Japanese scientists implant first Parkinson’s patient with replacement neurons derived from stem cells

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Neurons derived from stem cells.Credit: Silvia Riccardi/SPL

Currently, more than 10 million people worldwide live with Parkinson’s disease (PD). By 2020, in the US alone, people living with Parkinson’s are expected to outnumber the cases of multiple sclerosis, muscular dystrophy and Lou Gehrig’s disease combined.

There is no cure for Parkinson’s and treatment options consist of medications that patients ultimately develop tolerance to, or surgical therapies that are expensive. Therefore, therapeutic options that offer long-lasting treatment, or even a cure, are essential for treating PD.

Luckily for patients, Jun Takahashi’s team at Kyoto University has pioneered a stem cell based therapy for PD patients.

To understand their treatment strategy, however, we first have to understand what causes this disease. Parkinson’s results from decreased numbers of neurons that produce dopamine, a molecule that helps control muscle movements. Without proper dopamine production, patients experience a wide range of movement abnormalities, including the classic tremors that are associated with PD.

The current treatment options only target the symptoms, as opposed to the root cause of the disease. Takashi’s group decided to go directly to the source and improve dopamine production in these patients by correcting the dopaminergic neuron shortage.

The scientists harvested skin cells from a healthy donor and reprogrammed them to become induced pluripotent stem cells (iPSCs), or stem cells that become any type of cell. These iPSCs were then turned into the precursors of dopamine-producing neurons and implanted into 12 brain regions known to be hotspots for dopamine production.

The procedure was carried out in October and the patient, a male in his 50s, is still healthy. If his symptoms continue to improve and he doesn’t experience any bad side effects,  he will receive a second dose of dopamine-producing stem cells. Six other patients are scheduled to receive this same treatment and Takashi hopes that, if all goes well, this type of treatment can be ready for the general public by 2023.

This treatment was first tested in monkeys, where the researchers saw that not only did the implanted stem cells improve Parkinson’s symptoms and survive in the brain for at least two years, but they also did not cause any negative side effects.

This is only the third time iPSCs have been used as a treatment option in humans. The first was for macular degeneration in 2014.

CIRM is funding a similar, albeit earlier-stage program, with Jeanne Loring at Scripps.

 

Stem Cell Roundup: Clinical Trial on the Horizon for Parkinson’s Disease, New Probe Targets Tricky Cancer Cells – Rare Brain Disease May Be Key to Alzheimer’s Insights

Stem Cell Image of the Week: This week’s image shows dopamine producing brain cells. These are the cells that are depleted in people with Parkinson’s Disease.

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Photo courtesy of B. Bick, . Poindexter, UT Med. School/SPL

Parkinson’s disease news: a new clinical trial, a new face of the disease  (Kevin McCormack)

In his long and illustrious career Alan Alda has worn many hats. First as the star of the hit TV show “M*A*S*H” (the season finale of that is still the most watched TV show ever), then as a writer, director and movie star and, more recently, as the face of popular science and science communications. This week Alda revealed that he has Parkinson’s disease (PD).

In a post on Twitter he said:

“I have decided to let people know I have Parkinson’s to encourage others to take action. I was Diagnosed 3 and a half years ago, but my life is full. I act, I give talks, I do my podcast, which I love. If you get a diagnosis, keep moving!”

CIRM Board member David Higgins echoed those sentiments in an interview on KUSI TV News, San Diego. Dr. Higgins is the patient advocate member for Parkinson’s on the Board, and was diagnosed with PD in 2011, he says being active physically and intellectually are important in helping cope with PD and leading a normal life.

There was also some encouraging news about PD on the research front. Scientists in Japan are about to start a clinical trial using iPSCs to treat people with PD. The cells are created by taking blood stem cells from healthy donors and turning them into dopaminergic progenitors, precursors to the kind of cell destroyed by PD. The cells will then be transplanted into the brains of seven patients with PD.

The researchers, from Kyoto University, say previous studies show the cells could survive in monkeys for up to two years and help improve symptoms of Parkinson’s disease in the primates.

New Molecular Probe Targets Elusive Cancer Stem Cells in Mice (Adonica Shaw)

180802 cancer cells

A group of researchers at the University of Illinois made an advance in how we treat cancer patients this week. In a paper, published in the journal ACS Central Science, the researchers described a new and more effective way of identifying cancer stem cells in cultures of multiple human cancer cell lines as well as in live mice.

