A step forward in finding a treatment for a deadly neurological disorder

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MRI section of a brain affected by ALS with the front section of the brain highlighted

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a nasty disease that steadily attacks nerve cells in the brain and spinal cord. It’s pretty much always fatal within a few years. As if that wasn’t bad enough, ALS also can overlap with a condition called frontotemporal dementia (ALS/FTD). Together these conditions cause devastating symptoms of muscle weakness along with changes in memory, behavior and personality.

Now researchers at Cambridge University in the UK have managed to grow groups of cells called “mini-brains” that mimic ALS/FTD and could lead to new approaches to treating this deadly combination.

We have written about these mini-brains before. Basically, they are created, using the iPSC method, that takes skin or blood cells from a patient with a particular condition, in this case ALS/FTD, and turns them into the kind of nerve cells in the brain affected by the disease. Because they came from someone who had ALS/FTD they display many of the characteristics of the disease and this gives researchers a great tool to study the condition.

This kind of approach has been done before and given researchers a glimpse into what is happening in the brains of people with ALS/FTD. But in the past those cells were in a kind of clump, and it wasn’t possible to get enough nutrients to the cells in the middle of the clump for the mini-brain to survive for long.

What is different about the Cambridge team is that they were able to create these mini-brains using thin, slices of cells. That meant all the cells could get enough nutrients to survive a long time, giving the team a better model to understand what is happening in ALS/FTD.

In a news release, Dr András Lakatos, the senior author of the study, said: “Neurodegenerative diseases are very complex disorders that can affect many different cell types and how these cells interact at different times as the diseases progress.

“To come close to capturing this complexity, we need models that are more long-lived and replicate the composition of those human brain cell populations in which disturbances typically occur, and this is what our approach offers. Not only can we see what may happen early on in the disease – long before a patient might experience any symptoms – but we can also begin to see how the disturbances change over time in each cell.”

Thanks to these longer-lived cells the team were able to see changes in the mini-brains at a very early stage, including damage to DNA and cell stress, changes that affected other cells which play a role in muscle movements and behavior.

Because the cells developed using the iPSC method are from a patient with ALS/FTD, the researchers were able to use them to screen many different medications to see if any had potential as a therapy. They identified one, GSK2606414, that seemed to help in reducing the build-up of toxic proteins, reduced cell stress and the loss of nerve cells.

The team acknowledge that these results are promising but also preliminary and will require much more research to verify them.

CIRM has funded three clinical trials targeting ALS. You can read about that work here.

Wit, wisdom and a glimpse into the future

As of this moment, there are over two million podcasts and over 48 million episodes to listen to on your favorite listening device. If you’re a true crime enthusiast like me, you’ve surely heard of Casefile or one of the other 94 podcasts on the topic. But what if you’re looking for something a little less ghastly and a little more uplifting?

Dr. Daylon James, co-host of The Stem Cell Podcast

The Stem Cell Podcast is an informative and entertaining resource for scientists and science enthusiasts (or really, anyone) interested in learning about the latest developments in stem cell research.

Dr. Arun Sharma, co-host of The Stem Cell Podcast

On their latest episode, dynamic co-hosts and research scientists Dr. Daylon James and Dr. Arun Sharma sit down with our President & CEO, Dr. Maria Millan, to discuss the impact of California’s culture of innovation on CIRM, the challenge of balancing hope vs. hype in the context of stem cell research/therapies, and the evolution of the agency over the past 15 years.

Listen on as Dr. Millan highlights some of CIRM’s greatest victories and shares our mission for the future.

Celebrating Stem Cell Awareness Day

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The second Wednesday in October is celebrated as Stem Cell Awareness Day. It’s an event that CIRM has been part of since then Governor Arnold Schwarzenegger launched it back in 2008 saying: ”The discoveries being made today in our Golden State will have a great impact on many around the world for generations to come.”

