There’s a lot of
fiction, a lot of misinformation surrounding stem cells and stem cell research.
There are claims that are not based on solid science and clinics that are
offering so-called “treatments” that are unproven, even dangerous for patients.
Now you have a chance to talk to the experts in the field and get solid answers
from them about what’s working, what’s not, and how you can find a therapy that
might be appropriate for you.
Do you have
questions about the latest in research using stem cells to help people
recovering from a stroke? We’ll have someone who can answer them.
Want to know if stem
cells can help people battling cancer? Or what’s happening in finding a stem
cell treatment for diabetes or sickle cell disease, even autism, Alzheimer’s or
Parkinson’s disease? We’ll have experts to answers those.
This is all
happening in a special Facebook Live “Ask the Stem Cell Team” event on Thursday,
December 12th from 10.30am to 11.30amPDT. To take part
all you have to do is tune in on the day and post a question or you can send us
one ahead of time at info@cirm.ca.gov
We will do our best
to answer as many of them as we can during the Facebook Live event, and those
we don’t have time to get to we’ll answer in a blog at a later date.
Way back in the 1990’s scientists were hard at work decoding the human genome, trying to map and understand all the genes that make up people. At the time there was a sense of hope, a feeling that once we had decoded the genome, we’d have cures for all sorts of things by next Thursday. It didn’t quite turn out that way.
The same was true
for stem cell research. In the early days there was a strong feeling that this
was going to quite quickly produce new treatments and cures for diseases
ranging from Parkinson’s and Alzheimer’s to heart disease and stroke. Although
we have made tremendous strides we are still not where we hoped we’d be.
It’s a tough lesson
to learn, but an important one: good scientific research moves at its own pace
and pays little heed to our hopes or desires. It takes time, often a long time,
and money, usually a lot of money, to develop new treatments for deadly
diseases and disorders.
Many people, particularly those battling deadly diseases who are running out of time, are frustrated at the slow pace of stem cell research, at the years and years of work that it takes to get even the most promising therapy into a clinical trial where it can be tested in people. That’s understandable. If your life is on the line, it’s difficult to be told that you have to be patient. Time is a luxury many patients don’t have.
But that caution is
necessary. The last thing we want to do is rush to test something in people
that isn’t ready. And stem cells are a whole new way of treating disease, using
cells that may stay in the body for years, so we really need to be sure we have
done everything we can to ensure they are safe before delivering them to
people.
The field of gene
therapy was set back years after one young patient, Jesse Gelsinger,
died as a result of an early experimental treatment. We don’t want the same to
happen to stem cell research.
And yet progress is
being made, albeit not as quickly as any of us would like. At the end of the
first ten years of CIRM’s existence we had ten projects that we supported that
were either in, or applying to be in, a clinical trial sanctioned by the US
Food and Drug Administration (FDA). Five years later that number is 56.
Most of those are in
Phase 1 or 2 clinical trials which means they are still trying to show they are
both safe and effective enough to be made available to a wider group of people.
However, some of our projects are in Phase 3, the last step before, hopefully,
being given FDA approval to be made more widely available and – just as
important – to be covered by insurance.
Other CIRM-funded projects
have been given Regenerative Medicine Advanced Therapy (RMAT)
designation by the FDA, a
new program that allows projects that show they are safe and benefit patients
in early stage clinical trials, to apply for priority review, meaning they
could get approved faster than normal. Out of 40 RMAT designations awarded so
far, six are for CIRM projects.
We are working hard
to live up to our mission statement of accelerating stem cell treatments to
patients with unmet medical needs. We have been fortunate in having $3 billion
to spend on advancing this research in California; an amount no other US state,
indeed few other countries, have been able to match. Yet even that amount is
tiny compared to the impact that many of these diseases have. For example, the
economic cost of treating diabetes in the US is a staggering $327 billion a
year.
The simple truth is
that unless we, as a nation, invest much more in scientific research, we are
not going to be able to develop cures and new, more effective, treatments for a
wide range of diseases.
Time and money are
always going to be challenging when it comes to advancing stem cell research
and bringing treatments to patients. With greater knowledge and understanding
of stem cells and how best to use them we can speed up the timeline. But
without money none of that can happen.
Our blog is just one of many covering the topic of “What are the hurdles impacting patient access to cell and gene therapies” as part of Signal’s fourth annual blog carnival.
