The power of one voice: David Higgins’ role in advancing stem cell research

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David Higgins: Photo courtesy Nancy Ramos @ Silver Eye Photography

As we start a new year, we are fine tuning our soon-to-be-published 2018 Annual Report, summarizing our work over the past 12 months. The report is far more than just a collection of statistics about how many clinical trials we are funding (50 – not too shabby eh!) or that our support has generated an additional $3.2 billion in leveraged funding. It’s also a look at the people who have made this year so memorable – from patients and researchers to patient advocates. We start with our Board member David Higgins, Ph.D.  David is the patient advocate on our Board for Parkinson’s disease. He has a family history of Parkinson’s and has also been diagnosed with the disease himself.

How he sees his role

As a patient advocate my role is not to support any Parkinson’s program that comes in the door and get it funded. We have to judge the science at the same level for every disease and if you bring me a good Parkinson’s project, I will fight tooth and nail to support it. But if you bring me a bad one, I will not support it. I see my role as more of a consultant for the staff and Board, to help advise but not to impose my views on them.

I think what CIRM has done is to create a new way of funding the best science in the world. The involvement of the community in making these decisions is critical in making sure there is an abundance of oversight, that there is not a political decision made about funding. It’s all about the science. This is the most science-based organization that you could imagine.

The Board plays a big role in all this. We don’t do research or come up with the ideas, but we nurture the research and support the scientists, giving them the elements they need to succeed.

And, of course the taxpayers play a huge role in this, creating us in the first place and approving all the money to help support and even drive this research. Because of that we should be as conservative as possible in using this money. Being trustees of this funding is a privilege and we have to be mindful of how to best use it.

On the science

I love, love, love having access to the latest, most interesting, cutting edge research in the world, talking to scientists about what they are doing, how we can support them and help them to do it better, how it will change the world. You don’t have access to anything else like this anywhere else.

It’s like ice cream, you just enjoy every morsel of it and there’s no way you can find that level of satisfaction anywhere else. I really feel, as do other Board members, that we are helping people, that we are changing people’s lives.

I also love the learning curve. The amount I have learned about the field that I didn’t know before is amazing. Every meeting is a chance to learn something new and meeting the scientists who have spent years working on a project is so fascinating and rewarding.

 Unexpected pleasure

The other joy, and I hadn’t anticipated this, is the personal interaction I have with other Board members and staff members. They have become friends, people I really like and admire because of what they do and how committed they are.

When I talk about CIRM I tell people if you live in California you should be proud of how your money is being spent and how it’s making a difference in people’s lives. When I give a talk or presentation, I always end with a slide of the California flag and tell people you should be proud to be here.

 

 

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

Parkinsons

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.

 

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:

Hey, what’s the big idea? CIRM Board is putting up more than $16.4 million to find out

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David Higgins, CIRM Board member and Patient Advocate for Parkinson’s disease; Photo courtesy San Diego Union Tribune

When you have a life-changing, life-threatening disease, medical research never moves as quickly as you want to find a new treatment. Sometimes, as in the case of Parkinson’s disease, it doesn’t seem to move at all.

At our Board meeting last week David Higgins, our Board member and Patient Advocate for Parkinson’s disease, made that point as he championed one project that is taking a new approach to finding treatments for the condition. As he said in a news release:

“I’m a fourth generation Parkinson’s patient and I’m taking the same medicines that my grandmother took. They work but not for everyone and not for long. People with Parkinson’s need new treatment options and we need them now. That’s why this project is worth supporting. It has the potential to identify some promising candidates that might one day lead to new treatments.”

The project is from Zenobia Therapeutics. They were awarded $150,000 as part of our Discovery Inception program, which targets great new ideas that could have a big impact on the field of stem cell research but need some funding to help test those ideas and see if they work.

Zenobia’s idea is to generate induced pluripotent stem cells (iPSCs) that have been turned into dopaminergic neurons – the kind of brain cell that is dysfunctional in Parkinson’s disease. These iPSCs will then be used to screen hundreds of different compounds to see if any hold potential as a therapy for Parkinson’s disease. Being able to test compounds against real human brain cells, as opposed to animal models, could increase the odds of finding something effective.