After a primary tumor is treated, cancer stem cells may still lurk in the body, ready to metastasize and cause a recurrence of the cancer in a form that’s more aggressive and resistant to treatment. The researchers developed a molecular probe that seeks out these elusive cells and lights them up so they can be identified, tracked and studied not only in cell cultures, but in their native environment: the body.

While other commercial agents are available to flag cancer stem cells, their application is limited, Chan said. Some cannot distinguish between live and dead cells, others can mistakenly bind to wrong targets. The most popular – antibodies that seek out markers on the cell’s surface – are specific to cell types and their large size can prevent them from reaching the small spaces where cancer stem cells tend to lurk. All are designed for use in cell cultures or artificial tumor environments, which lack the complexity of the whole body, Chan said.

In contrast, their new probe, called AlDeSense, is a small molecule that binds to an enzyme related to the property of stemness in cancer cells. The probe becomes activated, emitting a fluorescent signal only when it reacts with the target enzyme – which cancer stem cells produce in high concentrations.

In a series of experiments, the group found that the enzyme seems to be a marker of stemness across many types of cancer, indicating that AlDeSense may be broadly applicable for clinical imaging.

The researchers demonstrated that AlDeSense is compatible with two major cellular techniques – flow cytometry and confocal imaging.

The ability to find and track cancer stem cells in the body, as well as their state of stemness – the signal decreases as the cells differentiate – allowed the researchers to follow cells from injection to tumor as they spread through the bodies of the mice, answering some fundamental questions of how cancer stem cells behave.

According to the researchers nobody knew what happens between injection of cancer stem cells and removal of a tumor prior to this study. There are a lot of models that hypothesize about how cancer stem cells differentiate and grow, but limited experimental data exists.

Through their study, they saw the stemness properties are maintained in the population, even after they metastasize. There’s something about the environment in the body that supports stem cell characteristics. With AlDeSense, now they can profile that environment.

Since they know that the probe only interacts with that one target, they can use the probe to look for a drug that can inhibit this enzyme and verify it in cells and in live animals. The group is currently pursuing a screening for inhibitors or drugs that can kill cancer stem cells by targeting this enzyme.

Tackling a Rare Brain Disease May Also Lead to Alzheimer’s Insights (Todd Dubnicoff)

Alzheimer’s disease and ALS are very complex neurodegenerative disorders, making it very difficult for researchers to tease out the underlying causes let alone find treatments. To make inroads into a better understanding of these incurable diseases, scientists at City of Hope decided to first tackle a related, yet relatively more simple, nervous system disorder called Alexander disease. And this week, the strategy paid off with newly published research in Cell Stem Cell, funded in part by CIRM, describing the development of a patient-derived stem cell model system that could help evaluate novel treatments for all of these neurodegenerative diseases.

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An Alexander disease patient's stem cell-derived astrocytes (green) inhibits the growth of precursor cells that, in healthy patients, becomes myelin and speed up the brain's communication network. Credit: Yanhong Shi/City of Hope

The team generated astrocytes, a type of nervous system cell, using induced pluripotent stem cells derived from Alexander disease patients. It was previously known that the mutation in Alexander disease causes the patient’s astrocytes to block another cell type’s ability to produce myelin, the protective covering over neurons that’s critical for communication between nerve cells. But it wasn’t clear how this inhibition happened. In this study, the team found a possible culprit, a protein called CHI3L1 that’s secreted by the patient-derived astrocytes (but not by those from healthy individuals) and interferes with myelin production. So, finding drugs that target CHI3L1 could lead to therapies for Alexander disease.

Dysfunctional astrocytes have also been implicated in ALS and Alzheimer’s disease. So, using this newly developed model system for studying astrocytes could lead to new therapeutic strategies. In a press release, team leader Dr. Yanhong Shi, PhD, provides a specific example how this could work:

“The bulk of ApoE4 resides in astrocytes; ApoE4 is a gene variant known for increasing the risk of Alzheimer’s disease. So, if we understand how astrocytes function, then we can develop therapies to treat Alexander disease and perhaps other diseases that involve astrocytes, such as Alzheimer’s and ALS.”

