health care staff, researchers and
faculty members, all working to go from the laboratory bench to
patient’s bedside with therapies.
Perhaps the most promising and
exciting research right now comes from combining blood-forming
stem cells with gene therapy. We’re working in about
eight areas right now, and the first cure, something that we definitely
can call a stem cell “cure,” is coming from this combined approach.
doctors will be able to prescribe this type of stem cell therapy.
Patients will use their own bone marrow or umbilical cord stem cells.
Teams such as ours, working in good manufacturing practice
facilities, will make vectors, essentially “biological delivery
vehicles,” carrying a good copy of the broken gene. They will be
reinserted into a patient’s cells and then infused back into the
patient, much like a bone marrow transplant.
“Perhaps the most promising and exciting research right now comes from combining blood-forming stem cells with gene therapy.”
Along with treating the famous bubble baby disease,
where I had started my career, this approach looks very promising for
sickle cell anemia. We’re hoping to use it to treat several different
inherited metabolic diseases. These are conditions characterized by an
abnormal build-up of toxic materials in the body’s cells. They interfere
with organ and brain function. It’s caused by just a single enzyme.
Using the combined stem cell gene therapy, we can effectively put a good
copy of the gene for that enzyme back into a patient’s bone marrow stem
cells. Then we do a bone marrow transplantation and bring back a
person’s normal functioning cells.
The beauty of this therapy is
that it can work for the lifetime of a patient. All of the blood cells
circulating in a person’s system would be repaired. It’s the number one
stem cell cure happening right now. Plus, it’s a therapy that won’t be
rejected. These are a patient’s own stem cells. It is just one type of
stem cell, and the first that’s being commercialized to change cells
throughout the body.
Q: Let’s step back for a moment. In 2004, voters approved Proposition 71.
It has funded a majority of the stem cell research here at UC Davis and
throughout California. What’s been the impact of that ballot measure
and how is it benefiting patients?
We have learned so
much about different types of stem cells, and which stem cell will be
most appropriate to treat each type of disease. That’s huge. We had to
first do that before being able to start actual stem cell therapies. CIRM [California Institute for Regenerative Medicine] has funded Alpha Stem Cell Clinics.
We have one of them here at UC Davis and there are only five in the
entire state. These are clinics where the patients can go for
high-quality clinical stem cell trials approved by the FDA
[U.S. Food and Drug Administration]. They don’t need to go to
“unapproved clinics” and spend a lot of money. And they actually
“By the end of this year, we’ll have 50 clinical trials.”
By the end of this year, we’ll have 50 clinical trials [here at UC Davis Health]. There are that many in the works.
Our Alpha Clinic
is right next to the hospital. It’s where we’ll be delivering a lot of
the immunotherapies, gene therapies and other treatments. In fact, I
might even get to personally deliver stem cells to the operating room
for a patient. It will be for a clinical trial involving people who have
broken their hip. It’s exciting because it feels full circle, from
working in the laboratory to bringing stem cells right to the patient’s
We have ongoing clinical trials
for critical limb ischemia, leukemia and, as I mentioned, sickle cell
disease. Our disease teams are conducting stem cell clinical trials
targeting sarcoma, cellular carcinoma, and treatments for dysphasia [a
swallowing disorder], retinopathy [eye condition], Duchenne muscular
dystrophy and HIV. It’s all in the works here at UC Davis Health.
also great potential for therapies to help with renal disease and
kidney transplants. The latter is really exciting because it’s like a
mini bone marrow transplant. A kidney recipient would also get some
blood-forming stem cells from the kidney donor so that they can better
accept the organ and not reject it. It’s a type of stem cell therapy
that could help address the burden of being on a lifelong regime of
immunosuppressant drugs after transplantation.
Q: You and
your colleagues get calls from family members and patients all the
time. They frequently ask about stem cell “miracle” cures. What should
people know about unproven treatments and unregulated stem cell clinics?
That’s a great question.The number one rule is that if
you’re asked to pay money for a stem cell treatment, don’t do it. It’s a
big red flag.