Dr. Mathew Blurton-Jones, leader of team that developed the chimeric “Mighty Mouse” model at the University of California, Irvine
In ancient Greek mythology, a Chimera was a creature that was usually depicted as a lion with an additional goat head and a serpent for a tail. Due to the Chimera’s animal hybrid nature, the term “chimeric” came to fruition in the scientific community as a way to describe an organism containing two or more different sets of DNA.
A CIRM-funded study conducted by Dr. Mathew Blurton-Jones and his team at UC Irvine describes a way for human brain immune cells, known as microglia, to grow and function inside mice. Since the mice contain a both human cells and their own mice cells, they are described as being chimeric.
In order to develop this chimeric “mighty mouse” model, Dr. Blurton-Jones and his team generated induced pluripotent stem cells (iPSCs), which have the ability to turn into any kind of cell, from cell samples donated by adult patients. For this study, the researchers converted iPSCs into microglia, a type of immune cell found in the brain, and implanted them into genetically modified mice. After a few months, they found that the implanted cells successfully integrated inside the brains of the mice.
By finding a way to look at human microglia grow and function in real time in an animal model, scientists can further analyze crucial mechanisms contributing to neurological conditions such as Alzheimer’s, Parkinson’s, traumatic brain injury, and stroke.
For this particular study, Dr. Blurton-Jones and his team looked at human microglia in the mouse brain in relation to Alzheimer’s, which could hold clues to better understand and treat the disease. The team did this by introducing amyloid plaques, protein fragments in the brain that accumulate in people with Alzheimer’s, and evaluating how the human microglia responded. They found that the human microglia migrated toward the amyloid plaques and surrounding them, which is what is observed in Alzheimer’s patients.
In a press release, Dr. Blurton-Jones expressed the importance of studying microglia by stating that,
“Microglia are now seen as having a crucial role in the development and progression of Alzheimer’s. The functions of our cells are influenced by which genes are turned on or off. Recent research has identified over 40 different genes with links to Alzheimer’s and the majority of these are switched on in microglia. However, so far we’ve only been able to study human microglia at the end stage of Alzheimer’s in post-mortem tissues or in petri dishes.”
Furthermore, Dr. Blurton-Jones highlighted the importance of looking at human microglia in particular by saying that,
“The human microglia also showed significant genetic differences from the rodent version in their response to the plaques, demonstrating how important it is to study the human form of these cell.”
The full results of this study were published in Cell.
Speakers at the Alpha Stem Cell Clinics Network Symposium: Photo by Marco Sanchez
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
disease, cerebral
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
way forward.
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
Huntington’s disease.
We rather
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.
Alpha Stem Cell Clinics Network Symposium: Photo by Marco Sanchez
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.
Bringing these
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.
Cierra Jackson: Photo by Marco Sanchez
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.
CIRM’s Dr. Maria Millan (right) at a panel presentation at the Stanford Drug Discovery Symposium. Panel from left to right are: James Doroshow, NCI; Sandy Weill, former CEO Citigroup; Allan Jones, CEO Allen Institute
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
trial.
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.
In 1983 President Ronald Reagan named November as Alzheimer’s Awareness month, to raise awareness about the growing impact the disease was having on Americans. At the time there were less than two million people with the disease. Today that number has grown to more than five million and is expected to reach 16 million by the year 2050. There is no cure and no effective treatments.
To mark Alzheimer’s Awareness month we are reprinting an article that CIRM Board member and Patient Advocate for Alzheimer’s, Lauren Miller, wrote for Lenny magazine, charting her own personal journey with the disease.
Two thousand eleven was a year of nonstop high points in my life. My creative dreams came true when I filmed a little indie movie I co-wrote about friendship and phone sex called For a Good Time, Call … My romantic dreams came true when I married the love of my life at a beautiful wedding surrounded by our friends and family. And then my professional dreams exploded with magical confetti when we sold our tiny, candy-colored, female-driven comedy to Focus Features after it premiered at the Sundance Film Festival. So many moments I had dreamed about for years were actually happening.
It was the happiest time of my life!
Except that it also wasn’t. It was actually kind of the worst.