Friday Stem Cell Roundup: Making Nerves from Blood; New Clues to Treating Parkinson’s

Stanford lab develops method to make nerve cells from blood.

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Induced neuronal (iN) cells derived from adult human blood cells. Credit: Marius Wernig, Stanford University.

Back in 2010, Stanford Professor Marius Wernig and his team devised a method to directly convert skin cells into neurons, a nerve cell. This so-called transdifferentiation technique leapfrogs over the need to first reprogram the skin cells into induced pluripotent stem cells. This breakthrough provided a more efficient path to studying how genetics plays a role in various mental disorders, like autism or schizophrenia, using patient-derived cells. But these types of genetic analyses require data from many patients and obtaining patient skin samples hampered progress because it’s not only an invasive, somewhat painful procedure but it also takes time and money to prepare the tissue sample for the transdifferentiation method.

This week, the Wernig lab reported on a solution to this bottleneck in the journal, PNAS. The study, funded in part by CIRM, describes a variation on their transdifferentiation method which converts T cells from the immune system, instead of skin cells, into neurons. The huge advantage with T cells is that they can be isolated from readily available blood samples, both fresh or frozen. In a press release, Wernig explains this unexpected but very welcomed result:

“It’s kind of shocking how simple it is to convert T cells into functional neurons in just a few days. T cells are very specialized immune cells with a simple round shape, so the rapid transformation is somewhat mind-boggling. We now have a way to directly study the neuronal function of, in principle, hundreds of people with schizophrenia and autism. For decades we’ve had very few clues about the origins of these disorders or how to treat them. Now we can start to answer so many questions.”

Two studies targeting Parkinson’s offer new clues to treating the disease (Kevin McCormack)
Despite decades of study, Parkinson’s disease remains something of a mystery. We know many of the symptoms – trembling hands and legs, stiff muscles – are triggered by the loss of dopamine producing cells in the brain, but we are not sure what causes those cells to die. Despite that lack of certainty researchers in Germany may have found a way to treat the disease.

Mitochondria

Simple diagram of a mitochondria.

They took skin cells from people with Parkinson’s and turned them into the kinds of nerve cell destroyed by the disease. They found the cells had defective mitochondria, which help produce energy for the cells. Then they added a form of vitamin B3, called nicotinamide, which helped create new, healthy mitochondria.

In an article in Science & Technology Research News Dr. Michela Deleidi, the lead researcher on the team, said this could offer new pathways to treat Parkinson’s:

“This substance stimulates the faulty energy metabolism in the affected nerve cells and protects them from dying off. Our results suggest that the loss of mitochondria does indeed play a significant role in the genesis of Parkinson’s disease. Administering nicotinamide riboside may be a new starting-point for treatment.”

The study is published in the journal Cell Reports.

While movement disorders are a well-recognized feature of Parkinson’s another problem people with the condition suffer is sleep disturbances. Many people with Parkinson’s have trouble falling asleep or remaining asleep resulting in insomnia and daytime sleepiness. Now researchers in Belgium may have uncovered the cause.

Working with fruit flies that had been genetically modified to have Parkinson’s symptoms, the researchers discovered problems with neuropeptidergic neurons, the type of brain cell that helps regulate sleep patterns. Those cells seemed to lack a lipid, a fat-like substance, called phosphatidylserine.

In a news release Jorge Valadas, one of the lead researchers, said replacing the missing lipid produced promising results:

“When we model Parkinson’s disease in fruit flies, we find that they have fragmented sleep patterns and difficulties in knowing when to go to sleep or when to wake up. But when we feed them phosphatidylserine–the lipid that is depleted in the neuropeptidergic neurons–we see an improvement in a matter of days.”

Next, the team wants to see if the same lipids are low in people with Parkinson’s and if they are, look into phosphatidylserine – which is already approved in supplement form – as a means to help ease sleep problems.

Celebrating Exciting CIRM-Funded Discovery Research on World Parkinson’s Day

April 11th is World Parkinson’s Disease Awareness Day. To mark the occasion, we’re featuring the work of CIRM-funded researchers who are pursuing new, promising ideas to treat patients with this debilitating neurodegenerative disease.