Discovering a new way

The Zenobia project was one of 14 programs approved for the Discovery Inception award. You can see the others on our news release. They cover a broad array of ideas targeting a wide range of diseases from generating human airway stem cells for new approaches to respiratory disease treatments, to developing a novel drug that targets cancer stem cells.

Dr. Maria Millan, CIRM’s President and CEO, said the Stem Cell Agency supports this kind of work because we never know where the next great idea is going to come from:

“This research is critically important in advancing our knowledge of stem cells and are the foundation for future therapeutic candidates and treatments. Exploring and testing new ideas increases the chances of finding treatments for patients with unmet medical needs. Without CIRM’s support many of these projects might never get off the ground. That’s why our ability to fund research, particularly at the earliest stage, is so important to the field as a whole.”

The CIRM Board also agreed to invest $13.4 million in three projects at the Translation stage. These are programs that have shown promise in early stage research and need funding to do the work to advance to the next level of development.

  • $5.56 million to Anthony Oro at Stanford to test a stem cell therapy to help people with a form of Epidermolysis bullosa, a painful, blistering skin disease that leaves patients with wounds that won’t heal.
  • $5.15 million to Dan Kaufman at UC San Diego to produce natural killer (NK) cells from embryonic stem cells and see if they can help people with acute myelogenous leukemia (AML) who are not responding to treatment.
  • $2.7 million to Catriona Jamieson at UC San Diego to test a novel therapeutic approach targeting cancer stem cells in AML. These cells are believed to be the cause of the high relapse rate in AML and other cancers.

At CIRM we are trying to create a pipeline of projects, ones that hold out the promise of one day being able to help patients in need. That’s why we fund research from the earliest Discovery level, through Translation and ultimately, we hope into clinical trials.

The writer Victor Hugo once said:

“There is one thing stronger than all the armies in the world, and that is an idea whose time has come.”

We are in the business of finding those ideas whose time has come, and then doing all we can to help them get there.

 

 

 

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.

Stem Cell Patient Advocates, Scientists and Doctors Unite Around a Common Cause

Some phrases just bring a smile to your face: “It’s a girl/boy”, “Congratulations, you got the job”, and “Another beer sir?” (or maybe that last one is just me). One other phrase that makes me smile is “packed house”. That’s why I was smiling so much at our Patient Advocate Event at UC San Diego last week. The room was jammed with around 150 patients and patient advocates who had come to hear about the progress being made in stem cell research.

Jonathan Thomas, Chair of the CIRM governing Board, kicked off the event with a quick run-through of our research, focusing on our clinical trials. As we have now funded 29 clinical trials, it really was a quick run-through, but JT did focus on a couple of remarkable stories of cures for patients suffering from Severe Combined Immunodeficiency (SCID) and Chronic Granulomatous Disease.

His message was simple. We have come a long way, but we still have a long way to go to fulfill our mission of accelerating stem cell treatments to patients with unmet medical needs. We have a target of 40 new clinical trials by 2020 and JT stressed our determination to do everything we can to reach that goal.

David Higgins, Parkinson’s Disease Advocate and CIRM Board Member (Credit Cory Kozlovich, UCSD)

Next up was David Higgins, who has a unique perspective. David is a renowned scientist, he’s also the Patient Advocate for Parkinson’s disease on the CIRM Board, and he has Parkinson’s disease. David gave a heartfelt presentation on the changing role of the patient and their growing impact on health and science.

In the old days, David said, the patient was merely the recipient of whatever treatment a doctor determined was appropriate. Today, that relationship is much more like a partnership, with physician and patient working together to determine the best approach.

He said CIRM tries to live up to that model by engaging the voice of the patient and patient advocate at every stage of the approval process, from shaping concepts to assessing the scientific merits of a project and deciding whether to fund it, and then doing everything we can to help it succeed.

He said California can serve as the model, but that patients need to make their voices heard at the national level too, particularly in light of the proposed huge budget cuts for the National Institutes of Health.

Dr. Jennifer Braswell. (Credit Cory Kozlovich, UCSD)

U.C. San Diego’s Dr. Jennifer Braswell gave some great advice on clinical trials, focusing on learning how to tell a good trial from a questionable one, and the questions patients need to ask before agreeing to be part of one.

