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)


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It’s time to vote for the Stem Cell Person of the Year

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Paul Knoepfler

Oh well, it’s going to be another year of disappointment for me. Not only did I fail to get any Nobel Prize (I figured my blogs might give me a shot at Literature after they gave it to Bob Dylan last year), but I didn’t get a MacArthur Genius Award. Now I find out I haven’t even made the short list for the Stem Cell Person of the Year.

The Stem Cell Person of the Year award is given by UC Davis researcher, avid blogger and CIRM Grantee Paul Knoepfler. (You can vote for the Stem Cell Person of the Year here). In his blog, The Niche, Paul lists the qualities he looks for:

“The Stem Cell Person of the Year Award is an honor I give out to the person in any given year who in my view has had the most positive impact in outside-the-box ways in the stem cell and regenerative medicine field. I’m looking for creative risk-takers.”

“It’s not about who you know, but what you do to help science, medicine, and other people.”

Paul invites people to nominate worthy individuals – this year there are 20 nominees – people vote on which one of the nominees they think should win, and then Paul makes the final decision. Well, it is his blog and he is putting up the $2,000 prize money himself.

This year’s nominees are nothing if not diverse, including

  • Anthony Atala, a pioneering researcher at Wake Forest Institute for Regenerative Medicine in North Carolina
  • Bao-Ngoc Nguyen, who helped create California’s groundbreaking new law targeting clinics which offer unproven stem cell therapies
  • Judy Roberson, a tireless patient advocate, and supporter of stem cell research for Huntington’s disease

Whoever wins will be following in some big footsteps including patient advocates Ted Harada and Roman Reed, as well as scientists like Jeanne Loring, Masayo Takahashi,  and Elena Cattaneo.

So vote early, vote often.

LINK: Vote for the 2017 Stem Cell Person of the Year

Stories that caught our eye: stem cell transplants help put MS in remission; unlocking the cause of autism; and a day to discover what stem cells are all about

multiple-sclerosis

Motor neurons

Stem cell transplants help put MS in remission: A combination of high dose immunosuppressive therapy and transplant of a person’s own blood stem cells seems to be a powerful tool in helping people with relapsing-remitting multiple sclerosis (RRMS) go into sustained remission.

Multiple sclerosis (MS) is an autoimmune disorder where the body’s own immune system attacks the brain and spinal cord, causing a wide variety of symptoms including overwhelming fatigue, blurred vision and mobility problems. RRMS is the most common form of MS, affecting up to 85 percent of people, and is characterized by attacks followed by periods of remission.

The HALT-MS trial, which was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), took the patient’s own blood stem cells, gave the individual chemotherapy to deplete their immune system, then returned the blood stem cells to the patient. The stem cells created a new blood supply and seemed to help repair the immune system.

Five years after the treatment, most of the patients were still in remission, despite not taking any medications for MS. Some people even recovered some mobility or other capabilities that they had lost due to the disease.

In a news release, Dr. Anthony Fauci, Director of NIAID, said anything that holds the disease at bay and helps people avoid taking medications is important:

“These extended findings suggest that one-time treatment with HDIT/HCT may be substantially more effective than long-term treatment with the best available medications for people with a certain type of MS. These encouraging results support the development of a large, randomized trial to directly compare HDIT/HCT to standard of care for this often-debilitating disease.”

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Scripps Research Institute

Using stem cells to model brain development disorders. (Karen Ring) CIRM-funded scientists from the Scripps Research Institute are interested in understanding how the brain develops and what goes wrong to cause intellectual disabilities like Fragile X syndrome, a genetic disease that is a common cause of autism spectrum disorder.

Because studying developmental disorders in humans is very difficult, the Scripps team turned to stem cell models for answers. This week, in the journal Brain, they published a breakthrough in our understanding of the early stages of brain development. They took induced pluripotent stem cells (iPSCs), made from cells from Fragile X syndrome patients, and turned these cells into brain cells called neurons in a cell culture dish.

They noticed an obvious difference between Fragile X patient iPSCs and healthy iPSCs: the patient stem cells took longer to develop into neurons, a result that suggests a similar delay in fetal brain development. The neurons from Fragile X patients also had difficulty forming synaptic connections, which are bridges that allow for information to pass from one neuron to another.

Scripps Research professor Jeanne Loring said that their findings could help to identify new drug therapies to treat Fragile X syndrome. She explained in a press release;

“We’re the first to see that these changes happen very early in brain development. This may be the only way we’ll be able to identify possible drug treatments to minimize the effects of the disorder.”

