Documentary: "The Beginning of the End of Parkinson's Disease"

FULL TRANSCRIPT:

NARRATOR:

Ever since Dr. James Parkinson described the disorder that now bears his name in the 1817 article An Essay On the Shaking Palsy, men and women across the globe have been fervently searching for a cure for Parkinson’s Disease.

According to the Parkinson’s Disease Foundation, an estimated 7 to 10 million people around the world suffer from Parkinson’s – also called PD – and millions more of their loved ones suffer with them, hoping and waiting for a treatment that can halt the progression of the physical and mental degeneration that characterizes this mysterious disease.

Until recently, the only available treatments focused on minimizing the symptoms of the disorder and improving the patient’s quality of life. Drugs such as Levodopa and other dopamine agonists, which attempt to mimic dopamine’s effect in the brain, have been used with some success in controlling shaking, muscle stiffness, and other motor symptoms in the early stages of PD, but lose their effect over time and cause undesirable side effects, such involuntary muscle movements known as dyskinesia.

No drug, to date, has been able to slow the disease’s progress.

However new research from an international team of scientists led by McLean Hospital’s Molecular Neurobiologist Lab may be the spark of hope for which PD patients have been waiting for nearly 200 years.

According to research unveiled in July 2015, existing malaria drugs may not only be able to minimize the symptoms of PD, but also slow the progress of the disease itself. Although the research is still in its early stages and much more remains to be determined about the efficacy of this treatment in humans, the Molecular Neurobiology Lab at McLean Hospital is hoping to begin clinical trials soon using modified versions of the drugs amodiaquine and chloroquine.

DR KIM:

There are many very powerful and useful drugs that can help Parkinson’s disease, which are mainly dopamine agonists or dopamine precursors which work at the pharmacological tool to enhance the availability of dopamine. However, at present, all currently-available drugs are only symptomatic and there is no drug that can slow down or stop the disease progression. Our approach is to develop novel therapeutics, which can slow down the disease progression.

Based on our molecular and developmental studies, we identified many important protein factors – transcription factors – which are essential for dopamine neurons based on our work and many other people’s work. And, in summary, there are two major pathways important for dopamine neurons and those two pathways are merging on Nurr1 protein, so based on that, we thought Nurr1 is a very potential drug target for Parkinson’s disease. So we generated a high-throughput screening system, and then, because my lab is not big pharma and cannot screen many, many drugs – candidates – we just focused on screening FDA-approved drugs and surprisingly out of 1,000 FDA drugs, we got three hit compounds that later on was shown to activate Nurr1 function.

NARRATOR:

Amodiaquine and Chloroquine were two drugs among 960 compounds and FDA-approved medications that were tested for their ability to boost the activity of the vital protein Nurr1. This special molecule is key in the maintenance of dopamine neurons and in protecting them from the inflammation that leads to their death in cases of PD. Research strongly suggests that decreased Nurr1 activity and/or effectiveness is behind the degeneration of these neurons and is one of the immediate causes of Parkinson’s.

DR KIM:

Nurr1 is a nuclear receptor belonging to a big family of proteins like glucocorticoid receptor or thyroid receptor. In the case of Nurr1, its ligand is not known, so it is one of the orphan nuclear receptors, which means it’s ligand is not identified yet. So Nurr1 is known to be very essential for Parkinson’s disease, largely based on the pioneering work by Professor Thomas Perlmann at the Karolinska Institute and many others’ work pinpointing that Nurr1 is a very crucial protein for dopamine neurons’ health. So based on that, we thought that was a promising drug target.

NARRATOR:

Nurr1 is known as a nuclear receptor – a molecule that senses steroids, hormones, and other regulatory molecules in the brain and facilitates the expression of certain genes in response to them. You might think of this system as an organic dimmer switch. When the receptors and their unique corresponding molecules – called “ligands” – come together in sufficient quantities, they turn the expression of a gene “up” – increasing rate at which those genes are transcribed into vital proteins. When the ligand is missing, the receptor is largely ineffective, and the gene is turned “down.”

The Nurr1 receptor was previously thought to be ligand-independent – or able to turn to turn gene expression up on its own. However, Dr. Kim and his team of scientists have proved that this is not the case.