Birgitt Schuele, Parkinson’s Institute

CIRM Grant: Quest Award – Discovery Stage Research

Research: Birgitt and her team at the Parkinson’s Institute in Sunnyvale, California, are using CRISPR gene editing technology to reduce the levels of a toxic protein called alpha synuclein, which builds up in the dopaminergic brain cells affected by Parkinson’s disease.

Birgitt Schuele

“My hope is that I can contribute to stopping disease progression in Parkinson’s. If we can develop a drug that can get rid of accumulated protein in someone’s brain that should stop the cells from dying. If someone has early onset PD and a slight tremor and minor walking problems, stopping the disease and having a low dose of dopamine therapy to control symptoms is almost a cure.”

Parkinson’s disease in a dish. Dopaminergic neurons made from Parkinson’s patient induced pluripotent stem cells. (Image credit: Birgitt Schuele)


Jeanne Loring, Scripps Research Institute

CIRM Grant: Quest Award – Discovery Stage Research

Research: Jeanne Loring and her team at the Scripps Research Institute in La Jolla, California, are deriving dopaminergic neurons from the iPSCs of Parkinson’s patients. Their goal is to develop a personalized, stem cell-based therapy for PD.

Jeanne Loring

“We are working toward a patient-specific neuron replacement therapy for Parkinson’s disease.  By the time PD is diagnosed, people have lost more than half of their dopamine neurons in a specific part of the brain, and loss continues over time.  No drug can stop the loss or restore the neurons’ function, so the best possible option for long term relief of symptoms is to replace the dopamine neurons that have died.  We do this by making induced pluripotent stem cells from individual PD patients and turning them into the exact type of dopamine neuron that has been lost.  By transplanting a patient’s own cells, we will not need to use potentially dangerous immunosuppressive drugs.  We plan to begin treating patients in a year to two years, after we are granted FDA approval for the clinical therapy.”

Skin cells from a Parkinson’s patient (left) were reprogrammed into induced pluripotent stem cells (center) that were matured into dopaminergic neurons (right) to model Parkinson’s disease. (Image credit: Jeanne Loring)


Justin Cooper-White, Scaled BioLabs Inc.

CIRM Grant: Quest Award – Discovery Stage Research

Research: Justin Cooper-White and his team at Scaled Biolabs in San Francisco are developing a tool that will make clinical-grade dopaminergic neurons from the iPSCs of PD patients in a rapid and cost-effective manner.

Justin Cooper-White

“Treating Parkinson’s disease with iPSC-derived dopaminergic neuron transplantation has a strong scientific and clinical rationale. Even the best protocols are long and complex and generally have highly variable quality and yield of dopaminergic neurons. Scaled Biolabs has developed a technology platform based on high throughput microfluidics, automation, and deep data which can optimize and simplify the road from iPSC to dopaminergic neuron, making it more efficient and allowing a rapid transition to GMP-grade derivation of these cells.  In our first 6 months of CIRM-funded work, we believe we have already accelerated and simplified the production of a key intermediate progenitor population, increasing the purity from the currently reported 40-60% to more than 90%. The ultimate goal of this work is to get dopaminergic neurons to the clinic in a robust and economical manner and accelerate treatment for Parkinson’s patients.”

High throughput differentiation of dopaminergic neuron progenitors in  microbioreactor chambers in Scaled Biolabs’ cell optimization platform. Different chambers receive different differentiation factors, so that optimal treatments for conversion to dual-positive cells can be determined (blue: nuclei, red: FOXA2, green: LMX1A).


Xinnan Wang, Stanford University

CIRM Grant: Basic Biology V

Research: Xinnan Wang and her team at Stanford University are studying the role of mitochondrial dysfunction in the brain cells affected in Parkinson’s disease.

Xinnan Wang

“Mitochondria are a cell’s power plants that provide almost all the energy a cell needs. When these cellular power plants are damaged by stressful factors present in aging neurons, they release toxins (reactive oxygen species) to the rest of the neuron that can cause neuronal cell death (neurodegeneration).  We hypothesized that in Parkinson’s mutant neurons, mitochondrial quality control is impaired thereby leading to neurodegeneration. We aimed to test this hypothesis using neurons directly derived from Parkinson’s patients (induced pluripotent stem cell-derived neurons).”