This was around five years into my mom’s diagnosis of Alzheimer’s. Up until that point, her disease had been in the early stages. Her symptoms manifested in the repeated stories she told, occasionally slurred or confused speech, and a serious attachment to my dad. But Alzheimer’s is like a train that can’t be stopped once it leaves the station. And although these early days were really scary, they were nothing compared to what happened as the disease barreled through my mom’s once vibrant and beautiful mind.
She lived in Florida, and I was all the way across the country in Los Angeles. When she was first diagnosed, she told me I wasn’t allowed to move back to Florida to be with her. She wanted me to live my life — one that she had worked so hard to support. She was selfless like that. It was more important to her that I pursue my dreams, my relationship, and my own life as an independent woman than to have me close while she was disappearing piece by piece.
I visited Florida as often as I could, and, in the first few years of her disease, she and my dad visited me in LA. In 2007, they came out for the premiere of Knocked Up — a huge celebration for my then-boyfriend, as it was his first starring role in a movie. We had a barbecue for friends and family at our house the day before the premiere, and while it was a delicious taco, rib, mac-’n’-cheese extravaganza, what I remember is having to show my mom where the silverware drawer was a dozen times. She also kept adding turkey to the vegetarian chili and I had to keep taking it out. I remember my sister-in-law asking if my mom was OK, and I remember telling her “she’s not.”
As the years went by, she got worse. When we were making For A Good Time, Call…, I wanted my parents to come to Los Angeles to visit the set of the movie I had worked so hard to put together. But my mom had started wandering off and having bathroom issues — this reality was enough to keep them home. It devastated my movie-buff dad (who had a closet full of 500-plus VHS tapes of all the greatest hits) that he couldn’t visit the set of his daughter’s first film, which his son was also executive producing. And it devastated me that I couldn’t show my mom that I was actually doing what she wanted — I was living my life. But there was no time to be sad about it; there was a pink phone ringing and I had to answer it with a smile because the cameras were rolling and I was literally living my dream! Or so I told myself.
The night before my wedding, at the rehearsal dinner, my mom told me, “I just want to go home. I don’t want to be here.” I knew it was because she didn’t know where she was. The pain of knowing that she didn’t know she was at my wedding was like that Alzheimer’s train plowing right through my heart.
I brought my new husband and his parents to Florida for Thanksgiving that year — we went to Disney World. I showed them where I was a cheerleader for my awesome high-school football team (go Dreadnaughts!) and made them eat a Publix sub sandwich, my favorite hometown food. We also witnessed my mom pacing the house endlessly, not making much sense with her words, and mistaking the floor for a toilet. It was not quite the way I envisioned introducing my in-laws to the home I grew up in.
Although things were finally happening in my career in a way I had dreamed about for years — I was going on auditions, having meetings with producers about writing exciting scripts, and traveling around as my little-movie-that-could was released in actual theaters — my outlook on life was growing darker and darker with each passing day. Every person I saw run a stop sign was responsible for ruining the world. If I heard someone say something I didn’t agree with, it meant everyone was stupid and there was no hope for humanity. And most of all, I was convinced that the whole concept of life was just utter shit if this is what happened to the greatest woman I’ve ever known, a woman who had lived her life giving so much to so many.
Once my stress resulted in silver-dollar-size bacne, three (minor) car accidents in four months, and general life-rage that was bordering on getting out of control, it seemed like the right time to talk to a professional.
My new therapist listened, she gave me tissues, she told me it was OK to feel all the pain I was feeling. She let me go on and on to her about how life was just so unfair. And she didn’t even make me feel ungrateful for discounting all the legitimately amazing stuff in my life, because the agony I was in needed attention.
But eventually, she started to suggest that perhaps not everything was totally awful. Maybe there were a few good things in my life. Like, maybe my wonderful husband? Or my generous and awesome friends? Or even my career that felt like it was finally happening?
“Nope!” I insisted. “None of those things matter because everyone is dumb and there’s no point to any of this, and it’s all just a cycle of sadness and devastation, yadda, yadda, negative, negative, fuck, ahhhh! …”
As it always does, time passed. My parents moved to Los Angeles, and I got a front-row seat to my mom’s decline. She was now fully incontinent, had stopped walking, and had essentially stopped communicating. Having her close felt good, but seeing her become a shell of who she used to be was draining. When I wasn’t at her house, life continued as it normally did for me — spending my days alone, writing about and ruminating on my anger, spending my evenings and weekends laughing with friends over good food, and occasionally attending premieres for my (very fortunate and hard-working) husband’s movies. My therapist kept insisting that “in life, there can be good and there can be bad, and, in fact, they can coexist.” Even though I was living it, I refused to believe her.