In the past we would have helped coordinate presentations by scientists in schools and participated in public events. COVID of course has changed all that. So, this year, to help mark the occasion we asked some people who have been in the forefront of making Governor Schwarzenegger’s statement come true, to share their thoughts and feelings about the day. Here’s what they had to say.

What do you think is the biggest achievement so far in stem cell research?

Dr. Jan Nolta

Jan Nolta, PhD., Director of the Stem Cell Program at UC Davis School of Medicine, and directs the new Institute for Regenerative Cures. “The work of Don Kohn and his UCLA colleagues and team members throughout the years- developing stem cell gene therapy cures for over 50 children with Bubble baby disease. I was very fortunate to work with Don for the first 15 years of my career and know that development of these cures was guided by his passion to help his patients.

Dr. Clive Svendsen

Clive Svendsen, PhD. Director, Board of Governors Regenerative Medicine Institute at Cedars-Sinai: “Without a doubt the discovery of how to make human iPSCs by Shinya Yamanaka and Jamie Thomson.”

When people ask you what kind of impact CIRM and stem cell research has had on your life what do you say?

Ronnie and his parents celebrating his 1st birthday. (Photo courtesy of Pawash Priyank)

Pawash Priyank and Upasana Thakur, parents of Ronnie, who was born with a life-threatening immune disorder but is thriving today thanks to a CIRM-funded clinical trial at UC San Francisco. “This is beyond just a few words and sentences but we will give it a shot. We are living happily today seeing Ronnie explore the world day by day, and this is only because of what CIRM does every day and what Stem cell research has done to humanity. Researchers and scientists come up with innovative ideas almost every day around the globe but unless those ideas are funded or brought to implementation in any manner, they are just in the minds of those researchers and would never be useful for humanity in any manner. CIRM has been that source to bring those ideas to the table, provide facilities and mechanisms to get those actually implemented which eventually makes babies like Ronnie survive and see the world. That’s the impact CIRM has. We have witnessed and heard several good arguments back in India in several forums which could make difference in the world in different sectors of lives but those ideas never come to light because of the lack of organizations like CIRM, lack of interest from people running the government. An organization like CIRM and the interest of the government to fund them with an interest in science and technology actually changes the lives of people when some of those ideas come to see the light of real implementation. 

What are your biggest hopes for the future at UC Davis?

Jan Nolta, PhD: “The future of stem cell and gene therapy research is very bright at UC Davis, thanks to CIRM and our outstanding leadership. We currently have 48 clinical trials ongoing in this field, with over 20 in the pipeline, and are developing a new education and technology complex, Aggie Square, next to the Institute for Regenerative Cures, where our program is housed. We are committed to our very diverse patient population throughout the Sacramento region and Northern California, and to expanding and increasing the number of novel therapies that can be brought to all patients who need them.”

What are your biggest hopes for the future at Cedars-Sinai?

Clive Svendsen, PhD: “That young investigators will get CIRM or NIH funding and be leaders in the regenerative medicine field.”

What do you hope is the future for stem cell research?

Pawash Priyank and Upasana Thakur: “We always have felt good about stem cell therapy. For us, a stem cell has transformed our lives completely. The correction of sequencing in the DNA taken out of Ronnie and injecting back in him has given him life. It has given him the immune system to fight infections. Seeing him grow without fear of doing anything, or going anywhere gives us so much happiness every hour. That’s the impact of stem cell research. With right minds continuing to research further in stem cell therapy bounded by certain good processes & laws around (so that misuse of the therapy couldn’t be done) will certainly change the way treatments are done for certain incurable diseases. I certainly see a bright future for stem cell research.”

On a personal note what is the moment that touched you the most in this journey.

Jan Nolta, PhD: “Each day a new patient or their story touches my heart. They are our inspiration for working hard to bring new options to their care through cell and gene therapy.”

Clive Svendsen, PhD: “When I realized we would get the funding to try and treat ALS with stem cells”

How important is it to raise awareness about stem cell research and to educate the next generation about it?