When it comes to advertised therapies: “The number one rule is that if you’re asked to pay money for a stem cell treatment, don’t do it. It’s a big red flag.”
there are unscrupulous people out there in “unapproved clinics” who
prey on desperate people. What they are delivering are probably not even
stem cells. They might inject you with your own fat cells, which
contain very few stem cells. Or they might use treatments that are not
matched to the patient and will be immediately rejected. That’s
dangerous. The FDA is shutting these unregulated clinics down one at a
time. But it’s like “whack-a-mole”: shut one down and another one pops
On the other hand, the Alpha Clinic is part of our
mission is to help the public get to the right therapy, treatment or
clinical trial. The big difference between those who make patients pay
huge sums of money for unregulated and unproven treatments and UC Davis
is that we’re actually using stem cells. We produce them in rigorously
regulated cleanroom facilities. They are certified to contain at least 99% stem cells.
and family members can always call us here. We can refer them to a
genuine and approved clinical trial. If you don’t get stem cells at the
beginning [of the clinical trial] because you’re part of the placebo
group, you can get them later. So it’s not risky. The placebo is just
saline. I know people are very, very desperate. But there are no miracle
cures…yet. Clinical trials, approved by the FDA, are the only way we’re
going to develop effective treatments and cures.
Scientific breakthroughs take a lot of patience and time. How do you and
your colleagues measure progress and stay motivated?
Motivation? “It’s all for the patients.”
all for the patients. There are not good therapies yet for many
disorders. But we’re developing them. Every day brings a triumph.
Measuring progress means treating a patient in a clinical trial, or
developing something in the laboratory, or getting FDA approval. The big
one will be getting biological license approval from the FDA, which
means a doctor can prescribe a stem cell or gene therapy treatment. Then
it can be covered by a patient’s health insurance.
I’m a cancer
survivor myself, and I’m also a heart patient. Our amazing team here at
UC Davis has kept me alive and in great health. So I understand it from
both sides. I understand the desperation of “Where do I go?” and “What
do I do right now?” questions. I also understand the science side of
things. Progress can feel very, very slow. But everything we do here at
the Institute for Regenerative Cures is done with patients in mind, and
We know that each day is so important when you’re watching
a loved one suffer. We attend patient events and are part of things
like Facebook groups, where people really pour their hearts out. We say
to ourselves, “Okay, we must work harder and faster.” That’s our
motivation: It’s all the patients and families that we’re going to help
who keep us working hard.
Battling cancer is always a balancing act. The methods we use – surgery, chemotherapy and radiation – can help remove the tumors but they often come at a price to the patient. In cases where the cancer has spread to the bone the treatments have a limited impact on the disease, but their toxicity can cause devastating problems for the patient. Now, in a CIRM-supported study, researchers at UC Irvine (UCI) have developed a method they say may be able to change that.
Bone metastasis –
where cancer starts in one part of the body, say the breast, but spreads to the
bones – is one of the most common complications of cancer. It can often result
in severe pain, increased risk of fractures and compression
of the spine. Tackling them is difficult because some cancer cells can
alter the environment around bone, accelerating the destruction of healthy bone
cells, and that in turn creates growth factors that stimulate the growth of the
cancer. It is a vicious cycle where one problem fuels the other.
Now researchers at
UCI have developed a method where they combine engineered mesenchymal stem cells (taken from the bone marrow) with
targeting agents. These act like a drug delivery device, offloading
different agents that simultaneously attack the cancer but protect the bone.
In a news release Weian Zhao, lead author of the study, said:
“What’s powerful about this
strategy is that we deliver a combination of both anti-tumor and anti-bone
resorption agents so we can effectively block the vicious circle between
cancers and their bone niche. This is a safe and almost nontoxic treatment
compared to chemotherapy, which often leaves patients with lifelong issues.”
published in the journal EBioMedicine,
has already been shown to be effective in mice. Next, they hope to be able to
do the safety tests to enable them to apply to the Food and Drug Administration
for permission to test it in people.
The team say if this
approach proves effective it might also be used to help treat other bone-related
diseases such as osteoporosis and multiple myeloma.
When you have a great story to tell the best and most effective way to get it out to the widest audience is still the media, both traditional mainstream and new social media. Recently we have seen three great examples of how that can be done and, hopefully, the benefits that can come from it.
