Emerging Targeted Therapeutics for Genetic Subtypes of Parkinsonism

Abstract

In recent years, a precision medicine approach, which customizes medical treatments based on patients' individual profiles and incorporates variability in genes, the environment, and lifestyle, has transformed medical care in numerous medical fields, most notably oncology. Applying a similar approach to Parkinson's disease (PD) may promote the development of disease-modifying agents that could help slow progression or possibly even avert disease development in a subset of at-risk individuals. The urgent need for such trials partially stems from the negative results of clinical trials where interventions treat all PD patients as a single homogenous group. Here, we review the current obstacles towards the development of precision interventions in PD. We also review and discuss the clinical trials that target genetic forms of PD, i.e., GBA-associated and LRRK2-associated PD.

Keywords: GBA; Genetic Parkinson’s disease; LRRK2; SNCA; TORC1 inhibitor; Venglustat; ambroxol; clinical trial; kinase inhibitor; small molecule compounds.

Fig. 1

Genetic architecture of Parkinson’s disease, modified from [4] and [5], showing the continuum of variants of different effect strengths and allele frequencies. The size of the bubbles roughly corresponds to population allele frequencies. Colors symbolize modes of inheritance: dominant (red), recessive (yellow), risk loci (green). The genetic risks for PD can be roughly divided into three groups (dotted areas; see main text for more details). The group of common low-risk genes (lower right corner) includes more than 90 putative independent genome-wide significant signals identified in a GWAS meta-analysis based on more than 13,000 patients and 95,000 controls [6]. Similar to LRRK2 and SNCA, some mutations in VPS13C and GCH1 are likely causal or confer high risk for PD [6]

Fig. 2

World map of SNCA-associated Parkinsonism. A total of 140 cases have been reported in the literature. Circles reflect frequency per region. Data and image were retrieved from the MDSGene Website [21]

Fig. 3

Treatment approaches for GBA-associated PD include the modulation of glycosphingolipid turnover and restoration of enzyme function