Pawash Priyank and Upasana Thakur: “Implementing stem cell therapy as a curriculum in the educational systems right from the beginning of middle school and higher could prevent false propaganda of it through social media. Awareness among people with accurate articles right from the beginning of their education is really important. This will also encourage the new generation to choose this as a subject in their higher studies and contribute towards more research to bring more solutions for a variety of diseases popping up every day.”

Building a better brain (model) in the lab

Leica Picture of a brain organoid: courtesy National Institute of Allergy and Infectious Diseases, NIH

One of the biggest problems with trying to understand what is happening in a disease that affects the brain is that it’s really difficult to see what is going on inside someone’s head. People tend to object to you trying to open their noggin while they are still using it.

New technologies can help, devices such as MRI’s – which chart activity and function by measuring blood flow – or brain scans using electroencephalograms (EEGs), which measure activity by tracking electrical signaling and brain waves. But these are still limited in what they can tell us.

Enter brain organoids. These are three dimensional models made from clusters of human stem cells grown in the lab. They aren’t “brains in a dish” – they can’t function or think independently – but they can help us develop a deeper understanding of how the brain works and even why it doesn’t always work as well as we’d like.

Now researchers at UCLA’s Broad Center of Regenerative Medicine have created brain organoids that demonstrate brain wave activity similar to that found in humans, and even brain waves found in particular neurological disease.

The team – with CIRM funding – took skin tissue from healthy individuals and, using the iPSC method – which enables you to turn these cells into any other kind of cell in the body – they created brain organoids. They then studied both the physical structure of the organoids by examining them under a microscope, and how they were functioning by using a probe to measure brain wave activity.

In a news release Dr. Ranmal Samarasinghe, the first author of the study in the journal Nature Neuroscience, says they wanted to do this double test for a very good reason: “With many neurological diseases, you can have terrible symptoms but the brain physically looks fine. So, to be able to seek answers to questions about these diseases, it’s very important that with organoids we can model not just the structure of the brain but the function as well.”

Next, they took skin cells from people with a condition called Rhett syndrome. This is a rare genetic disorder that affects mostly girls and strikes in the first 18 months of life, having a severe impact on the individual’s ability to speak, walk, eat or even breathe easily. When the researchers created brain organoids with these cells the structure of the organoids looked similar to the non-Rhett syndrome ones, but the brain wave activity was very different. The Rhett syndrome organoids showed very erratic, disorganized brain waves.

When the team tested an experimental medication called Pifithrin-alpha on the Rhett organoids, the brain waves became less erratic and more like the brain waves from the normal organoids.

“This is one of the first tangible examples of drug testing in action in a brain organoid,” said Samarasinghe. “We hope it serves as a stepping stone toward a better understanding of human brain biology and brain disease.”

Paving the way for a treatment for dementia

What happens in a stroke

When someone has a stroke, the blood flow to the brain is blocked. This kills some nerve cells and injures others. The damaged nerve cells are unable to communicate with other cells, which often results in people having impaired speech or movement.

While ischemic and hemorrhagic strokes affect large blood vessels and usually produce recognizable symptoms there’s another kind of stroke that is virtually silent. A ‘white’ stroke occurs in blood vessels so tiny that the impact may not be noticed. But over time that damage can accumulate and lead to a form of dementia and even speed up the progression of Alzheimer’s disease.

Now Dr. Tom Carmichael and his team at the David Geffen School of Medicine at UCLA have developed a potential treatment for this, using stem cells that may help repair the damage caused by a white stroke. This was part of a CIRM-funded study (DISC2-12169 – $250,000).

Instead of trying to directly repair the damaged neurons, the brain nerve cells affected by a stroke, they are creating support cells called astrocytes, to help stimulate the body’s own repair mechanisms.

In a news release, Dr. Irene Llorente, the study’s first author, says these astrocytes play an important role in the brain.

“These cells accomplish many tasks in repairing the brain. We wanted to replace the cells that we knew were lost, but along the way, we learned that these astrocytes also help in other ways.”