Looking ahead, Loring and her team will apply their stem cell model to other developmental diseases. She said, “Now we have the tools to ask the questions to advance people’s health.”

A Day to Discover What Stem Cells Are All about.  (Karen Ring) Everyone is familiar with the word stem cells, but do they really know what these cells are and what they are capable of? Scientists are finding creative ways to educate the public and students about the power of stem cells and stem cell research. A great example is the University of Southern California (USC), which is hosting a Stem Cell Day of Discovery to educate middle and high school students and their families about stem cell research.

The event is this Saturday at the USC Health Sciences Campus and will feature science talks, lab tours, hands-on experiments, stem cell lab video games, and a resource fair. It’s a wonderful opportunity for families to engage in science and also to expose young students to science in a fun and engaging way.

Interest in Stem Cell Day has been so high that the event has already sold out. But don’t worry, there will be another stem cell day next year. And for those of you who don’t live in Southern California, mark your calendars for the 2017 Stem Cell Awareness Day on Wednesday, October 11th. There will be stem cell education events all over California and in other parts of the country during that week in honor of this important day.

 

 

Stem Cells May Help Endangered Species Live Long and Prosper

It’s the year 2286. The transmission signal of an alien space probe is wreaking havoc on Earth, knocking out the worldwide power grid and causing massive storms. It turns out the mysterious orbiting probe is trying to communicate with humpback whales through whale song and the devastation won’t stop until contact is made. But there’s a tiny problem: in that future, the humpback has long since become extinct. So the captain and crew travel back in time to snag two whales and save 23rd century civilization. Phew!

My fellow science fiction nerds will recognize that plot line from 1986’s Star Trek IV: A Voyage Home. It’s pure fantasy and yet there is a real lesson for our present day world: you shouldn’t underestimate how the extinction of a species will impact our world. For instance, the collapse and potential extinction of the bee population and other pollinators threatens to destabilize our global food supply.

Northern White Rhinos: At the Brink of Extinction
Beyond how it may affect us humans, I think there’s also a moral obligation to save endangered species that have dwindled in number directly due to human actions. It may be too late for the northern white rhino though. Because their horns are highly sought after as a status symbol and for use in traditional medicine, poachers have wiped out the population and now only three – Sudan, Najin and Fatu (grandfather, mother and daughter) – exist in the world. Sadly, none of them can breed naturally so they quietly graze in a Kenyan conservation park as their species heads towards extinction.

whiterhino

One of the three remaining northern white rhinos in the world (Image source: The Guardian)

Jeanne Loring, a CIRM grantee and professor at The Scripps Research Institute, still sees a glimmer of hope in the form of stem cells. In an essay published yesterday in Genetic Engineering and Biotechnology News, Loring describes her research team’s efforts to apply stem cell technology toward saving the Northern White Rhino and other endangered species.

Their efforts began about ten years ago in 2007, the same year that Shinya Yamanaka’s lab first reported that human fibroblasts, collected from a skin sample, can be reprogrammed into an embryonic stem cell-like state with the capacity to indefinitely make copies of themselves and to specialize into almost every cell type of the body. The properties of these induced pluripotent stem (iPS) cells have provided an important means for studying all sorts of human diseases in a lab dish and for deriving potential cell therapies.

FrozenZoo® and iPS Cells: A Modern Day Noah’s Ark?

But it was a free tour at the San Diego Safari Park just two months after Yamanka’s discovery which inspired the Loring lab to chart this additional research path using iPS cells. In exchange for the free safari ride, the team reciprocated by chatting with Oliver Ryder, director of the San Diego Zoo Institute for Conservation Research, about using stem cells to help save endangered species. Ryder’s institute runs the FrozenZoo® a cell and tissue bank containing thousands of frozen samples from a diverse set of species. In her essay, Loring recounts what happened after the visit:

“It was obvious to us: why not try to reprogram fibroblasts from the FrozenZoo®? When my group returned to the lab from the safari, I asked them: who would like to try to reprogram fibroblasts from an endangered species? It was far from a safe bet, but a young postdoctoral researcher who had recently joined my lab from Israel said that she’d love to give it a try. Inbar Friedrich Ben-Nun spent the next couple of years trying out methods in parallel on human cells and fibroblasts from the zoo. We chose fibroblasts from the drill because it is [an endangered] primate, making it more likely that the technology used for humans would work.