She said it has to:

  • Be at a highly regarded medical center
  • Be based on strong pre-clinical evidence
  • Involved well-informed and compassionate physicians and nurses
  • Acknowledge that it carries some risk.

“You all know that if it sounds too good to be true, it probably is. If someone says a clinical trial carries no risk that’s a red flag, you know that’s not true. There is risk. Good researchers work hard to reduce the risk as much as possible, but you cannot eliminate it completely.”

She said even sites such as www.clinicaltrials.gov – a list of all the clinical trials registered with the National Institutes of Health – have to be approached cautiously and that you should talk to your own physican before signing up for anything.

Finally, UC San Diego’s Dr. Catriona Jamieson talked about her research into blood cancers, and how her work would not have been possible without the support of CIRM. She also highlighted the growing number of trials being carried out at through the CIRM Alpha Stem Cell Clinic Network, which helps scientists and researchers share knowledge and resources, enabling them to improve the quality of the care they provide patients.

The audience asked the panelists some great questions about the need for;

  • A national patient database to make it easier to recruit people for clinical trials
  • For researchers to create a way of letting people know if they didn’t get into a clinical trial so the patients wouldn’t get their hopes up
  • For greater public education about physicians or clinics offering unproven therapies

Adrienne Shapiro, an advocate for sickle cell disease patients, asks a question at Thursday’s stem cell meeting in La Jolla. (Bradley J. Fikes)

The meeting showed the tremendous public interest in stem cell research, and the desire to move it ahead even faster.

This was the first of a series of free public events we are holding around California this year. Next up, Los Angeles. More details of that shortly.

Listening is fine. Action is better. Why patients want more than just a chance to have their say.

FDA

Type in the phrase “the power of the patient voice” in any online search engine and you’ll generate thousands of articles and posts about the importance of listening to what patients have to say. The articles are on websites run by a diverse group from patients and researchers, to advocacy organizations and pharmaceutical companies. Everyone it seems recognizes the importance of listening to what the patient says. Even the Food and Drug Administration (FDA) has gotten in on the act. But what isn’t as clear is does all that talking and listening lead to any action?

In the last few years the FDA launched its ‘Patient-Focused Drug Development Initiative’, a series of public meetings where FDA officials invited patients and patient advocates to a public meeting to offer their perspectives on their condition and the available therapies. Each meeting focused on a different disease or condition, 20 in all, ranging from Parkinson’s and breast cancer to Huntington’s and sickle cell disease.

The meetings followed a standard format. Patients and patient advocates were invited to talk about the disease in question and its impact on their life, and then to comment on the available treatments and what they would like to see happen that could make their life better.

The FDA then gathered all those observations and comments, including some submitted online, and put them together in a report. Here’s where you can find all 20 FDA Voice of the Patient reports.  The reports all end with a similar concluding paragraph. Here’s what the conclusion for the Parkinson’s patient report said:

“The insight provided during this meeting will aid in FDA’s understanding of what patients truly value in a treatment and inform the agency’s evaluation of the benefits and risk of future treatments for Parkinson’s disease patients.”

And now what? That’s the question many patients and patient advocates are asking. I spoke with several people who were involved in these meetings and all came away feeling that the FDA commissioners who held the hearings were sincere and caring. But none believe it has made any difference, that it has led to any changes in policy.

For obvious reasons none of those I spoke to wanted to be identified. They don’t want to do anything that could in any way jeopardize a potential treatment for their condition. But many felt the hearings were just window dressing, that the FDA held them because it was required by Congress to do so. The Ageny, however, is not required to act on the conclusions or make any changes based on the hearings. And that certainly seems to be what’s happened.

Producing a report is fine. But if that report then gets put on a shelf and ignored what is the value of it? Patients and patient advocates want their voices to be heard. But more importantly they want what they say to lead to some action, to have some positive outcome. Right now they are wondering if they were invited to speak, but no one was really listening.

Could the Answer to Treating Parkinson’s Disease Come From Within the Brain?

Sometimes a solution to a disease doesn’t come in the form of a drug or a stem cell therapy, but from within ourselves.

Yesterday, scientists from the Karolinska Institutet in Sweden reported an alternative strategy for treating Parkinson’s disease that involves reprogramming specific cells in the brain into the nerve cells killed off by the disease. Their method, which involves delivering reprogramming genes into brain cells called astrocytes, was able to alleviate motor symptoms associated with Parkinson’s disease in mice.