The researchers took skin tissue and, using the iPSC method (which enables researchers to turn cells into any other kind of cell in the body) turned it into astrocytes. They then boosted the ability of these astrocytes to produce chemical signals that can stimulate healing among the cells damaged by the stroke.

These astrocytes were then not only able to help repair some of the damaged neurons, enabling them to once again communicate with other neurons, but they also helped another kind of brain cell called oligodendrocyte progenitor cells or OPCs. These cells help make a protective sheath around axons, which transmit electrical signals between brain cells. The new astrocytes stimulated the OPCs into repairing the protective sheath around the axons.

Mice who had these astrocytes implanted in them showed improved memory and motor skills within four months of the treatment.  

And now the team have taken this approach one step further. They have developed a method of growing these astrocytes in large amounts, at very high quality, in a relatively short time. The importance of that is it means they can produce the number of cells needed to treat a person.

“We can produce the astrocytes in 35 days,” Llorente says. “This process allows rapid, efficient, reliable and clinically viable production of our therapeutic product.”

The next step is to chat with the Food and Drug Administration (FDA) to see what else they’ll need to do to show they are ready for a clinical trial.

The study is published in the journal Stem Cell Research.

Learning life lessons in the lab

Rohan Upadhyay, CIRM SPARK student 2021

One of the most amazing parts of an amazing job is getting to know the students who take part in CIRM’s SPARK (Summer Program to Accelerate Regenerative Medicine Knowledge) program. It’s an internship giving high school students, that reflect the diversity of California, a chance to work in a world-class stem cell research facility.

This year because of the pandemic I didn’t get a chance to meet them in person but reading the blogs they wrote about their experiences I feel as if I know them anyway.

The blogs were fun, creative, engaging and dealt with many issues, as well as stem cell and gene therapy research.

A common theme was how hard the students, many of whom knew little about stem cells before they started, had to work just to understand all the scientific jargon.

Areana Ramirez, who did her internship at UC Davis summed it up nicely when she wrote:

“Despite the struggles of taking over an hour to read a scientific article and researching what every other word meant, it was rewarding to know that all of the strain I had put on my brain was going toward a larger understanding of what it means to help others. I may not know everything about osteogenic differentiation or the polyamine pathway, but I do know the adversities that patients with Snyder-Robinson are facing and the work that is being done to help them. I do know how hard each one of our mentors are working to find new cures and are coming up with innovating ideas that will only help humankind.”

Lauren Ginn at City of Hope had the same experience, but said it taught her a valuable lesson:

“Make no mistake, searching for answers through research can sometimes feel like shooting arrows at a bulls-eye out of sight. Nonetheless, what CIRM SPARK has taught me is the potential for exploration that lies in the unknown. This internship showed me that there is so much more to science than the facts printed in textbooks.”

Rohan Upadhyay at UC Davis discovered that even when something doesn’t work out, you can still learn a lot:

“I asked my mentor (Gerhard Bauer) about what he thought had occurred. But unlike the textbooks there was no obvious answer. My mentor and I could only speculate what had occurred. It was at this point that I realized the true nature of research: every research project leads to more questions that need to be answered. As a result there is no endpoint to research. Instead there are only new beginnings.”

Melanie Nguyen, also at UC Davis, wrote her blog as a poem. But she saved the best part for the prose at the end:

“Like a hematopoietic stem cell, I have learned that I am able to pursue my different interests, to be multi-potential. One can indulge in the joys of biology while simultaneously live out their dreams of being an amateur poet. I choose it all. Similarly, a bone marrow stem cell can become whatever it may please—red, white, platelet. It’s ability to divide and differentiate is the source of its ingenuity. I view myself in the same light. Whether I can influence others with research, words, or stories, I know that with each route I will be able to make change in personalized ways.”

