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.

Polygenic Risk Scores Contribute to Personalized Medicine of Parkinson’s Disease

“…The apparent PD heterogeneity necessitates the personalized medicine concept, which postulates that various genetic and pathophysiological contributions may underlie distinct subgroups. This, in turn, has encouraged the search for targeted treatments, for example for subgroups of patients who have particular genetic mutations [6]. Beyond Mendelian mutations, i.e., rare variants with strong effects, efforts to quantify the joint effect of dozens of common genetic variants, and to develop predictive tools measuring this cumulative genetic load within each individual, are hoped to facilitate population stratification and identification of high-risk individuals.…”

Prodromal Parkinson's disease: hype or hope for disease-modification trials?

“…A second major challenge to address relates to concerns that the ‘one drug fits all’ approach that has been used in all disease-modification trials in PD so far, ignores patient heterogeneity in terms of underlying molecular pathologies and may thus obscure the disease subtype-specific efficacy of an intervention [ 94 ]. Future trials in prodromal PD will have to deal with this, for example, by selecting target populations with specific molecular pathologies for corresponding target-specific interventions—like the use of kinase-inhibitors in LRRK2 mutation carriers [ 50 ]. In order to roll out such ‘personalized’ strategies beyond prodromal monogenic PD subtypes, there is still a largely unmet need for a biomarker-supported platform to identify pathogenetic disease subtypes.…”

“…Finally, asymptomatic carriers of mutations in monogenic PD genes, e.g. LRRK2, or in risk genes like glucocerebrosidase ( GBA ), identified as first-degree relatives of PD patients, also represent potential prodromal target populations for disease-modification trials [ 19 , 49 , 50 ]. Such cohorts are attractive, since they have a defined underlying molecular disease mechanism that can be targeted with specific (‘personalized’) interventions.…”

Assessing the role of polygenic background on the penetrance of monogenic forms in Parkinson’s disease

“…The probability that any given pathogenic variant carrier crosses the threshold to develop a disease is influenced by the underlying liability conferred by the polygenic background 32 . Few pharmaceutical companies are conducting clinical trials by recruiting only PD cases with monogenic variants in LRRK2 or GBA into account 33 . Hence, it is imperative to understand the combined effect of PRS and those monogenic risk variants for choosing the trial participants and designing personalized therapeutic strategies.…”