First, let’s go old
school. Earlier this month Caroline Chen wrote a wonderful
in-depth article about clinics that are cashing in on a gray area in stem
cell research. The piece, a collaboration between the New Yorker magazine and
ProPublica, focused on the use of amniotic stem cell treatments and the gap
between what the clinics who offer it are claiming it can do, and the reality.
Here’s one paragraph
profiling a Dr. David Greene, who runs a company providing amniotic fluid to
clinics. It’s a fine piece of writing showing how the people behind these
therapies blur the lines between fact and reality, not just about the cells but
also about themselves:
“Greene said that amniotic stem cells derive their healing power from an ability to develop into any kind of tissue, but he failed to mention that mainstream science does not support his claims. He also did not disclose that he lost his license to practice medicine in 2009, after surgeries he botched resulted in several deaths. Instead, he offered glowing statistics: amniotic stem cells could help the heart beat better, “on average by twenty per cent,” he said. “Over eighty-five per cent of patients benefit exceptionally from the treatment.”
backpedals on that claim, saying:
“I don’t claim that this is a treatment. I don’t claim that it cures anything. I don’t claim that it’s a permanent fix. All I discuss is maybe, potentially, people can get some improvements from stem-cell care.”
This week CBS2
TV in Chicago did their own investigative story about how the number of local
clinics offering unproven and unapproved therapies is on the rise. Reporter Pam
Zekman showed how misleading newspaper ads brought in people desperate for
something, anything, to ease their arthritis pain.
She interviewed two
patients who went to one of those clinics, and ended up out of pocket, and out
“They said they would regenerate the cartilage,” Patricia Korona recalled. She paid $4500 for injections in her knee, but the pain continued. Later X-rays were ordered by her orthopedic surgeon.
“He found bone on bone,” Korona said. “No cartilage grew, which tells me it failed; didn’t work.”
John Zapfel paid $14,000 for stem cell injections on each side of his neck and his shoulder. But an MRI taken by his current doctor showed no improvement.
“They ripped me off, and I was mad.” Zapfel said.
TV and print reports
like this are a great way to highlight the bogus claims made by many of these
clinics, and to shine a light on how they use hype to sell hope to people who
are in pain and looking for help.
At a time when
journalism seems to be increasingly under attack with accusations of “fake news”
it’s encouraging to see reporters like these taking the time and news outlets
devoting the resources to uncover shady practices and protect vulnerable
But the news isn’t
all bad, and the use of social media can help highlight the good news.
That’s what happened
yesterday in our latest CIRM
Facebook Live “Ask the Stem Cell Team” event. The event focused on the
future of stem cell research but also included a really thoughtful look at the
progress that’s been made over the last 10-15 years.
We had two great
guests, UC Davis stem cell researcher and one of the leading bloggers on the
field, Paul Knoepfler PhD; and David
Higgins, PhD, a scientist, member of the CIRM Board and a Patient Advocate
for Huntington’s Disease. They were able to highlight the challenges of the
early years of stem cell research, both globally and here at CIRM, and show how
the field has evolved at a remarkable rate in recent years.
subject of the “bogus clinics” came up – Paul has become a national expert on
these clinics and is quoted in the New Yorker article – as did the subject of
the frustration some people feel at what they consider to be the too-slow pace
of progress. As David Higgins noted, we all think it’s too slow, but we are not
going to race recklessly ahead in search of something that might heal if we
might also end up doing something that might kill.
A portion of the
discussion focused on funding and, in particular, what happens if CIRM is no
longer around to fund the most promising research in California. We are due to
run out of funding for new projects by the end of this year, and without a
re-infusion of funds we will be pretty much closing our doors by the end of
2020. Both Paul and David felt that could be disastrous for the field here in
California, depriving the most promising projects of support at a time when
they needed it most.
It’s probably not
too surprising that three people so closely connected to CIRM (Paul has
received funding from us in the past) would conclude that CIRM is needed for
stem cell research to not just survive but thrive in California.
A word of caution
before you watch: fashion conscious people may be appalled at how my pocket handkerchief
took on a life of its own.
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.