Instead, an unknown ligand does indeed partner with it to activate the processes that keep the dopamine neurons alive and healthy. While the exact identity of this molecule is unknown, it is strongly suspected to be similar to amodiaquine and chloroquine, because of all 960 compounds tested, only amodiaquine, chloroquine, and to a lesser extent, the anti-inflammatory drug glafenine significantly improved its activity. The common bond between these compounds? An identical chemical scaffold of 4-amino-7-chloroquinoline. This physical structure appears to be the matching piece to the Nurr1 puzzle.

DR KIM:

So previously, x-ray crystallography study of Nurr1 showed that the ligand binding domain of Nurr1 is occupied by bulky amino acids and there is no space for the ligand to enter and bind. So that is why Nurr1 is known to be a ligand-independent nuclear receptor. However, protein structure is very flexible and there are certain cases where the ligand can go to the ligand binding domain and make a change and then make a space for the ligand to bind to the ligand binding domain. Having said that, initially, we didn’t expect that we could find the chemicals that can bind to the ligand binding domain, we just made the high-throughput screening system and got the hit compounds and then we found that those hit compounds all bind to the ligand binding domain. So, simply speaking, we were quite lucky.

NARRATOR:

But just how closely do these puzzle pieces match, and could anti-malaria drugs play a major role in decelerating the progress of Parkinson’s? That’s what the Molecular Neurobiology Lab led by Dr. Kim is about to find out at the McLean Hospital. Previous research by the same team, however, showed significant promise.

DR KIM:

So, based on our mechanisms, we think that in Parkinson’s patients, in the early phase, there are still 30 or 40 percent remaining neurons, but some of them – about half of them or one-quarter of them are not very functional. So we believe that Nurr1 agonists can make them more functional and more active, meaning that there are healthier dopaminargic circuits and then slowing down the disease progress. We found that, interestingly, amodiaquine and chloroquine can enhance Nurr1’s activator function and also repressor function.

In other words, in dopamine neurons, Nurr1 is a very strong activator and activates all necessary proteins for the dopamine neuron. And outside the dopamine neuron, in immune cells or glial cells, Nurr1 is also known to work as a repressor and then it represses the expression of the toxic cytokine expression in the inflammation. So, based on our results, we believe that amodiaquine or chloroquine – agonists of Nurr1 – can help the inactive dopamine nuerons or dying dopamine neurons rejuvenate them and make them more active. As a result, the dopamine neurons can be more healthier and then the disease progress can be slowed down.

NARRATOR:

When tested in the lab, stem cells that were treated with amodiaquine and chloroquine saw an increased expression of dopamine-specific genes and an increase in the creation of tyrosine hydroxylase neurons, which are responsible for catalyzing the conversion of the amino acid L-tyrosine to L-Dopa, a precursor of dopamine. Further testing suggested that Nurr1 was directly responsible for these increases, by means of the drugs. It’s hypothesized, therefore, that amodiaquine and chloroquine could stimulate the expression of the genes that facilitate dopamine production in PD patients.

Further research also indicated that both drugs also increase Nurr1’s protective abilities, which may keep dopamine neurons from dying off and causing the symptoms of Parkinson’s. To create an animal version of PD, rats are commonly given the neurotoxin 6-OHDA, which selectively kills the majority of their dopamine neurons without touching the rest of their brain.

DR KIM:

There are several animal models of Parkinson’s disease and we used one of them. And the model we used here was the 6-hydroxydopamine lesioned rat model. So 6-hydroxydopamine is a neurotoxin and when it is injected to the striatum or dopamine neurons in a stereotexting manner, it selectively kills dopamine neurons and then makes the Parkinson-like symptoms. So then, when we administered these drugs for two weeks and then wait one month or so, then the behavior deficit of these models are recovered. So when 6-OHDA lesioned on one side, animals turn to the lesioned side, ipsilaterally. But when the lesioned side’s dopamine neurons are recovered, the rotation behavior decreased significantly. So that’s how we measure if dopamine function is improved or recovered.

NARRATOR:

Without the benefit of the drugs, the damage done by the neurotoxin was great. However, when given amodiaquine and chloroquine, the rate of neuron death was significantly reduced. A corresponding decrease in pro-inflammatory gene expression in the surrounding protective microglia cells was also observed, suggesting that the drug may significantly decrease the rate of neural death.

All of these victories at the cellular level, however, are largely unimportant to PD patients who are not distressed by molecular dysfunctions, but by practical, everyday disabilities. The measure of any PD treatment will ultimately be the extent to which it alleviates the debilitating symptoms of the disease. To that end, 6-OHDA-lesioned rats – those in which PD has been created by destroying dopamine on one side of the brain only – were tested for motor improvements when given amodiaquine for six weeks.