For Lizbeth Bonilla, at Stanford, her experiences transcended the personal and took on an even bigger significance:

“As a first-generation Mexican American, my family was thrilled about this internship and opportunity especially knowing it came from a prestigious institution. Unfortunately there is very little to no representation in our community in regards to the S.T.E.M. field. Our dreams of education and prosperity for the future have to be compromised because of the lack of support and resources. To maintain pride in our culture, we focus on work ethics and family, hoping it will be the next generations’ time to bring successful opportunities home. However, while this is a hope widely shared the effort to have it realized is often limited to men. A Latina woman’s success and interest in education are still celebrated, but not expected. As a first-generation Latina, I want to prove that I can have a career and hopefully contribute to raising the next leading generation, not with the hope that dreams are possible but to be living proof that they are.”

Reading the blogs it was sometimes easy to forget these are 16 and 17 year old students. They write with creativity, humor, thoughtfulness and maturity. They learned a lot about stem cell research over the summer. But I think they also learned a lot more about who they are as individuals and what they can achieve.

City of Hope scientists use stem cells to develop ‘mini-brains’ to study Alzheimer’s and to test drugs in development

Alzheimer’s is a progressive disease that destroys memory and other important mental functions. According to the non-profit HFC, co-founded by CIRM Board member Lauren Miller Rogen and her husband Seth Rogen, more than 5 million Americans are living with Alzheimer’s. It is the 6th leading cause of death in the U.S and it is estimated that by 2050 as many as 16 million Americans will have the disease. Alzheimer’s is the only cause of death among the top 10 in the U.S. without a way to prevent, cure, or even slow its progression, which is it is crucial to better understand the disease and to develop and test potential treatments.

It is precisely for this reason that researchers led by Yanhong Shi, Ph.D. at City of Hope have developed a ‘mini-brain’ model using stem cells in order to study Alzheimer’s and to test drugs in development.

The team was able to model sporadic Alzheimer’s, the most common form of the disease, by using human induced pluripotent stem cells (iPSCs), a kind of stem cell that can be created from skin or blood cells of people through reprogramming and has the ability to turn into virtually any other kind of cell. The researchers used these iPSCs to create ‘mini-brains’, also known as brain organoids, which are 3D models that can be used to analyze certain features of the human brain. Although they are far from perfect replicas, they can be used to study physical structure and other characteristics. 

The scientists exposed the ‘mini-brains’ to serum that mimics age-associated blood-brain barrier (BBB) breakdown. The BBB is a protective barrier that surrounds the brain and its breakdown has been associated with Alzheimer’s and other age-related neurodegenerative diseases . After exposure, the team tested the ‘mini-brains’ for various Alzheimer’s biomarkers. These markers included elevated levels of proteins known as amyloid and tau that are associated with the disease and synaptic breaks linked to cognitive decline.

Research using brain organoids has shown that exposure to serum from blood could induce multiple Alzheimer’s symptoms. This suggests that combination therapies targeting multiple areas would be more effective than single-target therapies currently in development.

The team found that attempting a single therapy, such as inhibiting only amyloid or tau proteins, did not reduce the levels of tau or amyloid, respectively. These findings suggest that amyloid and tau likely cause disease progression independently. Furthermore, exposure to serum from blood, which mimics BBB breakdown, could cause breaks in synaptic connections that help brains remember things and function properly.

Image Description: Yanhong Shi, Ph.D.

In a press release from the Associated Press, Dr. Shi elaborated on the importance of their model for studying Alzheimer’s.

“Drug development for Alzheimer’s disease has run into challenges due to incomplete understanding of the disease’s pathological mechanisms. Preclinical research in this arena predominantly uses animal models, but there is a huge difference between humans and animals such as rodents, especially when it comes to brain architecture. We, at City of Hope, have created a miniature brain model that uses human stem cell technology to study Alzheimer’s disease and, hopefully, to help find treatments for this devastating illness.”

The full results of this study were published in Advance Science.

Dr. Shi has previously worked on several CIRM-funded research projects, such as looking at a potential link between COVID-19 and a gene for Alzheimer’s as well as the development of a therapy for Canavan disease.

