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.

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

In honor of World Parkinson’s day (April 11^th), 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.