Parkinson's disease: From human genetics to clinical trials

Abstract

Combining genetic insights into the pathogenesis of Parkinson's disease (PD) with findings from animal and cellular models of this disorder has advanced our understanding of the pathways that lead to the characteristic degeneration of dopaminergic neurons in the brain's nigrostriatal pathway. This has fueled an increase in candidate compounds designed to modulate these pathways and to alter the processes underlying neuronal death in this disorder. Using mitochondrial quality control and the macroautophagy/lysosomal pathways as examples, we discuss the pipeline from a comprehensive genetic architecture for PD through to clinical trials for drugs targeting pathways linked to neurodegeneration in PD. We also identify opportunities and pitfalls on the road to a clinically effective disease-modifying treatment for this disease.

Fig. 1. The genetic architecture of PD

Mendelian genes are shown in red, strong risk factors are shown in blue, and weak risk factors identified by GWAS are shown in green. Examples of Mendelian genes include SNCA, PARK2, and PINK1, with GBA variants being a standout example of a strong risk factor. GAK and HLA-DRB5 are examples of low-risk, high-frequency gene variants recently identified by GWAS. Some genes, such as LRRK2, are found in several or all of the categories.

Fig. 2. Examples of aberrant cellular pathways in PD

(A) Shown is the involvement of Parkin, Pink1, and FBXO7 in the regulation of mitophagy. Damaged mitochondria (red) are identified and tagged for degradation through the process of mitophagy, which is disrupted in individuals carrying mutations in these proteins. In the absence of functional mitophagy, cellular damage and eventual cell death results from the accumulation of dysfunctional mitochondria. (B) Potential involvement of Mendelian loci and genetic risk factors for PD in the autophagy/lysosomal pathway. Mutations and genetic risk variants in genes such as those encoding LRRK2, VPS35, GBA, RAB7L1, and GAK may result in disruption of protein degradation pathways and accumulation of misfolded or aggregated proteins, leading to cytotoxicity and neuronal cell death.

Fig. 3. The drug pipeline in PD

(A) The number of interventional phase I trials (black) for new molecular entities that are disease-modifying or that alleviate symptoms shows a trend upwards over the last 10 years. The number of phase II (red, mean = 12.9 SD = 2.8) and phase III (blue, mean = 11.58 SD = 5.0) trials has remained stable. (B) The number of new molecular entities entering interventional PD trials each year. Phase I (mean = 4.7 SD = 2.8), phase II (mean = 9.6 SD = 1.6), phase III (mean = 4.7 SD = 2.2). (C) Ten-year average for new molecular entities in phase I, phase II and phase III trials. Data are from www.clinicaltrials.gov. Interventional (symptom or disease-modifying) PD clinical trials using a drug, biologic, or gene therapy were selected; PET molecular imaging studies were excluded.

Fig. 4. Measuring efficacy of disease-modifying strategies in PD

(A) Assessing disease modification versus symptomatic benefit using compound washout. Black line represents placebo, blue line represents a disease-modifying therapeutic, dashed light blue line represents a symptomatic therapeutic such as L-DOPA, red arrow represents a change in UPDRS. (B) Using time to initiation of symptomatic treatment as an end point in PD clinical trials. Black line represents placebo, blue line represents a disease-modifying therapeutic, red arrow represents the change in time required for the initiation of symptomatic treatment.