Scientists use stem cell ‘mini-brains’ to better understand signs of frontotemporal dementia

Dementia is a general term that describes a set of diseases that impair the ability to remember, think, or make decisions that interfere with doing everyday activities. According to the World Health Organization (WHO), around 50 million people worldwide have dementia with nearly 10 million new cases every year. Although it primarily affects older people it is not a normal part of aging. As our population ages its critical to better understand why this occurs.

Frontotemporal dementia is a rare form of dementia where people start to show signs between the ages of 40 and 60. It affects the front and side (temporal) areas of the brain, hence the name. It leads to behavior changes and difficulty with speaking and thinking. This form of the disease is caused by a genetic mutation called tau, which is known to be associated with Alzheimer’s disease and other dementias.

A CIRM supported study using induced pluripotent stem cells (iPSCs) led by Kathryn Bowles, Ph.D. and conducted by a team of researchers at Mount Sinai were able to recreate much of the damage seen in a widely studied form of the frontotemporal dementia by growing special types of ‘mini-brains’, also known as cerebral organoids.

iPSCs are a kind of stem cell that can be created from skin or blood cells through reprogramming and have the ability to turn into virtually any other kind of cell. The team used iPSCs to create thousands of tiny, 3D ‘mini-brains’, which mimic the early growth and development of the brain.

The researchers examined the growth and development of these ‘mini-brains’ using stem cells derived from three patients, all of whom carried a mutation in tau. They then compared their results with those observed in “normal” mini-brains which were derived from patient stem cells in which the disease-causing mutation was genetically corrected.

After six months, signs of neurodegeneration were seen in the patient ‘mini-brains’. The patient-derived ‘mini-brains’ had fewer excitatory neurons compared to the “normal” ones which demonstrates that the tau mutation was sufficient to cause higher levels of cell death of this specific class of neurons. Additionally, the patient-derived ‘mini-brains’ also had higher levels of harmful versions of tau protein and elevated levels of inflammation.

In a news release from Mount Sinai, Dr. Bowles elaborated on the results of this study.

“Our results suggest that the V337M mutant tau sets off a vicious cycle in the brain that puts excitatory neurons under great stress. It hastens the production of new proteins needed for maturation but prevents disposal of the proteins that are being replaced.”

The full results of this study were published in Cell.

UCSD researchers use stem cell model to better understand pregnancy complication

A team of UC San Diego researchers recently published novel preeclampsia models to aid in understanding this pregnancy complication that occurs in one of 25 U.S. pregnancies. Researchers include (left to right): Ojeni Touma, Mariko Horii, Robert Morey and Tony Bui. Credit: UC San Diego

Pregnant women often tread uncertain waters in regards to their health and well-being as well as that of their babies. Many conditions can arise and one of these is preeclampsia, a type of pregnancy complication that occurs in approximately one in 25 pregnancies in the United States according to the Center for Disease Control (CDC). It occurs when expecting mothers develop high blood pressure, typically after 20 weeks of pregnancy, and that in turn reduces the blood supply to the baby. This can lead to serious, even fatal, complications for both the mother and baby.

A CIRM supported study using induced pluripotent stem cells (iPSCs), a kind of stem cell that can turn into virtually any cell type, was able to create a “disease in a dish” model in order to better understand preeclampsia.

Credit: UC San Diego

For this study, Mariko Horii, M.D., and her team of researchers at the UC San Diego School of Medicine obtained cells from the placenta of babies born under preeclampsia conditions. These cells were then “reprogrammed” into a stem cell-like state, otherwise known as iPSCs. The iPSCs were then turned into cells resembling placental cells in early pregnancy. This enabled the team to create the preeclampsia “disease in the dish” model. Using this model, they were then able to study the processes that cause, result from, or are otherwise associated with preeclampsia.

The findings revealed that cellular defects observed are related to an abnormal response in the environment in the womb. Specifically, they found that preeclampsia was associated with a low-oxygen environment in the uterus. The researchers used a computer modeling system at UC San Diego known as Comet to detail the differences between normal and preeclampsia placental tissue.

