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.

 

 

 

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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.

Approach that inspires DREADD could create new way to treat Parkinson’s disease

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Dopamine producing brain nerve cells, made from embryonic stem cells

Imagine having a treatment for Parkinson’s that acts like a light switch, enabling you to turn it on or off depending on your needs. Well, that’s what researchers at the University of Wisconsin-Madison have come up with. And if it works, it might help change the way we treat many other diseases.

For years researchers have been trying to come up with a way of replacing the dopamine-producing brain nerve cells, or neurons, that are attacked and destroyed by Parkinson’s. Those cells regulate movement and as they are destroyed they diminish a person’s ability to control their body, their movement and even their emotions.

Attempts to transplant dopamine-producing cells into the brains of people with Parkinson’s disease have met with mixed results. In some cases the transplanted cells have worked. In many cases the cells don’t make enough dopamine to control movement. In about 10 percent of cases the cells make too much dopamine, causing uncontrolled movements called graft-induced dyskinesia.

But now the researchers at UW Madison have found a new approach that might change that. Using the gene-editing tool CRISPR (you can read about that here) they reprogrammed embryonic stem cells to become two different types of neurons containing a kind of genetic switch called a DREADD, which stands for designer receptor exclusively activated by designer drug. When they gave mice the designer drug they created to activate DREADD, one group of cells boosted production of dopamine, the other group shut down its dopamine production.

In a news release about the study, which is published in the journal Cell Stem Cell, lead author Su-Chun Zhang says this kind of control is essential in developing safe, effective therapies:

“If we are going to use cell therapy, we need to know what the transplanted cell will do. If its activity is not right, we may want to activate it, or we may need to slow or stop it.”

Zhang says the cells developed using this approach have another big advantage:

“We can turn them on or off, up or down, using a designer drug that can only act on cells that express the designer receptor. The drug does not affect any host cell because they don’t have that specialized receptor. It’s a very clean system.”

Tests in mice showed that the cells, and the designer drug, worked as the researchers hoped they would with some cells producing more dopamine, and others halting production.

It’s an encouraging start but a lot more work needs to be done to make sure the the genetically engineered stem cells, and the designer drug, are safe and that they can get the cells to go to the part of the brain that needs increased dopamine production.

As Zhang says, having a method of remotely controlling the action of transplanted cells, one that is reversible, could create a whole new way of treating diseases.

“This is the first proof of principle, using Parkinson’s disease as the model, but it may apply to many other diseases, and not just neurological diseases.”

Bringing down the gatekeeper for a stem cell-based Parkinson’s cure

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University of Buffalo researchers converted these dopamine neurons directly from human skin cells. Image shows a protein found only in neurons (red) and an enzyme that synthesizes dopamine (green). Cell DNA is labeled in blue.

On the surface, a stem cell-based cure for Parkinson’s disease seems pretty straight-forward. This age-related neurodegenerative disorder, which leads to progressively worsening tremors, slowness of movement and muscle rigidity, is caused by the death of a specific type of nerve cell, or neuron, that produces the chemical dopamine in a specific region of the brain. So it would seem that simply transplanting stem cell-derived dopamine-producing neurons (DA neurons) in the brains of Parkinson’s patients to replace the lost cells would restore dopamine levels and alleviate Parkinson’s symptoms.

Easier said than done
Well, it hasn’t turned out to be that easy. After initial promising results using fetal brain stem cell transplants in the 80’s and 90’s, larger clinical trials showed no significant benefit and even led to a worsening of symptoms in some patients. One potential issue with those early trials could have been variable cell composition of the fetal cell-based therapy. On top of that, the availability of fetal tissue is limited and the quantities of transplantable cells obtained from these samples are very low.

More recently, researchers have been busy at generating more pure populations of DA neurons from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs). Great progress has been made so far, but the field is still hampered by not being able to make enough DA neurons from hESCs and iPSCs in a timely manner.

Cutting out the pluripotent “middle man”
This week a research team at the University of Buffalo reported in Nature Communications about a much more efficient method for producing DA neurons. It’s a finding that could provide a strong push towards stem cell-based therapy development for Parkinson’s disease.

The team bypassed the need to start with hESCs or iPSCs and instead converted skin cells directly into DA neurons. A thorough analysis of the cells confirmed that they were functional and matched that characteristics of the specific dopamine neurons that are lost in Parkinson’s.

This direct reprogramming of skin cells into DA neurons as well as other cells is a technique pioneered by several independent researchers including some of our own grantees. This method is thought to have a few advantages over the specialization of immature hESCs or iPSCs into tissue-specific cells. Not only is the direct reprogramming process faster it also doesn’t require cell division so there’s less concern about the introduction of DNA mutations and the potential of tumor formation. Another plus for direct reprogramming is the possibility of inducing the direct conversion of one cell type into another inside the body rather than relying on the manipulation of hESCs and iPSCs in the lab. Still, despite these advantages the efficiency of direct reprogramming is still very low. That’s where the University of Buffalo team comes into the picture.

Bringing down the gatekeeper
The researchers led by physiology and biophysics professor Jian Feng, made a few key modifications to increase the efficiency of the current skin cell to DA neuron direct reprogramming methods. They first reduced the level of a protein call p53. This protein has several nicknames like “guardian of our genes” and “tumor suppressor” because it plays critical roles in controlling cell division and DNA repair and, in turn, helps keep a clamp on cell growth.

Reducing the presence of p53 during the direct reprogramming process led to a much more efficient conversion of skin cells to DA neurons. And because the conversion from a skin cell to a neuron happens quickly – just a couple days – timing the introduction of cell nutrients specific to neurons had to be carefully watched. Together, these tweaks improved upon previous studies as Feng mentioned in a University of Buffalo press release:

“The best previous method could take two weeks to produce 5 percent dopamine neurons. With ours, we got 60 percent dopamine neurons in ten days.”

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Jian Feng, PhD, professor of physiology and biophysics, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo

IMHO (In my humble opinion)
I imagine there’s a lot more work ahead to get this method of deriving DA neurons from skin ready for the clinic. This reprogramming technique relied on the introduction of neuron-specific genes into the skin cells using a deactivated virus as the means of delivery. Even though the virus is inactive, its viral DNA randomly inserts into the cells’ chromosomes which can turn on genes that cause cancer. Therefore, a non-viral version of this method would need to be developed for clinical use.

Also, as mentioned earlier, since p53 inhibits tumors by suppressing uncontrolled cell division, it would be important to make sure that a reduction of p53 didn’t lead to any long-term negative consequences, like the transplantation of potentially cancerous cells into the patient.

Still, this dramatic increase in efficiency for making functional DA neurons and the identification of p53 as a key control point for direct reprogramming are very exciting developments for a disease field that is committed to finding cures for its patients.

Related links:

From the Stem Cellar archives: blogs about direct reprogramming
Video: CIRM Grantee Marius Wernig discusses direct reprogramming
Video: Thirty second elevator pitch describing direct reprogramming