At CIRM we are always happy to highlight success stories, particularly when they involve research we are funding. But we are also mindful of the need not to overstate a finding. To quote the Greek philosopher Aristotle (who doesn’t often make an appearance on this blog), “one swallow does not a summer make”. In other words, one good result doesn’t mean you have proven something works. But it might mean that you are on the right track. And that’s why we are welcoming the news about a clinical trial we are funding with Sangamo Therapeutics.
The trial is for the treatment of beta-thalassemia, (beta-thal) a severe form of anemia caused by a genetic mutation. People with beta-thal require life-long blood transfusions because they have low levels of hemoglobin, a protein needed to help the blood carry oxygen around the body. Those low levels of oxygen can cause anemia, fatigue, weakness and, in severe cases, can lead to organ damage and even death. The life expectancy for people with the more severe forms of the condition is only 30-50 years.
In this clinical
trial the Sangamo team takes
a patient’s own blood stem cells and, using a gene-editing technology called
zinc finger nuclease (ZFN), inserts a working copy of the defective hemoglobin
gene. These modified cells are given back to the patient, hopefully generating
a new, healthy, blood supply which potentially will eliminate the need for
chronic blood transfusions.
announced that the first patient treated in this clinical trial seems to be
doing rather well.
The therapy, called
ST-400, was given to a patient who has the most severe form of beta-thal. In
the two years before this treatment the patient was getting a blood transfusion
every other week. While the treatment initially caused an allergic reaction,
the patient quickly rebounded and in the seven weeks afterwards:
Demonstrated evidence of being able to
produce new blood cells including platelets and white blood cells
Showed that the genetic edits made by
ST-400 were found in new blood cells
Hemoglobin levels – the amount of
oxygen carried in the blood – improved.
In the first few weeks
after the therapy the patient needed some blood transfusions but in the next
five weeks didn’t need any.
Obviously, this is
encouraging. But it’s also just one patient. We don’t yet know if this will
continue to help this individual let alone help any others. A point Dr. Angela
Smith, one of the lead researchers on the project, made in a news
“While these data are very early
and will require confirmation in additional patients as well as longer
follow-up to draw any clinical conclusion, they are promising. The detection of
indels in peripheral blood with increasing fetal hemoglobin at seven weeks is
suggestive of successful gene editing in this transfusion-dependent beta
thalassemia patient. These initial results are especially encouraging given the
patient’s β0/ β0 genotype, a patient population
which has proved to be difficult-to-treat and where there is high unmet medical
a first step. But a promising one. And that’s always a great way to start.
There are limitations to studying cells under a microscope. To understand some of the more complex processes, it is critical to see how these cells behave in an environment that is similar to conditions in the body. The production of organoids has revolutionized this approach.
Organoids are three-dimensional structures derived from stem cells that have similar characteristics of an actual organ. There have been several studies recently published that have used this approach to understand a wide scope of different areas.
In one such instance, researchers at The University of Cambridge were able to grow a “mini-brain” from human stem cells. To demonstrate that this organoid had functional capabilities similar to that of an actual brain, the researchers hooked it up to a mouse spinal cord and surrounding muscle. What they found was remarkable– the “mini-brain” sent electrial signals to the spinal cord that made the surrounding muscles twitch. This model could pave the way for studying neurodegenerative diseases such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS).
Speaking of SMA, researchers in Singapore have used organoids to come up with some findings that might be able to help people battling the condition.
SMA is a neurodegenerative disease caused by a protein
deficiency that results in nerve degeneration, paralysis and even premature
death. The fact that it mainly affects children makes it even worse. Not much
is known how SMA develops and even less how to treat or prevent it.
That’s where the research from the A*STAR’s Institute of
Molecular and Cell Biology (IMCB) comes in. Using the iPSC method
they turned tissue samples from healthy people and people with SMA into spinal
They then compared the way the cells
developed in the organoids and found that the motor nerve cells from healthy
people were fully formed by day 35. However, the cells from people with SMA
started to degenerate before they got to that point.
They also found that the protein
problem that causes SMA to develop did so by causing the motor nerve cells to
divide, something they don’t normally do. So, by blocking the mechanism that
caused the cells to divide they were able to prevent the cells from dying.
“We are one of the first labs to report the formation of spinal organoids. Our study presents a new method for culturing human spinal-cord-like tissues that could be crucial for future research.”