What is Parkinson’s Disease and how is it treated?

Parkinson’s disease (PD) is a progressive neurodegenerative disease that’s characterized by the death of dopamine-producing nerve cells (called dopaminergic neurons) in an area of the brain that controls movement.

Dopaminergic neurons grown in a culture dish. (Image courtesy of Faria Zafar, Parkinson’s Institute).

PD patients experience tremors in their hands, arms and legs, have trouble starting and stopping movement, struggle with maintaining balance and have issues with muscle stiffness. These troublesome symptoms are caused by a lack dopamine, a chemical made by dopaminergic neurons, which signals to the part of the brain that controls how a person initiates and coordinates movement.

Over 10 million people in the world are affected by PD and current therapies only treat the symptoms of the disease rather than prevent its progression. Many of these treatments involve drugs that replace the lost dopamine in the brain, but these drugs lose their effectiveness over time as the disease kills off more neurons, and they come with their own set of side effects.

Another strategy for treating Parkinson’s is replacing the lost dopaminergic neurons through cell-based therapies. However this research is still in its early stages and would require patients to undergo immunosuppressive therapy because the stem cell transplants would likely be allogeneic (from a donor) rather than autologous (from the same individual).

Drug and cell-based therapies both involve taking something outside the body and putting it in, hoping that it does the right thing and prevents the disease. But what about using what’s already inside the human body to fight off PD?

This brings us to today’s study where scientists reprogrammed brain cells in vivo (meaning inside a living organism) to produce dopamine in mice with symptoms that mimic Parkinson’s. Their method, which was published in the journal Nature Biotechnology, was successful in alleviating some of the Parkinson’s-related movement problems the mice had. This study was funded in part by a CIRM grant and received a healthy amount of coverage in the media including STATnews, San Diego Union-Tribune and Scientific American.

Reprogramming the brain to make more dopamine

Since Shinya Yamanaka published his seminal paper on reprogramming adult somatic cells into induced pluripotent stem cells, scientists have taken the building blocks of his technology a step further to reprogram one adult cell type into another. This process is called “direct reprogramming” or “transdifferentiation”. It involves delivering a specific cocktail of genes into cells that rewrite the cells identity, effectively turning them into the cell type desired.

The Karolinska team found that three genes: NEUROD1, ASCL1 and LMX1A combined with a microRNA miR218 were able to reprogram human astrocytes into induced dopaminergic neurons (iDANs) in a lab dish. These neurons looked and acted like the real thing and gave the scientists hope that this combination of factors could reprogram astrocytes into iDANs in the brain.

The next step was to test these factors in mice with Parkinson’s disease. These mice were treated with a drug that killed off their dopaminergic neurons giving them Parkinson’s-like symptoms. The team used viruses to deliver the reprogramming cocktail to astrocytes in the brain. After a few weeks, the scientists observed that some of the “infected” astrocytes developed into iDANs and these newly reprogrammed neurons functioned properly, and more importantly, helped reverse some of the motor symptoms observed in these mice.

This study offers a new potential way to treat Parkinson’s by reprogramming cells in the brain into the neurons that are lost to the disease. While this research is still in its infancy, the scientists plan to improve the safety of their technology so that it can eventually be tested in humans.

Bonus Blog Interview for World Parkinson’s Day

Ernest Arenas, Karolinska Institutet

In honor of World Parkinson’s day (April 11th), I’m providing a bonus blog interview about this research. I reached out to the senior author of this study, Dr. Ernest Arenas, to ask him a few more questions about his publication and the future studies his team is planning.

Q) What are the major findings of your current study and how do they advance research on Parkinson’s disease?

The current treatment for Parkinson’s disease (PD) is symptomatic and does not change the course of the disease. Cell replacement therapies, such as direct in vivo reprogramming of in situ [local] astrocytes into dopamine (DA) neurons, work by substituting the cells lost by disease and have the potential to halt or even reverse motor alterations in PD.

Q) Can you comment on the potential for gene therapy treatments for Parkinson’s patients?