Dopaminergic neurons derived from human iPSCs shown in green, yellow and red. (Image credit: Atossa Shaltouki, Stanford)


Related Blogs:

Stem Cell Roundup: Rainbow Sherbet Fruit Fly Brains, a CRISPR/iPSC Mash-up and more

This week’s Round Up is all about the brain with some CRISPR and iPSCs sprinkled in:

Our Cool Stem Cell Image of the Week comes from Columbia University’s Zuckerman Institute:

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(Credit: Jon Enriquez/Mann Lab/Columbia’s Zuckerman Institute).

This rainbow sherbet-colored scientific art is a microscopy image of a fruit fly nervous system in which brain cells were randomly labeled with different colors. It was a figure in a Neuron study published this week showing how cells derived from the same stem cells can go down very different developmental paths but then later are “reunited” to carry out key functions, such as in this case, the nervous system control of leg movements.


A new therapeutic avenue for Parkinson’s diseaseBuck Institute

Many animal models of Parkinson’s disease are created by mutating specific genes to cause symptoms that mimic this incurable, neurodegenerative disorder. But, by far, most cases of Parkinson’s are idiopathic, a fancy term for spontaneous with no known genetic cause. So, researchers at the Buck Institute took another approach: they generated a mouse model of Parkinson’s disease using the pesticide, paraquat, exposure to which is known to increase the risk of the idiopathic form of Parkinson’s.

Their CIRM-funded study in Cell Reports showed that exposure to paraquat leads to cell senescence – in which cells shut down and stop dividing – particularly in astrocytes, brain cells that support the function of nerve cells. Ridding the mice of these astrocytes relieved some of the Parkinson’s like symptoms. What makes these results so intriguing is the team’s analysis of post-mortem brains from Parkinson’s patients also showed the hallmarks of increased senescence in astrocytes. Perhaps, therapeutic approaches that can remove senescent cells may yield novel Parkinson’s treatments.


Discovery may advance neural stem cell treatments for brain disordersSanford-Burnham Prebys Medical Discovery Institute (via Eureka Alert)

Another CIRM-funded study published this week in Nature Neuroscience may also help pave the way to new treatment strategies for neurologic disorders like Parkinson’s disease. A team at Sanford Burnham Prebys Medical Discovery Institute (SBP) discovered a novel gene regulation system that brain stem cells use to maintain their ability to self-renew.

The study centers around messenger RNA, a molecular courier that transcribes a gene’s DNA code and carries it off to be translated into a protein. The team found that the removal of a chemical tag on mRNA inside mouse brain stem cells caused them to lose their stem cell properties. Instead, too many cells specialized into mature brain cells leading to abnormal brain development in animal studies. Team lead Jing Crystal Zhao, explained how this finding is important for future therapeutic development:

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Crystal Zhao

“As NSCs are increasingly explored as a cell replacement therapy for neurological disorders, understanding the basic biology of NSCs–including how they self-renew–is essential to harnessing control of their in vivo functions in the brain.”


Researchers Create First Stem Cells Using CRISPR Genome ActivationThe Gladstone Institutes

Our regular readers are most likely familiar with both CRISPR gene editing and induced pluripotent stem cell (iPSC) technologies. But, in case you missed it late last week, a Cell Stem Cell study out of Sheng Ding’s lab at the Gladstone Institutes, for the first time, combined the two by using CRISPR to make iPSCs. The study got a lot of attention including a review by Paul Knoepfler in his blog The Niche. Check it out for more details!

 

CIRM interviews Lorenz Studer: 2017 recipient of the Ogawa-Yamanaka Stem Cell Prize [Video]

For eight long years, researchers who were trying to develop a stem cell-based therapy for Parkinson’s disease – an incurable movement disorder marked by uncontrollable shaking, body stiffness and difficulty walking – found themselves lost in the proverbial wilderness. In initial studies, rodent stem cells were successfully coaxed to specialize into dopamine-producing nerve cells, the type that are lost in Parkinson’s disease. And further animal studies showed these cells could treat Parkinson’s like symptoms when transplanted into the brain.