Oliver [Ryder] chose the northern white rhino, a particular favorite of his, and one of the world’s most endangered mammals.  Through hard work and insight, Inbar reprogrammed both species, and in 2011, we published the first report of making iPSCs from endangered species (Ben-Nun, et al., 2011). Nature Methods featured our work, with a cover illustration of an ark stuffed with endangered animals.”

 

 

 

So how exactly would these iPS cells be used to save the northern white rhino and other animals from the brink of extinction? Last December, Ben-Nun along with 20 other scientists and zoologists from four continents met in Vienna to map out a strategy. They published their plan on May 3rd in Zoo Biology.

The Stem Cell-Based Plan to Save the Northern White
In the first phase, an in vitro fertilization (IVF) procedure for the rhino – never before attempted – will be worked out. Frozen sperm samples from four now-deceased rhinos plus one sample from Sudan are ready for IVF. Researchers then hope to collect eggs from Najin and Fatu and implant embryos in surrogates of a related species, the southern white rhino. However, even if IVF is successful, the offspring would not represent enough genetic diversity to ultimately thrive as a species in the wild. So in the second phase, iPS cells will be generated using tissue fibroblast samples from several more northern whites that were banked in The FrozenZoo®. Those iPS cells will be specialized into sperm and eggs to provide a larger, more diverse set of embryos which again will be implanted in surrogate rhinos. Breeding animals using iPS-derived sperm and eggs has only been successful in mice so much work remains.

“Does this plan have any chance of succeeding?” Loring asks. Her response is cautiously optimistic:

“I know it will be difficult, but I think it’s not impossible. Perhaps the most important advance is that such a diverse group agreed on a plan—it wasn’t just a stem cell biologist like me imagining how the cells might be used, but rather a whole chain of experts who can imagine how to accomplish each step.”

 

Not all experts agree with this strategy. In a Nature News interview back in May, Michael Knight, chair of the International Union for Conservation Nature’s African Rhino Specialist Group, expressed concerns that the effort is misdirected:

“It’s Star Trek-type science. They should not be pushing this idea that they’re saving a species. If you want to save a [rhino] species, put your money into southern white conservation.”

IMHO
Knight’s point is well-taken that conventional conservation approaches are critical to ensure that the southern white rhino doesn’t meet the same disastrous fate as the northern white. But if the funding is available, it seems worth the effort to also attempt this innovative iPS strategy, a technology that’s deep in development now and not awaiting Captain Kirk’s distant Star Trek future.

A step forward for Parkinson’s disease?

Imagine how frustrating it would be to not know whether you could physically sit through a dinner with friends or to worry about getting stuck in the grocery isle, fighting against a body that refuses to move. These nightmare-like experiences are what many Parkinson’s disease (PD) patients deal with on a daily basis.

PD affects approximately one million people in the US, and there is no prevention or cure. While substantial funding efforts are being dedicated to PD research (CIRM, Michael J. Fox Foundation, Parkinson’s Disease Foundation, to name a few), a cure is still years or maybe even decades away.

However, a new stem cell therapy from Australia has the potential to make waves in what’s been a relatively flat sea of PD stem cell therapies that haven’t yet secured the funding or jumped the regulatory hurdles to make it into clinical trials. Biotech journalist Bradley Fikes broke the story yesterday in the San Diego Union Tribune. Fikes is one of my favorite science writers so instead of attempting to re-write an already eloquent piece, I’ll just mention a few highlights.

Stem cells down under

International Stem Cell Corporation (ISCO), a company based in Carlsbad, California, has developed a stem cell therapy that involves transplanting brain stem cells into the brains of PD patients. While stem cell therapy is viewed by some as the holy grail for PD – having the potential to replace lost dopamine-producing nerve cells in the brain – so far, no stem cell-derived therapy has been approved for testing in PD patients. (Previous clinical trials using fetal stem cells didn’t pan out.)

The Australian government approved the use of ISCO’s parthenogenic stem cell therapy in twelve PD patients in a clinical trial that is slated to start in the first quarter of 2016 (pending final approval from the Royal Melbourne Hospital review board). This therapy uses brain stem cells derived from pluripotent stem cells obtained from unfertilized human eggs, thus avoiding the ethical issues attached to use of embryonic stem cells. (For sciency details check out the ISCO website).

The goal of the trial will be to determine if ISCO’s stem cell therapy is safe and also effective at reducing PD symptoms like tremors and stunted movement. Fikes explained that ISCO chose Australia for it’s proposed clinical trial for regulatory reasons.

