Studying the rare to understand the common and treat all has been a fruitful strategy in the hunt for disease modifying treatments. Most forms of Parkinson’s (PD) are caused by the complex interplay of genetic and environmental factors, and in only 5-10% of cases can a single gene be identified. Nonetheless, 1 in 5 people with Parkinson’s report having an affected first or second degree relative. Experts in the field of Parkinson’s therapeutics review important genetic discoveries which have been the starting point for a vast amount of knowledge, and are now translating rapidly into the clinical trials of repurposed drugs at different sites across the world: the genes for alpha-synuclein (SNCA), glucocerebrosidase (GBA), and leucine-rich repeat kinase (LRRK2).

Alpha-synuclein, a protein which in Parkinson's undergoes misfolding and aggregation in brain cells, plays a major role in pathogenesis of the condition. Mutations and multiplications in the alpha synuclein or SNCA gene cause the familial variant of the condition, but it is now known that regions of DNA close to and around this particular gene also play an important role in idiopathic Parkinson’s, where the cause is unknown. Four major approaches to tackling alpha-synuclein have been developed. Those which aim to reduce its production have shown that the beta2 adrenergic agonist class of drugs, such as the asthma drug salbutamol, have been associated with lower PD risk and deserve further investigation. Efforts to stop the aggregation of a-synuclein into larger clumps using specially designed intrabodies, small antibody fragments which can enter cells, have translated into multiple dose safety studies. Also, agents which might enhance degradation and disposal of a-synuclein include MSDC-0160, a drug with antidiabetic properties which is now a solid candidate for clinical development for Parkinson’s. Furthermore, trials of the cancer drug Nilotinib in Parkinson's are currently underway assessing its safety and brain penetrance. Aiming to reduce alpha-synuclein aggregates outside cells has led to the development of immunotherapies that target and neutralise it, and several of these trials are now at different stages of development.

Glucocerebrosidase or GBA mutations are the most frequently occuring genetic risk factor for Parkinson’s. GBA mutations interfere with GCase, a lipid handling enzyme, with the detrimental knock on effect of interfering with the cell’s various degradation functions (autophagy) leading to a build up of alpha-synuclein which becomes toxic. One approach has been to increase GCase activity through gene editing in preclinical models. Another approach is to enhance GCase directly inside cells using small molecule chaperones. Two clinical trials evaluating the safety, tolerability and efficacy of the repurposed drug Ambroxol in people with Parkinson's, are currently underway.

LRRK2 mutations are still under study, and are thought to cause Parkinson’s by increasing the activity of a particular kinase (an enzyme) which either harms neurons directly or indirectly, through its effects on immune cells. The greatest challenge that has emerged in the development of safe and effective LRRK2 inhibitors has been adverse effects seen in preclinical studies, although work is continuing conservatively in this direction in line with FDA exposure guidelines.

Our Linked Clinical Trials committee have prioritised and are actively supporting many of these trials, as well as preclinical studies. Efforts into disease modification in Parkinson’s are accelerating, delivering important insights and achieving concrete milestones. 


Original article
Sardi, S. P., Cedarbaum, J. M., & Brundin, P. (2018). Targeted therapies for Parkinson's disease: From genetics to the clinic. Mov Disord. doi:10.1002/mds.27414