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Lorenz Studer, MD
Photo Credit: Sloan Kettering

But when identical recipes were used to make human stem cell-derived dopamine nerve cells the same animal experiments didn’t work. By examining the normal developmental biology of dopamine neurons much more closely, Lorenz Studer cracked the case in 2011. Now seven years later, Dr. Studer, director of the Center for Stem Cell Biology at the Memorial-Sloan Kettering Cancer Center, and his team are on the verge of beginning clinical trials to test their Parkinson’s cell therapy in patients

It’s for these bottleneck-busting contributions to the stem cell field that Dr. Studer was awarded the Gladstone Institutes’ 2017 Ogawa-Yamanaka Stem Cell Prize. Now in its third year, the prize was founded by philanthropists Hiro and Betty Ogawa along with  Shinya Yamanaka, Gladstone researcher and director of the Center for iPS Cell Research and Application at Kyoto University, and is meant to inspire and celebrate discoveries that build upon Yamanaka’s Nobel prize winning discovery of induced pluripotent stem cells (iPSCs).

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(L to R) Shinya Yamanaka, Andrew Ogawa, Deepak Srivastava present Lorenz Studer the 2017 Ogawa-Yamanaka Stem Cell Prize at Gladstone Institutes. Photo Credit: Todd Dubnicoff/CIRM

Studer was honored at the Gladstone in November and presented the Ogawa-Yamanka Stem Cell Prize Lecture. He was kind enough to sit down with me for a brief video interview (watch it below) a few minutes before he took the stage. He touched upon his Parkinson’s disease research as well as newer work related to hirschsprung disease, a dangerous intestinal disorder often diagnosed at birth that is caused by the loss of nerve cells in the gut. Using human embryonic stem cells and iPSCs derived from hirschsprung patients, Studer’s team has worked out the methods for making the gut nerve cells that are lost in the disease. This accomplishment has allowed his lab to better understand the disease and to make solid progress toward a stem cell-based therapy.

His groundbreaking work has also opened up the gates for other Parkinson’s researchers to make important insights in the field. In fact, CIRM is funding several interesting early stage projects aimed at moving therapy development forward:

We posted the 8-minute video with Dr. Studer today on our official YouTube channel, CIRM TV. You can watch the video here:

And for a more detailed description of Studer’s research, watch Gladstone’s webcast recording of his entire lecture:

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

Stopping brain cancer in its tracks.

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

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

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

Monje explained in a Stanford news release,

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

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

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

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

Parkinson’s Institute CIRM Research Featured on KTVU News.

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

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

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

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

Click on photo to view video.

Mark your calendars for Stem Cell Awareness Day!

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

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

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

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

Stem cell therapy for Parkinson’s disease shows promise in monkeys

Tremors, muscle stiffness, shuffling, slow movement, loss of balance. These are all symptoms of Parkinson’s disease (PD), a neurodegenerative disorder that progressively destroys the dopamine-producing neurons in the brain that control movement.

While there is no cure for Parkinson’s disease, there are drugs like Levodopa and procedures like deep brain stimulation that alleviate or improve some Parkinsonian symptoms. What they don’t do, however, is slow or reverse disease progression.

Scientists are still trying to figure out what causes Parkinson’s patients to lose dopaminergic neurons, and when they do, they hope to stop the disease in its early stages before it can cause the debilitating symptoms mentioned above. In the meantime, some researchers see hope for treating Parkinson’s in the form of stem cell therapies that can replace the brain cells that are damaged or lost due to the disease.

Dopaminergic neurons derived from induced pluripotent stem cells. (Xianmin Zeng, Buck Institute)

Promising results in monkeys

This week, a team of Japanese scientists reported in the journal Nature that they treated monkeys with Parkinson’s-like symptoms by transplanting dopaminergic neurons made from human stem cells into their brains. To prevent the monkeys from rejecting the human cells, they were treated with immunosuppressive drugs. These transplanted neurons survived for more than two years without causing negative side effects, like tumor growth, and also improved PD symptoms, making it easier for the monkeys to move around.

The neurons were made from induced pluripotent stem cells (iPSCs), which are stem cells that can become any cell type in the body and are made by transforming mature human cells, like skin, back to an embryonic-like state. The scientists transplanted neurons made from the iPSCs of healthy people and PD patients into the monkeys and saw that both types of neurons survived and functioned properly by producing dopamine in the monkey brains.

Experts in the field spoke to the importance of these findings in an interview with Nature News. Anders Bjorklund, a neuroscientist at Lund University in Sweden, said “it’s addressing a set of critical issues that need to be investigated before one can, with confidence, move to using the cells in humans,” while Lorenz Studer, a stem-cell scientist at the Memorial Sloan Kettering Cancer Center in New York City, said that “there are still issues to work out, such as the number of cells needed in each transplant procedure. But the latest study is ‘a sign that we are ready to move forward.’”