Just yesterday the CIRM Board awarded almost $4 million to Ankasa Regenerative Therapeutics to try and develop a treatment for another debilitating back problem called degenerative spondylolisthesis.
And finally, organoid modeling was used to better understand and study an infectious disease. Scientists from the Max Planck Institute for Infection Biology in Berlin created fallopian tube organoids from normal human cells. Fallopian tubes are the pair of tubes found inside women along which the eggs travel from the ovaries to the uterus. The scientists observed the effects of chronic infections of Chlamydia, a sexually transmittable infection. It was discovered that chronic infections lead to permanent changes at the DNA level as the cells age. These changes to DNA are permanent even after the infection is cleared, and could be indicative of the increased risk of cervical cancer observed in women with Chlamydia or those that have contracted it in the past.
Every three minutes, one person in the United States is diagnosed with a blood cancer, which amounts to over 175,000 people every year. Every nine minutes, one person in the United States dies from a blood cancer, which is over 58,000 people every year. These eye opening statistics from the Leukemia & Lymphoma Society demonstrate why almost one in ten cancer deaths in 2018 were blood cancer related.
For those unfamiliar with the term, a blood cancer is any type of cancer that begins in blood forming tissue, such as those found in the bone marrow. One example of a blood cancer is leukemia, which results in the production of abnormal blood cells. Chemotherapy and radiation are used to wipe out these cells, but the blood cancer can sometimes return, something known as a relapse.
What enables the return of a blood cancer such as leukemia ? The answer lies in the properties of cancer stem cells, which have the ability to multiply and proliferate and can resist the effects of certain types of chemotherapy and radiation. Researchers at Tel Aviv University are looking to decrease the rate of relapse in blood cancer by targeting a specific type of cancer stem cell known as a leukemic stem cell, which are often found to be the most malignant.
Dr. Michael Milyavsky and his team at Tel Aviv University have developed a biosensor that is able to isolate, label, and target specific genes found in luekemic stem cells. Their findings were published on January 31, 2019 in Leukemia.
“The major reason for the dismal survival rate in blood cancers is the inherent resistance of leukemic stem cells to therapy, but only a minor fraction of leukemic cells have high regenerative potential, and it is this regeneration that results in disease relapse. A lack of tools to specifically isolate leukemic stem cells has precluded the comprehensive study and specific targeting of these stem cells until now.”
In addition to isolating and labeling leukemic stem cells, Dr. Milyavsky and his team were able to demonstrate that the leukemic stem cells labeled by their biosensor were sensitive to an inexpensive cancer drug, highlighting the potential this technology has in creating more patient-specific treatment options.
In the article, Dr. Milyavsky said:
” Using this sensor, we can perform personalized medicine oriented to drug screens by barcoding a patient’s own leukemia cells to find the best combination of drugs that will be able to target both leukemia in bulk as well as leukemia stem cells inside it.”
The researchers are now investigating genes that are active in leukemic stem cells in the hope finding other druggable targets.
CIRM has funded two clinical trials that also use a more targeted approach for cancer treatment. One of these trials uses an antibody to treat chronic lymphocytic leukemia (CLL) and the other trial uses a different antibody to treat acute myeloid leukemia (AML).
A variety of diseases can be traced to a simple root cause: problems in the bone marrow. The bone marrow contains specialized stem cells known as hematopoietic stem cells (HSCs) that give rise to different types of blood cells. As mentioned in a previous blog about Sickle Cell Disease (SCD), one problem that can occur is the production of “sickle like” red blood cells. In blood cancers like leukemia, there is an uncontrollable production of abnormal white blood cells. Another condition, known as myelodysplastic syndromes (MDS), are a group of cancers in which immature blood cells in the bone marrow do not mature and therefore do not become healthy blood cells.
For diseases that originate in the bone marrow, one treatment involves introducing healthy HSCs from a donor or gene therapy. However, before this type of treatment can take place, all of the problematic HSCs must be eliminated from the patient’s body. This process, known as pre-treatment, involves a combination of chemotherapy and radiation, which can be extremely toxic and life threatening. There are some patients whose condition has progressed to the point where their bodies are not strong enough to withstand pre-treatment. Additionally, there are long-term side effects that chemotherapy and radiation can have on infant children that are discussed in a previous blog about pediatric brain cancer.