We see direct in vivo reprogramming of brain astrocytes into dopamine neurons in situ as a possible future alternative to DA cell transplantation. This method represents a gene therapy approach to cell replacement since we use a virus to deliver four reprogramming factors. In this method, the donor cells are in the host brain and there is no need to search for donor cells and no cell transplantation or immunosuppression. The method for the moment is an experimental prototype and much more needs to be done in order to improve efficiency, safety and to translate it to humans.

Q) Will reprogrammed iDANs be susceptible to Parkinson’s disease over time?

As any other cell replacement therapy, the cells would be, in principle, susceptible to Parkinson’s disease. It has been found that PD catches up with transplanted cells in 15-20 years. We think that this is a sufficiently long therapeutic window.

In addition, direct in vivo reprogramming may also be performed with drug-inducible constructs that could be activated years after, as disease progresses. This might allow adding more cells by turning on the reprogramming factors with pharmacological treatment to the host. This was not tested in our study but the basic technology to develop such strategies currently exist.

Q) What are your plans for future studies and translating this research towards the clinic?

In our experiments, we used transgenic mice in order to test our approach and to ensure that we only reprogrammed astrocytes. There is a lot that still needs to be done in order to develop this approach as a therapy for Parkinson’s disease. This includes improving the efficiency and the safety of the method, as well as developing a strategy suitable for therapy in humans. This can be achieved by further improving the reprogramming cocktail, by using a virus with a selective tropism [affinity] for astrocytes and that do not incorporate the constructs into the DNA of the host cell, as well as using constructs with astrocyte-specific promoters and capable of self-regulating depending on the cell context.

Our study demonstrates for the first time that it is possible to use direct reprogramming of host brain cells in order to rescue neurological symptoms. These results indicate that direct reprogramming has the potential to become a novel therapeutic approach for Parkinson’s disease and opens new opportunities for the treatment of patients with neurological disorders.

How Parkinson’s disease became personal for one stem cell researcher

April is Parkinson’s disease Awareness Month. This year the date is particularly significant because 2017 is the 200th anniversary of the publication of British apothecary James Parkinson’s “An Essay on the Shaking Palsy”, which is now recognized as a seminal work in describing the disease.

Schuele_headshotTo mark the occasion we talked with Dr. Birgitt Schuele, Director Gene Discovery and Stem Cell Modeling at the Parkinson’s Institute and Clinical Center in Sunnyvale, California. Dr. Schuele recently received funding from CIRM for a project using new gene-editing technology to try and halt the progression of Parkinson’s.

 

 

What got you interested in Parkinson’s research?

People ask if I have family members with Parkinson’s because a lot of people get into this research because of a family connection, but I don’t.  I was always excited by neuroscience and how the brain works, and I did my medical residency in neurology and had a great mentor who specialized in the neurogenetics of Parkinson’s. That helped fuel my interest in this area.

I have been in this field for 15 years, and over time I have gotten to know a lot of people with Parkinson’s and they have become my friends, so now I’m trying to find answers and also a cure for Parkinson’s. For me this has become personal.

I have patients that I talk to every couple of months and I can see how their disease is progressing, and especially for people with early or young onset Parkinson’s. It’s devastating. It has a huge effect on the person and their family, and on relationships, even how they have to talk to their kids about their risk of getting the disease themselves. It’s hard to see that and the impact it has on people’s lives. And because Parkinson’s is progressive, I get to see, over the years, how it affects people, it’s very hard.

Talk about the project you are doing that CIRM is funding

It’s very exciting. The question for Parkinson’s is how do you stop disease progression, how do you stop the neurons from dying in areas affected by the disease. One protein, identified in 1997 as a genetic form of Parkinson’s, is alpha-synuclein. We know from studying families that have Parkinson’s that if you have too much alpha-synuclein you get early onset, a really aggressive form of Parkinson’s.

I followed a family that carries four copies of this alpha-synuclein gene (two copies is the normal figure) and the age of onset in this family was in their mid 30’s. Last year I went to a funeral for one of these family members who died from Parkinson’s at age 50.

We know that this protein is bad for you, if you have too much it kills brains cells. So we have an idea that if you lower levels of this protein it might be an approach to stop or shield those cells from cell death.

We are using CRISPR gene editing technology to approach this. In the Parkinson’s field this idea of down-regulation of alpha-synuclein protein isn’t new, but previous approaches worked at the protein level, trying to get rid of it by using, for example, immunotherapy. But instead of attacking the protein after it has been produced we are starting at the genomic level. We want to use CRISPR as a way to down-regulate the expression of the protein, in the same way we use a light dimmer to lower the level of light in a room.