At the beginning of the trial, all the rats demonstrated significant rotational movement, literally running in circles due to the disability of the lesioned side of the brain. Treatments with L-Dopa, a naturally-occurring form of the traditional medication for PD, helped somewhat, but stimulated the characteristic dyskinesia-like behaviors seen in PD patients using Levidopa. Remarkably, the rats who received amodiaquine, not only saw a significant improvement in motor coordination above and beyond the level achieved by Levidopa, but also demonstrated next to no dyskinesia, leading to the possibility that these anti-malaria drugs may provide significant relief for PD without the debilitating side effects of the current drugs.

NARRATOR:

Taken together, these results from Dr. Kim’s team of scientists represent a significant breakthrough in Parkinson’s research. Next comes the most exciting step – evaluating the drugs’ efficacy in humans. Once this step is complete, the team will then work toward developing new and improved versions of the drug designed to protect the remaining dopamine neurons longer and more efficiently, with the goal of giving Parkinson’s patients a more normal life for a longer period of time.

DR KIM:

We hope to try small-scale clinical trials, and we want to use chloroquine not amodiaquine because amodiaquine is known to be more toxic. So when we use the chloroquine in our clinical trial we expect and hope that there will be a significant improvement, but we don’t know yet.

Amodiaquine and chloroquine are the first hit compounds without any further optimization, so it is expected that their efficacy is not optimal. So that’s why we hope that we can make better drugs. And we were very fortunate that our research was supported by the Michael J. Fox Foundation and we so far generated several hundred new compounds and we are very excited to test these new potential drug candidates.

NARRATOR:

The one drawback of these drugs – however effective they are or may become in the future – is that although they can rejuvenate and protect the ailing neurons that remain, they cannot address the large number of neurons that have already died. Over time, as the normal aging process takes place and more dopamine cells end their life span, the symptoms of Parkinson’s will eventually return, albeit after a much longer period of health.

However, an unexpected side effect of studying the neuro-molecular structures that led to the development of this improved treatment may be the discovery of a potential cure. This cure applies the knowledge gained through studying how and why these new drugs protect dopamine neurons to the development of a personalized cell replacement therapy. This treatment would transform the patient’s own normal skin cells into stem cells that could then be used to grow replacement dopamine neurons to transplant back into the brain. Although such a concept is not new, past efforts have met with mixed results, partially due to the body’s rejection of foreign cells and partially because of the difficulty in ensuring ALL stem cells become dopamine neurons and nothing else. However, the knowledge gained by Dr. Kim’s team may be instrumental in helping scientists be able to use a patient’s own cells for a personalized therapy that can keep Parkinson’s symptoms at bay for decades when used in conjunction with their new drugs.

DR KIM:

As a matter of fact, there are many proof of principle cases showing that cell therapy can work, which was pioneered by Swedish scientists several decades ago. They transplanted dopamine precursor cells, which are collected from fetuses, and grafted them to the Parkinson’s disease patient’s brain. And in some successful cases, Parkinson’s symptoms were almost gone, even after one or two decades.

So because of that, we and other people are also trying cell replacement therapy using stem cells. In particular, if we use the patient-derived stem cells, such as induced pluripotent stem cells, then we can make dopamine neurons – functional dopamine neurons – and then transplant them, which is a so-called “personalized cell therapy.” And we hope that both the drug development program and the stem cell therapy program can complement each other and then will be much better for the Parkinson’s disease patients.

NARRATOR:

As Parkinson’s patients and their families look to the future, there are many challenges on the horizon. The fear of what is to come and the struggles that already are are constant companions. However, thanks to advances such as McLean’s potential new drug treatment and the resulting leaps forward in stem cell research also provide great hope. Is it possible that one day soon, people will look upon Parkinson’s as they look upon diabetes, a common, manageable disorder that was once the source of great horror? Many thank so and believe that a breakthrough is right around the corner.

DR KIM:

There are multiple clinical trials and there are numerous scientists who are focused on developing novel therapeutics for Parkinson’s disease, and Nurr1 is one of those potential drug targets. So based on these, I am very optimistic that we’ll have a breakthrough new treatment for Parkinson’s disease in the very near future.

NARRATOR:

Until then, all eyes remain fixed on McLean hospital and other like-minded laboratories around the world, waiting with great anticipation to see the next new hope for the future.