Re-purposing Old Drugs for New Treatments for Parkinson's Disease: Can an Asthma Drug Slow Progression of PD
Drug discovery, that is taking a new chemical compound from the laboratory to a FDA approved drug, is a long, expensive and risky process. Most potential drugs fail to reach market; only 1% of compounds leaving the laboratory will reach the market. Many potential drugs fail in the prolonged toxicological studies in animals and in human studies when unforeseen risks emerge.
A clever scheme to speed up the process of developing new treatments is to focus on the over 1,400 FDA-approved drugs and other natural products, thus bypassing the time-consuming toxicity studies in animals and humans and simultaneously avoiding the risks of unexpected toxicity. In this scenario, FDA-approved compounds are screened in test tubes or cell cultures for effects on cellular processes that are thought to underlie development of PD. For example, in PD, alpha-synuclein, a normal cell constituent, is produced in higher quantities and is not cleared from the cell producing toxic accumulation of the protein. Thus, screening for drugs that affect the production, accumulation, aggregation and elimination of alpha-synuclein is an obvious target. Compounds that appeared promising in laboratory testing could then be tried in animal models of PD. Clinical trials could proceed relatively quickly because the drug would have already been proven safe in humans, although for a different purpose. This strategy of testing old drugs for new purposes is termed “repurposing” or “repositioning” drugs.
An exciting example of the potential of repurposing a drug for treatment of PD was reported several months ago in Science, a leading scientific journal. The investigators screened FDA-approved drugs for an effect on the expression of the gene responsible for synthesizing alpha-synuclein. To their surprise they found that beta 2 adrenoreceptor agonists (activators of the adrenergic system) suppressed the synthesis of alpha-synuclein. One of the beta 2 adrenorecptor agonists the scientists studied is a drug well known to many people - the drug in the Albuterol® inhalers used for treating asthma and COPD. Conversely, a drug that blocks the beta 2 adrenoreceptor caused an increase in the synthesis of alpha-synuclein. This drug is also a common drug that many readers will recognize; propranolol or Inderal®, which is used for treating high blood pressure and some tremors.
The next step was to determine if what was observed in cell culture was also true in animals. The investigators tested the effects of the beta 2 activators in mice and found that beta 2 adrenoreceptor agonist reduced the production of alpha-synuclein in the mouse just as it had in cell culture. MPTP is a toxin that selectively kills dopamine containing neurons and is used to create a model of PD in animals. Pretreating mice with beta-adrenoreceptor activator protected the animals dopamine neurons from the toxic effects of MPTP.
These facts would have made a good publication, but the investigators took the story one step further. Was there evidence that the beta-adrenoreceptor activators would affect alpha-synuclein production in humans? The expectation was that if Albuterol® reduced the production of alpha-synuclein, people taking Albuterol® would be less likely to develop PD. Conversely, people on propranolol, which would be expected to increase alpha-synuclein synthesis, would be more likely to develop PD. To address this question, they looked at Norwegian databases that identified Norwegians who developed PD between 2004 and 2011 and also whether they were taking Albuterol® or propranolol. Consistent with the results in cell culture and in mice, there were decreased numbers of PD cases in the Norwegians using Albuterol® and an increased number of cases in the Norwegians taking propranolol.
This is a compelling story, but needs confirmation in other laboratories and in other clinical databases. Further a clinical trial that prospectively looks at the effect of Albuterol® or a similar drug on the progression of PD is required. Side effects of Albuterol® are also a concern; it is not a drug that will be safe in everyone. Also, the optimal dose required to produce a clinical effect in PD is not known. However, the way forward is clear and we will hopefully soon learn if an old asthma drug will be a new treatment for PD.
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John G. Nutt, MD presented at the First World Parkinson Congress in Washington, DC, the Second World Parkinson Congress in Glasgow, Scotland and delivered the James Parkinson Special Lecture at the Fourth World Parkinson Congress in Portland, Oregon where he also Co-chaired the Local Organizing Committee. He is currently a professor of neurology and physiology/pharmacology at the Oregon Health and Science University (OHSU), and Director Emeritus of the OHSU Parkinson Center and of the Portland VA Parkinson's Disease Research, Educational and Clinical Center.
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions or positions of the World Parkinson Coalition®