The emerging science of precision medicine and pharmacogenomics for Parkinson's disease

Abstract

Current therapies for Parkinson’s disease are problematic because they are symptomatic and have adverse effects. New drugs have failed in clinical trials due to inadequate efficacy. At the core of the problem is trying to make one drug work for all Parkinson’s disease patients, when we know this premise is wrong because (a) Parkinson’s disease is not a single disease, and (b) no two individuals have the same biological make up. Precision medicine is the goal to strive for, but we are only at the beginning stages of building the infrastructure for one of the most complex projects in the history of science, and it will be a long time before Parkinson’s disease reaps the benefits. Pharmacogenomics, a cornerstone of precision medicine, has already proven successful for many conditions, and could also propel drug discovery and improve treatment for Parkinson’s disease. To make progress in pharmacogenomics of Parkinson’s disease, we need to change course from small inconclusive candidate gene studies to large-scale rigorously planned genome-wide studies that capture the nuclear genome and the microbiome. Pharmacogenomics studies must use homogenous subtypes of Parkinson’s disease, or apply brute force of statistical power to overcome heterogeneity which will require large sample sizes achievable only via internet-based methods and electronic databases. Large-scale pharmacogenomics studies, together with biomarker discovery efforts, will yield the knowledge necessary to design clinical trials with precision, to alleviate confounding by disease heterogeneity and inter-individual variability in drug response, two of the major impediments to successful drug discovery and effective treatment.

Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy

“…On the other hand, technological advances applied to PD, the use of potent modeling systems, and big data acquisition from global sources (ie, Google, cell phones, etc.) will likely unravel a wealth of precious data . Overall, we remain highly optimistic and expectant for major advances that will emerge out of the difficulties and uncertainties associated with too much information during a short period of time.…”

Application of Precision Medicine in Neurodegenerative Diseases

“…Although PD displays high clinical and pathological heterogeneity, patients can rely on specific drugs to control a wide range of symptoms, including bradykinesia, rigidity and resting tremor. Most of the drugs utilized for the treatment of PD essentially works by enhancing dopaminergic neurotransmission, among which Levodopa (L-Dopa) is the most effective drug to treat motor symptoms in early and advanced stages of PD ( 8 , 12 , 13 ). Except for L-Dopa (precursor of Dopamine), current therapies can be divided into “dopaminergic” and “non-dopaminergic” drugs ( 14 ).…”

Parkinson's disease therapy with Istradefylline and blood biomarkers of epigenetics

“…18,19 However, several issues associated with A 2A R antagonists/IST remain unclear in PD patients, such as neuronal protection from the pathological evolution of the disease, preventive effects against dyskinesia evolution, and pharmacological actions for up-regulated A 2A R expression, those have not yet been evaluated in any clinical trials. 20,21 In the present study, we examined the effects of the long-term use of IST as an adjunct to L-DOPA (IST-LD) in clinical practice and assessed blood biomarkers of epigenetics, including the A 2A R-p, A 2A R-m, and DNA methylation of the ADORA2A gene in peripheral blood lymphocytes (PBL).…”