Personalized medicine for Parkinson's?

Personalized medicine typically means that the treatment for a person’s disease is based on the genetic basis for the disease in that person.

The problem is that very few diseases are clearly caused by a single gene or even a finite number of genes. If that were the case for a GBA. LRRK2, PARKIN, DJ-1 or other mutation and Parkinson’s disease, then everyone with such a mutation would develop the disease. And that does not happen. Each of the known genes associated with Parkinson’s is a trigger that require other factors – generally unknown factors – for Parkinson’s to develop. While the risk of developing Parkinson’s with such a genetic abnormality is higher than in someone without that abnormality, most people with the abnormality do not develop Parkinson’s.

That means GBA, LRRK2, PARKIN, DJ-1 or other mutations predict but do not cause Parkinson’s. It's human nature to look at the relationship between predictive genetic markers and disease and start to think of them as causal genetic triggers, particularly when frustrated with the impact of available therapies. But the science does not support doing so.

There are reasons why advocating for personalized medicine provides hope. Examples of success include: Herceptin for breast cancer, Zelboraf for melanoma and gene therapies Casgevy and Lyfgenia for sickle cell disease, amongst others. But these are relatively uncommon situations, where a causal gene is identified along with a therapy that addresses that genetic cause.

Another reason for enthusiasm for personalized medicine is the recognition that people with Parkinson’s do not have the same experience. Some get worse quickly while others remain stable for years. Some respond better to dopaminergic therapies. Some are affected more by tremors, others by rigidity. Some develop cognitive problems while others do not. The way the disease presents – what we can see when we look in a mirror or at each other – is referred to scientifically as the phenotype. While phenotypes vary greatly in Parkinson’s, that does not mean that a treatment effective for the disease will not work for different phenotypes.

When I was practicing as a cardiologist, each person coming to clinic would present with a different phenotype. Everyone’s phenotype is slightly or very different from the next person. People look different. People walk differently. People speak differently. People experience happiness from different things. People are different. And people respond to therapies differently.

I remember a patient who had suffered from multiple visits to her local emergency room for shortness of breath, a common risk for someone with heart failure whose body tends to hold on to salt and water, which can accumulate in the lungs and make breathing tough. Her shortness of breath was despite taking a diuretic, which blocks the body from holding on to excess salt and water. The doctor who referred her to my clinic suspected that the problem was caused by the patient not taking her diuretic every day. I could not figure out why she was having this problem until one visit she offhandedly described her ER visits as being as regular as her menstrual cycle. It took a moment for that to register. I admit I would not have asked about the relationship without her comment (this is not taught in the textbooks). I suggested she double the dose of diuretic starting 3 days before her period. It worked!

I suppose it could be argued that this is personalized medicine, but that is not what is meant by doctors advocating for personalized medicine as we did not know what genes she expressed or if she had specific genetic mutations. Her phenotype was very unique; she required novel dosing of her medicine. But the disease was driven by the same problems as all the other people in clinic that day – including the tendency to hold on to salt and water.

Differences in phenotype are the rule in biology rather than the exception and do not mean we need to treat everyone differently (though I do believe a strict one-size fits all is also wrong) as is the doctrine of personalized medicine based on genetic differences. And remember that we do not know the genetic differences causing different phenotypes – or if it is genetics that drive these differences.  

In Parkinson's, our therapies are not good enough. In that setting, I hope all doctors would seek different approaches. One approach is pursuing personalized medicine. Another is to search for different ways to understanding the disease in order to identify therapies that can potentially address a new model. I believe in this approach. And as I've discussed, I believe the laboratory data showing the effects of elevated dopamine and of reducing dopamine synthesis mean that we should pursue dopamine reduction therapy.

What’s to come? In this newsletter, I’ll be providing updates on the progress by Right Brain Bio in preparing for and launching the clinical trial of RB-190 as a treatment for Parkinson’s. Here is the plan based on preliminary conversations with the FDA and several Parkinson’s experts.

The first trial will be run through a small number of centers and enroll a small group of people with mild Parkinson’s disease who are not receiving dopaminergic therapy. These people will be treated first with low doses of RB-190 (or placebo) that will be gradually increased to a level that will reduce dopamine levels. If dopamine deficiency is the cause of disease, doing so will not be possible because further reduction when levels are already low will worsen their clinical condition. This may seem a bit cavalier, but the FDA appeared to agree it made sense, particularly because there is a way to reverse the effects of RB-190 if a person does experience worsening of their Parkinson's. If people tolerate the drug then that will prove that dopamine deficiency is not the cause of Parkinson’s. The trial will continue to observe for evidence of improvement.

This newsletter will provide updates on the progress of this work. And as an example, we are pleased to have received our first investment which allows us to start planning for the manufacture of the drug.

You will recall we asked for feedback on our pitch. This first investment was successful with no pitch at all. Our first investor found us based on appearances on webinars and this newsletter. So please share this newsletter widely (and continue to do so weekly). Perhaps by doing so, it will reach others who have the means and interest to invest enough to allow the trial to begin.