Until eventually, I did.
In the fall of 2012, I started writing a screenplay about a woman who is left at the altar and ends up going on what would have been her honeymoon cruise with her estranged father. Obviously, this story has nothing to do with my real life (you just read about my wedding and my awesome dad), but I was drawn to the idea of a female character whose life doesn’t go the way she wants it to but who finds a way through the pain. It took me almost two years to finish a full draft, in part because I was still finding my own way through the pain. But when I did finish, I realized had written a story about a woman whose life has been seriously rocked, and, through her journey to get to the other side of her sadness, she experiences laughter, friendship, and adventure, as well as heartache, anger, and struggle for acceptance. Just like me.
I recently started thinking of my life as a dramedy. It’s full of jokes about penises, people comically falling, and moments of pure love and joy. It’s also full of pain, loss, and real anger. Ups and downs, highs and lows. But somewhere along the way, through my work in therapy, through talking about what I had been going through with my mom, through creating Hilarity for Charity, through writing, through living through my pain, I began to let in some of the good with the bad. To understand that it’s OK to feel both sad when I leave my mom’s house and excited about the dinner with friends I’m going to that night. That perhaps the point of life is to appreciate both the happy moments and the sad moments together. That they give each other meaning. That we have to have both, that we all have both, that experiencing both is actually OK. And if we need to spend a little time in the sad lane, the happy lane really can still run alongside it, if we allow it to.
Lauren Miller Rogen is a filmmaker and Alzheimer’s advocate living in Los Angeles. Her directorial debut,Like Father, which she also wrote and produced, launched globally on Netflix on Friday, August 3.
New developments in Alzheimer’s research are bringing us closer to more precise therapies for this debilitating disease.
Alzheimer’s disease, is characterized by the formation of amyloid plaques in the brain, which interfere with the normal communication flow between brain cells, leading to debilitating symptoms like memory loss and impaired decision-making. These plaques are made out of beta-amyloid proteins that stick together.
Over the past few years, researchers from several institutions have been working to develop antibodies that bind to and neutralize the toxic effects of the beta-amyloid. The search for effective antibodies, although promising, has been riddled with setbacks. Knowing this, a team of researchers from Brigham and Women’s Hospital in Boston, MA, decided to approach this issue from a different angle – by conducting experiments to identify a better way of targeting beta-amyloid. Their goal was to develop a more efficient antibody to be used in Alzheimer’s therapy.
Principal investigator Dominic Walsh and team came up with a novel technique to collect beta-amyloid and to prepare it in the laboratory.
Dominic Walsh, PH.D.
“Many different efforts are currently underway to find treatments for Alzheimer’s disease, and anti-[beta-amyloid] antibodies are currently the furthest advanced,” says Walsh. “But the question remains: what are the most important forms of [beta-amyloid] to target? Our study points to some interesting answers,” the lead researcher adds, and these answers are now reported in an open access paper published in the journal Nature Communications.”
Beta-amyloid can be found in many forms. At one end of the spectrum, it exists as a single protein, or monomer, which isn’t necessarily toxic.
At the other end, there is the beta-amyloid plaque, in which many beta-amyloid proteins become tangled together. Beta-amyloid plaques are large enough to be observed using a traditional microscope, and they are involved in the development of Alzheimer’s.
In the current study, as well as in a previous one, Walsh and team looked at beta-amyloid structures to identify the ones that are most harmful in the brain.
Typically specialists use synthetic beta-amyloid samples to create a laboratory model of Alzheimer’s disease in the brain. Very few scientists actually collect beta-amyloid from the brains of individuals diagnosed with the disease.
In the current study, Walsh and team focused on finding better a more specific antibody to target the toxic forms of beta-amyloid but not the less harmful forms. To do so, they developed a novel screening test that requires extracting beta-amyloid from brain samples from people with Alzheimer’s. They added these extracts to induced pluripotent stem cell-derived human neurons and observed the ability of the different antibodies to block the toxic effects of the beta-amyloid.