But this is a balancing act. Too much of the protein is bad, but so is too little. We know if you get rid of the protein altogether you get negative effects, you cause complications. So we want to find the right level and that’s complex because the right level might vary from person to person.

We are starting with the most extreme levels, with people who have twice as much of this protein as is normal. Once we understand that better, then we can look at people who have levels that are still higher than normal but not at the upper levels we see in early-onset Parkinson’s. They have more subtle changes in their production or expression of this protein. It’s a little bit of a juggling act and it might be different for different patients. We start with the most severe ones and work our way to the most common ones.

One of the frustrations I often hear from patients is that this is all taking so long. Why is that?

Parkinson’s has been overall frustrating for researchers as well. Around 100 years ago, Dr. Lewy first described the protein deposits and the main neuropathology in Parkinson’s. About 20 years ago, mutations in the alpha-synuclein gene were discovered, and now we know approximately 30 genes that are associated with, or can cause Parkinson’s. But it was all very descriptive. It told us what is going on but not why.

Maybe we thought it was straight forward and maybe researchers only focused on what we knew at that point. In 1957, the neurotransmitter dopamine was identified and since the 1960s people have focused on Parkinson’s as a dopamine-deficient problem because we saw the amazing effects L-Dopa had on patients and how it could help ease their symptoms.

But I would say in the last 15 years we have looked at it more closely and realized it’s more complicated than that. There’s also a loss of sense of smell, there’s insomnia, episodes of depression, and other things that are not physical symptoms. In the last 10 years or so we have really put the pieces together and now see Parkinson’s as a multi-system disease with neuronal cell death and specific protein deposits called Lewy Bodies. These Lewy Bodies contain alpha-synuclein and you find them in the brain, the gut and the heart and these are organs people hadn’t looked at because no one made the connection that constipation or depression could be linked to the disease. It turns out that Parkinson’s is much more complicated than just a problem in one particular region of the brain.

The other reason for slow progress is that we don’t have really good models for the disease that are predictive for clinical outcomes. This is why probably many clinical trials in the neurodegenerative field have failed to date. Now we have human induced pluripotent stem cells (iPSCs) from people with Parkinson’s, and iPSC-derived neurons allow us to better model the disease in the lab, and understand its underlying mechanisms  more deeply. The technology has now advanced so that the ability to differentiate these cells into nerve cells is better, so that you now have iPSC-derived neurons in a dish that are functionally active, and that act and behave like dopamine-producing neurons in the brain. This is an important advance.

Will this lead to a clinical trial?

That’s the idea, that’s our hope.

We are working with professor Dr. Deniz Kirik at the University of Lund in Sweden. He’s an expert in the field of viral vectors that can be used in humans – it’s a joint grant between us – and so what we learn from the human iPS cultures, he’ll transfer to an animal model and use his gene vector technology to see if we can see the same effects in vivo, in mice.

We are using a very special Parkinson’s mouse model – developed at UC San Francisco – that has the complete human genomic structure of the alpha-synuclein gene. If all goes well, we hope that ultimately we could be ready in a couple of years to think about preclinical testing and then clinical trials.

What are your hopes for the future?

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.

The next step is to develop better biomarkers to identify people at risk of developing Parkinson’s, so if you know someone is a few years away from developing symptoms, and you have the tools in place, you can start treatment early and stop the disease from kicking in, even before you clinically have symptoms.

Thinking about people who have been diagnosed with a disease, who are ten years into the disease, who already have side effects from the disease, it’s a little harder to think of regenerative medicine, using embryonic or iPSCs for this. I think that it will take longer to see results with this approach, but that’s the long-term hope for the future. There are many  groups working in this space, which is critical to advance the field.

Why is Parkinson’s Awareness Month important?

It’s important because, while a lot of people know about the disease, there are also a lot of misconceptions about Parkinson’s.

Parkinson’s is confused with Alzheimer’s or dementia and cognitive problems, especially the fact that it’s more than just a gait and movement problem, that it affects many other parts of the body too.

Using stem cells to fix bad behavior in the brain

 

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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.