Starting in the 1960s, investigations have reported markedly reduced dopamine levels in the striatum (which is the part of the brain that controls movement). However, these measurements were made on brain tissue turned into a soup-like liquid. That's important because such a soup is a mixture of fluids from inside and outside of cells, and from both dopaminergic and non-dopaminergic cells (with the former being the cells that control movement). It is known from a wide range of laboratory studies that measuring dopamine inside dopaminergic neurons is the most relevant measurement, as this is what determines whether the cell functions normally or not - as well as whether these neurons stay alive or die. We sought to determine the level of dopamine inside these critical brain cells in people with Parkinson's.

And we figured out how to estimate these levels. Here's how.

We know a few things that the scientists in the 1960s did not know. In addition to the loss of dopamine in the tissue, there is also loss of cells. And inside the cells there are also changes in people with Parkinson's. Cells need to sequester dopamine to prevent it from being metabolized. Much of the toxicity of dopamine is caused by its metabolites. And the way that dopamine is sequestered is by storing it inside little balls called vesicles. Unfortunately, Parkinson's causes loss of vesicles. A simple representation of the calculation process is this: take the total dopamine, scale it by the loss of cells and then scale that result by the loss of vesicles. This provides an estimate of the amount of dopamine inside a dopaminergic neuron, on average, when scaling the result by the loss of cells. And it provides an estimate of the amount of dopamine free inside the neurons - non-sequestered, when scaling the result by the loss of vesicles.

We learned that the amount of dopamine inside the cytosol of dopaminergic neurons - which is what determines whether the levels are toxic to these nerve cells - is markedly elevated in Parkinson's disease. And we published those results in the peer-reviewed journal, The Journal of Parkinson's Disease.

Once we learned that the dopaminergic neurons experience Parkinson's as a disease of dopamine excess, we knew we needed to find a way to reduce the dopamine levels in order to learn whether this finding represented a cause of disease or was merely associated with the disease, and in that case, only be an interesting finding and not relevant to treating the disease.

We looked for an existing drug that lowers dopamine with the plan to then test it in lab models of the disease. But we got lucky and found an ideal drug (which we call RB-190). Why is this ideal? First, the drug was already FDA-approved for a different disease (at high doses it prevents complications of a rare cancer) and therefore could be studied in clinical trials more quickly than a brand new drug. Second, the drug has been used in multiple studies using lab models of Parkinson's already. The proof was already there.

RB-190 was studied in eight preclinical models of Parkinson's with those data contained in 9 peer-reviewed publications. And in each one, whatever was being measured was demonstrated to be improved. The drug reverses disease pathology in 8 out of 8 models, or 9 out of 9 publications, including tests on mice, rats and cell cultures (mouse cells, dopaminergic cells and human iPS cells).

A logical set of questions should be asked as soon as using a drug to reduce dopamine levels is proposed. Since dopaminergic therapies can help symptoms, albeit temporarily, wouldn't a dopamine reducing drug have the risk of worsening symptoms? And with such a risk, how would a person with Parkinson's be expected to tolerate the drug? These (and related) concerns were discussed with the FDA during a pre-IND meeting (sorry for regulatory jargon) and the data presented appeared satisfactory to the FDA, as they agreed that the next step would be a Phase 2 clinical trial.

One warning. Because this drug is sold for a different disease, it could be tempting to have your doctor prescribe it to see if it helps. I believe that would be a bad idea, as the only dose available is probably much too large to be safe for someone with Parkinson's. So please do not conduct your own experiment.