This screening test allowed the team to discover a particular antibody — called “1C22” — that is able to block toxic forms of beta-amyloid more effectively than other antibodies currently being tested in clinical trials.
Walsh explained the implications of their novel screening method:
“We anticipate that this primary screening technique will be useful in the search to identify more potent anti-[beta-amyloid] therapeutics in the future.”
The Salk team. From left: Krishna Vadodaria, Lynne Moore, Carol Marchetto, Arianna Mei, Fred H. Gage, Callie Fredlender, Ruth Keithley, Ana Diniz Mendes. Photo courtesy Salk Institute
Astrocytes are some of the most common cells in the brain and central nervous system but they often get overlooked because they play a supporting role to the more glamorous neurons (even though they outnumber them around 50 to 1). But a new way of growing those astrocytes outside the brain could help pave the way for improved treatments for stroke, Alzheimer’s and other neurological problems.
Astrocytes – which get their name because of their star shape (Astron – Greek for “star” and “kyttaron” meaning cell) – have a number of key functions in the brain. They provide physical and metabolic support for neurons; they help supply energy and fuel to neurons; and they help with detoxification and injury repair, particularly in terms of reducing inflammation.
Studying these astrocytes in the lab has not been easy, however, because existing methods of producing them have been slow, cumbersome and not altogether effective at replicating their many functions.
Finding a better way
Now a team at the Salk Institute, led by CIRM-funded Professor Fred “Rusty” Gage, has developed a way of using stem cells to create astrocytes that is faster and more effective.
“This work represents a big leap forward in our ability to model neurological disorders in a dish. Because inflammation is the common denominator in many brain disorders, better understanding astrocytes and their interactions with other cell types in the brain could provide important clues into what goes wrong in disease.”
Stylized microscopy image of an astrocyte (red) and neuron (green). (Salk Institute)
In a step by step process the Salk team used a series of chemicals, called growth factors, to help coax stem cells into becoming, first, generic brain cells, and ultimately astrocytes. These astrocytes not only behaved like the ones in our brain do, but they also have a particularly sensitive response to inflammation. This gives the team a powerful tool in helping develop new treatment to disorders of the brain.
But wait, there’s more!
As if that wasn’t enough, the researchers then used the same technique to create astrocytes from induced pluripotent stem cells (iPSCs) – adult cells, such as skin, that have been re-engineered to have the ability to turn into any other kind of cell in the body. Those man-made astrocytes also showed the same characteristics as natural ones do.
Krishna Vadodaria, one of the lead authors on the paper, says having these iPSC-created astrocytes gives them a completely new tool to help explore brain development and disease, and hopefully develop new treatments for those diseases.
“The exciting thing about using iPSCs is that if we get tissue samples from people with diseases like multiple sclerosis, Alzheimer’s or depression, we will be able to study how their astrocytes behave, and how they interact with neurons.”
Gladstone Institutes Steven Finkbeiner and Gaia Skibinski: Photo courtesy Chris Goodfellow, Gladstone Institutes
Diseases of the brain have many different names, from Alzheimer’s and Parkinson’s to ALS and Huntington’s, but they often have similar causes. Researchers at the Gladstone Institutes in San Francisco are using that knowledge to try and find an approach that might be effective against all of these diseases. In a new CIRM-funded study, they have identified one protein that could help do just that.
Many neurodegenerative diseases are caused by faulty proteins, which start to pile up and cause damage to neurons, the brain cells that are responsible for processing and transmitting information. Ultimately, the misbehaving proteins cause those cells to die.
The researchers at the Gladstone found a way to counter this destructive process by using a protein called Nrf2. They used neurons from humans (made from induced pluripotent stem cells – iPSCs – hence the stem cell connection here) and rats. They then tested these cells in neurons that were engineered to have two different kinds of mutations found in Parkinson’s disease (PD) plus the Nrf2 protein.
Using a unique microscope they designed especially for this study, they were able to track those transplanted neurons and monitor what happened to them over the course of a week.
The neurons that expressed Nrf2 were able to render one of those PD-causing proteins harmless, and remove the other two mutant proteins from the brain cells.