Next stop, human trials

Jun Takahashi

Looking ahead, Jun Takahashi, the senior author on the study, explained that his team hopes to launch a clinical trial testing this iPSC-based therapy by the end of 2018. Instead of developing personalized iPSC therapies for individual PD patients, which can be time consuming and costly, Takahashi plans to make special donor iPSC lines (called human leukocyte antigen or HLA-homozygous iPSCs) that are immunologically compatible with a larger population of patients.

In a separate study published at the same time in Nature Communications, Takahashi and colleagues showed that transplanting neurons derived from immune-matched monkey iPSCs improved their survival and dampened the immune response.

The Nature News article does a great job highlighting the findings and significance of both studies and also mentions other research projects using stem cells to treat PD in clinical trials.

“Earlier this year, Chinese researchers began a Parkinson’s trial that used a different approach: giving patients neural-precursor cells made from embryonic stem cells, which are intended to develop into mature dopamine-producing neurons. A year earlier, in a separate trial, patients in Australia received similar cells. But some researchers have expressed concerns that the immature transplanted cells could develop tumour-causing mutations.

Meanwhile, researchers who are part of a Parkinson’s stem-cell therapy consortium called GForce-PD, of which Takahashi’s team is a member, are set to bring still other approaches to the clinic. Teams in the United States, Sweden and the United Kingdom are all planning trials to transplant dopamine-producing neurons made from embryonic stem cells into humans. Previously established lines of embryonic stem cells have the benefit that they are well studied and can be grown in large quantities, and so all trial participants can receive a standardized treatment.”

You can read more coverage on these research studies in STATnews, The San Diego Union Tribune, and Scientific American.

For a list of projects CIRM is funding on Parkinson’s disease, visit our website.

Harnessing DNA as a programmable instruction kit for stem cell function

DNA is the fundamental molecule to all living things. The genetic sequences embedded in its double-helical structure contain the instructions for producing proteins, the building blocks of our cells. When our cells divide, DNA readily unzips into two strands and makes a copy of itself for each new daughter cell. In a Nature Communications report this week, researchers at Northwestern University describe how they have harnessed DNA’s elegant design, which evolved over a billion years ago, to engineer a programmable set of on/off instructions to mimic the dynamic interactions that cells encounter in the body. This nano-sized toolkit could provide a means to better understand stem cell behavior and to develop regenerative therapies to treat a wide range of disorders.

Stupp

Instructing cells with programmable DNA-protein hybrids: switching bioactivity on and off Image: Stupp lab/Northwestern U.

While cells are what make up the tissues and organs of our bodies, it’s a bit more complicated than that. Cells also secrete proteins and molecules that form a scaffold between cells called the extracellular matrix. Though it was once thought to be merely structural, it’s clear that the matrix also plays a key role in regulating cell function. It provides a means to position multiple cell signaling molecules in just the right spot at the right time to stimulate a particular cell behavior as well as interactions between cells. This physical connection between the matrix, molecules and cells called a “niche” plays an important role for stem cell function.

Since studying cells in the laboratory involves growing them on plastic petri dishes, researchers have devised many methods for mimicking the niche to get a more accurate picture of how cells response to signals in the body. The tricky part has been to capture three main characteristics of the extracellular matrix all in one experiment; that is, the ability to add and then reverse a signal, to precisely position cell signals and to combine signals to manipulate cell function. That’s where the Northwestern team and its DNA toolkit come into the picture.

They first immobilized a single strand of DNA onto the surface of a material where cells are grown. Then they added a hybrid molecule – they call it “P-DNA” – made up of a particular signaling protein attached to a single strand of DNA that pairs with the immobilized DNA. Once those DNA strands zip together, that tethers the signaling protein to the material where the cells encounter it, effectively “switching on” that protein signal. Adding an excess of single-stranded DNA that doesn’t contain the attached protein, pushes out the P-DNA which can be washed away thereby switching off the protein signal. Then the P-DNA can be added back to restart the signal once again.