Could there be a targeted, non-toxic approach to eliminating unwanted HSCs that can be used in combination with stem cell therapies? Researchers at Stanford say yes and have very promising results to back up their claim.
Dr. Judith Shizuru and her team at Stanford University have developed an antibody that can eliminate problematic blood forming stem cells safely and efficiently. The antibody is able to identify a protein on HSCs and bind to it. Once it is bound, the protein is unable to function, effectively removing the problematic blood forming stem cells.
Dr. Shizuru is the senior author of a study published online on February 11th, 2019 in Blood that was conducted in mice and focused on MDS. The results were very promising, demonstrating that the antibody successfully depleted human MDS cells and aided transplantation of normal human HSCs in the MDS mouse model.
This proof of concept holds promise for MDS as well as other disease conditions. In a public release from Stanford Medicine, Dr. Shizuru is quoted as saying, “A treatment that specifically targets only blood-forming stem cells would allow us to potentially cure people with diseases as varied as sickle cell disease, thalassemia, autoimmune disorders and other blood disorders…We are very hopeful that this body of research is going to have a positive impact on patients by allowing better depletion of diseased cells and engraftment of healthy cells.”
The research mentioned was partially funded by us at CIRM. Additionally, we recently awarded a $3.7 million dollar grant to use the same antibody in a human clinical trial for the so-called “bubble baby disease”, which is also known as severe combined immunodeficiency (SCID). You can read more about that award on a previous blog post linked here.
iPSCs are not just pretty, they’re also pretty remarkable
Two Midwest universities are making headlines for their contributions to stem cell research. Both are developing important tools to advance this field of study, but in two unique ways.
Scientists at the University of Michigan (UM), have compiled an impressive repository of disease-specific stem cell lines. Cell lines are crucial tools for scientists to study the mechanics of different diseases and allows them to do so without animal models. While animal models have important benefits, such as the ability to study a disease within the context of a living mammal, insights gained from such models can be difficult to translate to humans and many diseases do not even have good models to use.
The stem cell lines generated at the Reproductive Sciences Program at UM, are thanks to numerous individuals who donated extra embryos they did not use for in vitro fertilization (IVF). Researchers at UM then screened these embryos for abnormalities associated with different types of disease and generated some 36 different stem cell lines. These have been donated to the National Institute of Health’s (NIH) Human Embryonic Stem Cell Registry, and include cell lines for diseases such as cystic fibrosis, Huntington’s Disease and hemophilia.
Using one such cell line, Dr. Peter Todd at UM, found that the genetic abnormality associated with Fragile X Syndrome, a genetic mutation that results in developmental delays and learning disabilities, can be corrected by using a novel biological tool. Because Fragile X Syndrome does not have a good animal model, this stem cell line was critical for improving our understanding of this disease.
In the next state over, at the University of Wisconsin-Madison (UWM), researchers are doing similar work but using induced pluripotent stem cells (iPSCs) for their work.
The Human Stem Cell Gene Editing Service has proved to be an important resource in expediting research projects across campus. They use CRISPR-Cas9 technology (an efficient method to mutate or edit the DNA of any organism), to generate human stem cell lines that contain disease specific mutations. Researchers use these cell lines to determine how the mutation affects cells and/or how to correct the cellular abnormality the mutation causes. Unlike the work at UM, these stem cell lines are derived from iPSCs which can be generated from easy to obtain human samples, such as skin cells.
The gene editing services at UWM have already proved to be so popular in their short existence that they are considering expanding to be able to accommodate off-campus requests. This highlights the extent to which both CRISPR technology and stem cell research are being used to answer important scientific questions to advance our understanding of disease.
The iPSC Repository was created by CIRM to house a collection of stem cells from thousands of individuals, some healthy, but some with diseases such as heart, lung or liver disease, or disorders such as autism. The goal is for scientists to use these cells to better understand diseases and develop and test new therapies to combat them. This provides an unprecedented opportunity to study the cell types from patients that are affected in disease, but for which cells cannot otherwise be easily obtained in large quantities.