In a news release to accompany the study in The Proceedings of the National Academy of Sciences, first author Gaia Skibinski, said Nrf2 acts like a house-cleaner brought in to tidy up a mess:
“Nrf2 coordinates a whole program of gene expression, but we didn’t know how important it was for regulating protein levels until now. Over-expressing Nrf2 in cellular models of Parkinson’s disease resulted in a huge effect. In fact, it protects cells against the disease better than anything else we’ve found.”
Steven Finkbeiner, the senior author on the study and a Gladstone professor, said this model doesn’t just hold out hope for treating Parkinson’s disease but for treating a number of other neurodegenerative problems:
“I am very enthusiastic about this strategy for treating neurodegenerative diseases. We’ve tested Nrf2 in models of Huntington’s disease, Parkinson’s disease, and ALS, and it is the most protective thing we’ve ever found. Based on the magnitude and the breadth of the effect, we really want to understand Nrf2 and its role in protein regulation better.”
The next step is to use this deeper understanding to identify other proteins that interact with Nrf2, and potentially find ways to harness that knowledge for new therapies for neurodegenerative disorders.
CIRM funds research trying to solve the Alzheimer’s puzzle
In science, there are a lot of terms that could easily mystify people without a research background; “translational” is not one of them. Translational research simply means to take findings from basic research and advance them into something that is ready to be tested in people in a clinical trial.
Yesterday our Governing Board approved $15 million in funding for four projects as part of our Translational Awards program, giving them the funding and support that we hope will ultimately result in them being tested in people.
Those projects use a variety of different approaches in tackling some very different diseases. For example, researchers at the Gladstone Institutes in San Francisco received $5.9 million to develop a new way to help the more than five million Americans battling Alzheimer’s disease. They want to generate brain cells to replace those damaged by Alzheimer’s, using induced pluripotent stem cells (iPSCs) – an adult cell that has been changed or reprogrammed so that it can then be changed into virtually any other cell in the body.
CIRM’s mission is to accelerate stem cell treatments to patients with unmet medical needs and Alzheimer’s – which has no cure and no effective long-term treatments – clearly represents an unmet medical need.
Another project approved by the Board is run by a team at Children’s Hospital Oakland Research Institute (CHORI). They got almost $4.5 million for their research helping people with sickle cell anemia, an inherited blood disorder that causes intense pain, and can result in strokes and organ damage. Sickle cell affects around 100,000 people in the US, mostly African Americans.
The CHORI team wants to use a new gene-editing tool called CRISPR-Cas9 to develop a method of editing the defective gene that causes Sickle Cell, creating a healthy, sickle-free blood supply for patients.
Right now, the only effective long-term treatment for sickle cell disease is a bone marrow transplant, but that requires a patient to have a matched donor – something that is hard to find. Even with a perfect donor the procedure can be risky, carrying with it potentially life-threatening complications. Using the patient’s own blood stem cells to create a therapy would remove those complications and even make it possible to talk about curing the disease.
While damaged cartilage isn’t life-threatening it does have huge quality of life implications for millions of people. Untreated cartilage damage can, over time lead to the degeneration of the joint, arthritis and chronic pain. Researchers at the University of Southern California (USC) were awarded $2.5 million to develop an off-the-shelf stem cell product that could be used to repair the damage.
The fourth and final award ($2.09 million) went to Ankasa Regenerative Therapeutics, which hopes to create a stem cell therapy for osteonecrosis. This is a painful, progressive disease caused by insufficient blood flow to the bones. Eventually the bones start to rot and die.
As Jonathan Thomas, Chair of the CIRM Board, said in a news release, we are hoping this is just the next step for these programs on their way to helping patients:
“These Translational Awards highlight our goal of creating a pipeline of projects, moving through different stages of research with an ultimate goal of a successful treatment. We are hopeful these projects will be able to use our newly created Stem Cell Center to speed up their progress and pave the way for approval by the FDA for a clinical trial in the next few years.”
Diets these days are a dime a dozen, and dietary trends come and go. First eggs were “out” because they contain cholesterol, but now they are back “in” because we now know that some types of cholesterol can be actually good for the body. Then there was the era of “fat-free” or “reduced-fat” foods. This was all the rage in the 90s until scientists realized that eliminating healthy fats from your diet can have negative consequences on your health.