Because the DNA sequences can be easily synthesized in the lab, it allows the researchers to program many different instructions to the cells. For instance, combinations of different protein signals can be turned on simultaneously and the length of the DNA strands can precisely control the positioning of cell-protein interactions. The researchers used this system to show that spinal cord neural stem cells, which naturally clump together in neurospheres when grown in a dish, can be instructed to spread out on the dish’s surface and begin specializing into mature brain cells. But when that signal is turned off, the cells ball up together again into the neurospheres.

Team lead Samuel Stupp looks to this reversible, on-demand control of cell activity as means to develop patient specific therapies in the future:

stupp-samuel

Samuel Stupp

“People would love to have cell therapies that utilize stem cells derived from their own bodies to regenerate tissue. In principle, this will eventually be possible, but one needs procedures that are effective at expanding and differentiating cells in order to do so. Our technology does that,” he said in a university press release.

 

 

Scientist grow diseased brain cells in bulk to study Alzheimer’s and Parkinson’s disease

Daily trips to the local grocery store have become a thing of the past for many with the rise of wholesale stores like Costco and online giants like Amazon. Buying in bulk is attractive for people who lead busy lives, have large families, or just love having endless pairs of clean socks.

Scientists who study neurodegenerative diseases like Alzheimer’s and Parkinson’s use disease-in-a-dish models that are much like the daily visits to the nearby Safeway. They can make diseased brain cells, or neurons, from human pluripotent stem cells and study them in the lab. But often, they can’t generate large enough quantities of cells to do important experiments like test new drugs or develop diagnostic platforms to identify disease at an earlier age.

What scientists need is a Costco for brain cells, a source that can make diseased brain cells in bulk. Such a method would open a new avenue of research into what causes neurodegeneration and how the aging process affects its progression.

This week, this need was answered. A team of researchers from Lund University in Sweden developed a method that can efficiently generate neurons from patients with a range of neurodegenerative diseases including Parkinson’s, Huntington’s and Alzheimer’s disease. The study was published in EMBO Molecular Medicine and was led by senior author Dr. Malin Parmar.

Diseased neurons made by the Lund University team. (Photo, Kennet Ruona)

Parmar and her team took an alternative approach to making their neurons. Their technology involves converting human skin cells into neurons without reprogramming the skin cells back to a pluripotent stem cell state first. This process is called “direct conversion” and is considered an effective shortcut for generating mature cells like neurons in a dish. Direct conversion of skin cells into neurons was first published by Dr. Marius Wernig, a CIRM-grantee and professor at Stanford University.

There is also scientific evidence suggesting that reprogramming patient cells back to a pluripotent state wipes out the effects of aging in those cells and has a Benjamin Button-like effect on the resulting neurons. By directly converting patient skin cells into neurons, many of these aging “signatures” are retained and the resulting neurons are more representative of the aging brain.

So how did they make brain cells in bulk? Parmar explained their method in a Lund University news release,

Malin Parmar

“Primarily, we inhibited a protein, REST, involved in establishing identity in cells that are not nerve cells. After limiting this protein’s impact in the cells during the conversion process, we’ve seen completely different results.”

 

Besides blocking REST, the team also turned on the production of two proteins, Ascl1 and Brn2, that are important for the development of neurons. This combination of activating pro-neural genes and silencing anti-neural genes was successful at converting skin cells into neurons on a large scale. Parmar further explained,

“We’ve been playing around with changing the dosage of the other components in the previous method, which also proved effective. Overall, the efficiency is remarkable. We can now generate almost unlimited amounts of neurons from one skin biopsy.”

As mentioned previously, this technology is valuable because it provides better brain disease models for scientists to study and to screen for new drugs that could treat or delay disease onset. Additionally, scientists can study the effects of the aging in the brain at different stages of neurodegeneration. Aging is a well-known risk factor for many neurodegenerative diseases, especially Alzheimer’s, so the ability to make large quantities of brain cells from elderly Alzheimer’s patients will unlock new clues into how age influences disease.

Co-author Dr. Johan Jakobsson concluded,

Johan Jakobsson

“This takes us one step closer to reality, as we can now look inside the human neurons and see what goes on inside the cell in these diseases. If all goes well, this could fundamentally change the field of research, as it helps us better understand the real mechanisms of the disease. We believe that many laboratories around the world would like to start testing on these cells to get closer to the diseases.”

For more on this study, check out this short video provided by Lund University.