Precision medicine in Parkinson's disease patients with LRRK2 and GBA risk variants - Let's get even more personal

Abstract

Parkinson's disease (PD) is characterized by motor deficits and a wide variety of non-motor symptoms. The age of onset, rate of disease progression and the precise profile of motor and non-motor symptoms display considerable individual variation. Neuropathologically, the loss of substantia nigra dopaminergic neurons is a key feature of PD. The vast majority of PD patients exhibit alpha-synuclein aggregates in several brain regions, but there is also great variability in the neuropathology between individuals. While the dopamine replacement therapies can reduce motor symptoms, current therapies do not modify the disease progression. Numerous clinical trials using a wide variety of approaches have failed to achieve disease modification. It has been suggested that the heterogeneity of PD is a major contributing factor to the failure of disease modification trials, and that it is unlikely that a single treatment will be effective in all patients. Precision medicine, using drugs designed to target the pathophysiology in a manner that is specific to each individual with PD, has been suggested as a way forward. PD patients can be stratified according to whether they carry one of the risk variants associated with elevated PD risk. In this review we assess current clinical trials targeting two enzymes, leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA), which are encoded by two most common PD risk genes. Because the details of the pathogenic processes coupled to the different LRRK2 and GBA risk variants are not fully understood, we ask if these precision medicine-based intervention strategies will prove "precise" or "personalized" enough to modify the disease process in PD patients. We also consider at what phases of the disease that such strategies might be effective, in light of the genes being primarily associated with the risk of developing disease in the first place, and less clearly linked to the rate of disease progression. Finally, we critically evaluate the notion that therapies targeting LRRK2 and GBA might be relevant to a wider segment of PD patients, beyond those that actually carry risk variants of these genes.

Keywords: Dopamine; GCase; Glucocerebrosidase; Leucine-rich repeat kinase-2; PD drug trials; PD risk variants; Parkinson’s disease; Personalized medicine; Precision medicine.

Fig. 1

Precision medicine in current and future drug trials. a Current precision medicine-based therapies rely on adjusting the hyperactive LRRK2 and hypoactive GBA in PD patients with risk variants of LRRK2 and GBA. b Several poorly understood factors including the putative disease-triggers, genes/environment, the immune system and functional differences among risk variants, may be necessary for developing more efficient and personalized therapies. c It is also possible that idiopathic PD patients with the same imbalances in LRRK2 and GBA as in LRRK2-PD and GBA-PD may benefit from a combinational treatment of both LRRK2 and GBA modulation