Horii and her team hope that these findings not only shed more light on the environment in the womb observed in preeclampsia, but also provided insight for future development of diagnostic tools and identification of potential medications. Furthermore, they hope that their iPSC disease model can be used to study other placenta-associated pregnancy disorders such as fetal growth restriction, miscarriage, and preterm birth.

The team’s next steps are to develop a 3D model to better study the relationship between environment and development of placental disease.

In a news release from UC San Diego, Horri elaborates more on these future goals.

“Currently, model systems are in two-dimensional cultures with single-cell types, which are hard to study as the placenta consists of maternal and fetal cells with multiple cell types, such as placental cells (fetal origin), maternal immune cells and maternal endometrial cells. Combining these cell types together into a three-dimensional structure will lead to a better understanding of the more complex interactions and cell-to-cell signaling, which can then be applied to the disease setting to further understand pathophysiology.”

The full study was published in Scientific Reports.

Stem cell treatment improves motor function in monkeys modeling Parkinson’s Disease

Neurodegenerative diseases impact millions of people worldwide with the risk of being affected by one of these diseases increasing as you get older. For many of these diseases, there are very few treatments available to patients. As life expectancy increases and the population continues to age, it is crucial to try and find treatments that can potentially slow the progression of these diseases or cure them entirely. This is one of the reasons why CIRM has committed directing around $1.5 billion in funding over the next few years to research related to neurological disorders.

One of the most common neurodegenerative diseases is Parkinson’s Disease (PD), a movement disorder that affects one million people in the U.S alone and leads to shaking, stiffness, insomnia, fatigue, and problems with walking, balance, and coordination.  It is caused by the breakdown and death of dopaminergic neurons, special nerve cells in the brain responsible for the production of dopamine, a chemical messenger that is crucial for normal brain activity.

A recent study published in Nature Medicine has shown improved motor function and growth of neurons over a two year period in monkeys modeling PD. The study was conducted by Su-Chun Zhang, M.D., Ph.D. and his team at the University of Wisconsin using induced pluripotent stem cells (iPSCs), a kind of stem cell that can become virtually any type of cell that can be made from skin cells. The hope is that these results can pave the way for starting human clinical trials.

In order to replicate PD in humans, the team injected 10 adult monkeys with a neurotoxin that produces PD like symptoms. As a result of this, all 10 monkeys developed slow movements, imbalances, tremors, and impaired coordination in the hand on the opposite side of the injection. Additionally, scans revealed that on the injected side, monkeys lost most brain activity involving dopamine in two key brain areas. The team then waited three years after injecting the neurotoxin before administering the therapy, during which time the monkeys’ symptoms persisted.

To generate iPSC lines, the team obtained skin cells from five of the monkeys. The iPSCs were then turned into dopamine neural progenitor cells, which have the ability to create dopamine. These newly created cells were then administered into the brains of the five monkeys, with each monkey receiving a treatment derived from their own skin cells. A sixth iPSC line from a donor monkey was used for the remaining five monkeys to see how the treatment would work if it was not derived from their own skin cells.

The results showed that the monkeys that received the treatment derived from their own skin cells recovered. These animals moved more, moved faster, and were nimbler than before the treatment. They gained the ability to grasp treats, use all four limbs for walking, and climb their cages with ease and increased agility. However, the monkeys that received iPSCs derived from a donor did not recover. Their symptoms remained unchanged or worsened compared to before the treatment.

In a news article, Zhang emphasizes how he and his team are proceeding with a treatment derived from one’s own cells (autologous) vs. one from a donor (allogeneic).

“I initially wanted to do allogeneic transplants in patients because the autologous approach is too expensive. However, after seeing [our] data, I changed my mind. I want to go with the autologous first… because I feel the chance of success is really, really high.”

CIRM is currently funding a human clinical trial ($5.5 million) that is using a gene therapy approach for PD.