“The nation’s clinical trial system is more ‘interactive’, which allows for better collaboration with Australia’s Therapeutic Goods Administration on trial design.”

A comparison of primate brains to show an increase in the number of neurons after treatment with ISCO's stem cells. The left side is a control sample. The right side is from a treated brain. — International Stem Cell Corp.

A comparison of primate brains to show an increase in the number of neurons after treatment with ISCO’s stem cells. The left side is a control sample. The right side is from a treated brain. — International Stem Cell Corp.

Great minds think alike

ISCO’s is only one of a handful of groups proposing stem cell therapies for PD. Fikes mentioned other therapies currently being tested that are derived from embryonic stem cells, induced pluripotent stem cells (iPSCs), and adult stem cells like the mesenchymal and fat stem cells.

Jeanne Loring, Scripps Research Institute

Jeanne Loring, Scripps Research Institute

He also highlighted important ongoing research by CIRM grantee Dr. Jeanne Loring from the Scripps Research Institute. Loring founded the Summit for Stem Cell organization that’s generating iPSCs from PD patients with hopes of treating these patients with a dose of their own brain stem cells.

When asked about the ISCO study, she told Fikes that she sees ISCO as a “partner in fighting Parkinson’s.”

“The whole idea is to treat patients by whatever means possible.” – Loring


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Why “Right to Try” laws are more feel good than do good

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L to R: Don Gibbons, CIRM; Jeanne Loring; Beth Roxland; Aaron Levine

In the last few years some 24 states have approved so-called “Right to Try” laws. These are intended to give terminally ill patients faster and easier access to experimental therapies. But a panel of experts at the World Stem Cell Summit in Atlanta today said they are more symbolic than anything and do little to actually help patients get much-needed therapies.

The Right to Try laws are modeled after a federal law that allows “compassionate use” of experimental medications and lets doctors prescribe investigational medicines being safely used in early stage clinical trials.

Beth Roxland, a bioethicist with Johnson & Johnson, says the name of the law is misleading:

“If you look at the actual text of these laws they only say you have the right to “ask” for these drugs. That right already exists in federal law but neither federal law nor these Right to Try laws say you have the right to access.”

Aaron Levine from Georgia Tech says it’s also misleading to assume that just because a state passes a Right to Try law that it has any legal impact. He says state laws don’t over rule the Food and Drug Administration’s (FDA) regulation of this area and so the federal government would still have the authority to stop this kind of access.

But Levine says these laws are interesting in that they are indicative of the growing determination of patients and patient advocates to work around obstacles to access and have a bigger say in their own care.

One of the audience members, William Decker from Baylor College of Medicine, says that in Texas a law was recently crafted saying that as long as a potential therapy had gone through a Phase 1 safety trial it should be offered to the public and the public should be able to pay for it.

“If you know how clinical trials work you know you can get almost any schlock through a Phase 1 trial and the kinds of things that you can get to the public without any idea if they work often turn out to not be very useful. We saw this as an avenue to promote fraud, and the last thing you should be doing to a dying patient is take their money or divert their attention away from something that might help them.”

Decker and his colleagues argued before the Texas Legislature that potential therapies should at least have to go through a Phase 2 trial to make sure they were not only safe but also showed some benefit for patients. In the end Texas lawmakers rejected the Phase 2 idea but did say patients could not be charged for the therapy, and there could be no compensation from insurers or anyone else for the manufacturer of the therapy.

He says removing the financial benefits and incentives pretty much ensured that no company would offer patients a therapy under this law.

Jeanne Loring, a CIRM grantee from the Scripps Research Institute, says that likely won’t stop other clinics in other states:

“Some stem cell clinics are using adipose (stem cells derived from fat) therapy as an option for every disease imaginable and I’m sure some will take advantage of these laws to say it gives them the right to offer these to patients and the patients will pay for them directly. “

Roxland says that may already be happening:

“I think there is some evidence on the stem cell side that companies have popped up in states that have these laws, to make it easier to offer their therapies to patients.”

The panel agreed that in most cases these laws don’t give patients any rights they don’t already have, but do give the appearance of making access easier. They said it’s feel-good legislation, allowing people to feel they are doing something without actually doing anything.

Aaron Levine said that while some companies may try to take advantage of these laws, the most serious ones won’t:

 “Almost any legitimate company that wants an FDA approved product wouldn’t want to take advantage of these laws. It could put their product at risk. Most companies that need to work with the FDA have no incentive to go this route.”