The theories behind different diets evolve constantly much like the theories behind complicated neurodegenerative diseases like Alzheimer’s disease (AD). Alzheimer’s is a debilitating disease that slowly robs patients of their minds, leaving them as shadows of their former selves. AD affects 47.5 million people globally with 7.7 million new patients diagnosed every year, thus making the disease one of the most important unmet medical needs to be addressed.
The causes of AD have eluded scientists for over a century. However, the main theory behind what causes AD involves the buildup of toxic proteins in the brain. These proteins accumulate to form structures called plaques and tangles that impair brain function and kill off brain cells.
Unfortunately, there is no cure for AD or treatments to stop its progression. This sobering fact is not due to a lack of effort by scientists and pharmaceutical companies. Dozens of drug therapies have or are being tested in clinical trials, many of them focusing on the removal of toxic protein levels in people with the disease. While there have been some pretty dramatic failures in these trials, a few are starting to show encouraging results.
Link Between Abnormal Fat Metabolism and Alzheimer’s Disease
Now, a new theory on AD involving the build up of toxic fat molecules in the brains of AD patients has been thrown into the mix. In a study published Thursday in Cell Stem Cell, scientists from Montreal reported the presence of fat droplets in AD patient brains in areas surrounding brain stem cells. Brain stem cells are responsible for growing new brain cells (such as nerves) and maintaining overall brain function and health. The scientists discovered that the fat droplets actually prevented the regenerative abilities of the brain stem cells, leading them to believe that the accumulation of fat droplets in the brain could be a cause of AD.
Fat is used as an energy source by cells and organs in the body in a process called “fatty acid metabolism”. Fat metabolism is very important for proper brain development but also in maintaining brain health and function in adults. Problems with fat metabolism in humans can cause diseases such as obesity, diabetes, and heart disease. So one can imagine that problems with fat metabolism in the brain could also have serious consequences.
In this study, scientists used a genetic mouse model of AD that had a “triple-threat” of genetic mutations that cause AD in humans. They studied the brain stem cells in these mice and found that the support cells surrounding the stem cells were full of fat droplets. They also noticed that when the fat droplets were present, the brain stem cells were not dividing to generate new brain cells (which is a common defect associated with AD). When they looked at brain tissue from nine AD patients, they also observed a similar pattern of an increased concentration of fat droplets surrounding areas of brain stem cells compared to healthy human brain tissue.
AD patient brains (lower panel) have more fat droplets shown in red than normal healthy brains (upper panel). (Hamilton et al., 2015)
Using a fancy science technique called mass spectrometry, the scientists found that the fat droplets were made up of a fat triglyceride called oleic acid, which is a common component of vegetable and animal fats. To prove that oleic acid was bad for brain stem cells, they took normal healthy mice and injected oleic acid into their brains. They observed that adding this fat negatively affected the stem cells’ regenerative ability to divide. Going one step further, the scientists used drugs to block the formation of oleic acid in their AD mouse model, and saw that removing this fat allowed the brain stem cells to divide and function properly.
The major conclusions generated from this study were summarized nicely by senior author Karl Fernandes in a news release:
We discovered that these fatty acids are produced by the brain, that they build up slowly with normal aging, but that the process is accelerated significantly in the presence of genes that predispose to Alzheimer’s disease. In mice predisposed to the disease, we showed that these fatty acids accumulate very early on, at two months of age, which corresponds to the early twenties in humans. Therefore, we think that the build-up of fatty acids is not a consequence but rather a cause or accelerator of the disease.
Don’t Count Your Chickens Just Yet
While this study suggests that fat accumulation in the brain is a cause of AD, more research will need to be done to confirm that abnormal fat metabolism is the culprit. Some experiments can be done quickly such as treating their AD mouse model with the drugs that block the formation of the “bad fat” and monitoring them for an extended time period to see if blocking oleic acid accumulation prevents the onset of AD symptoms like memory loss. Other experiments, such as therapeutically targeting abnormal brain fat deposits in human, will be more long term projects with unknown results.
Dr. Alois Alzheimer
Nontheless, this study nicely ties back to an observation by Dr. Alois Alzheimer who first reported about AD in 1906 . When he dissected the brains of AD patients who had passed away, he found five major pathologies that distinguished their brains from healthy brains. One of these traits was an increased concentration of fat droplets. Thus findings from Fernandes and his group revive a century old notion that fat metabolism could be a cause of AD and open doors for the development of new therapeutic strategies to fight AD.
