Novel approaches targeting α-Synuclein for Parkinson's Disease: Current progress and future directions for the disease-modifying therapies

• Novel disease-modifying therapeutics are being evaluated targeting α-Synuclein pathology in Parkinson's disease and other Synucleinopathies. • The therapeutic approach under investigation includes inhibiting α-Synuclein aggregation and promoting degradation of α-Synuclein aggregates. • Immunomodulatory drugs for α-Synucleinopathies may offer an effective disease-modifying strategy for Parkinson's disease patients. Parkinson's Disease (PD) is a common and debilitating neurodegenerative disorder affecting millions worldwide. The hallmark pathological feature of PD is the accumulation and aggregation of α-Synuclein (α-Syn), a protein involved in synaptic function and neuronal survival. The formation of α-Syn aggregates, also known as Lewy bodies and Lewy neurites, leads to neuronal dysfunction and death, resulting in PD's characteristic motor and non-motor symptoms. Current treatments for PD are mainly symptomatic and do not address the underlying cause of the disease. Therefore, there is an urgent need for disease-modifying therapies that can prevent, slow, or reverse the progression of PD by targeting α-Syn aggregation. In this review, we summarize the current status of pharmacological interventions that aim to reduce α-Syn levels in PD and other Synucleinopathies by various mechanisms, such as inhibiting α-Syn aggregation, enhancing α-Syn clearance, modulating α-Syn-related enzymes, or blocking α-Syn transmission. We focus on agents that have reached phase 1 or 2 clinical trials and provide an overview of their preclinical and clinical data and their safety and efficacy profiles. While fewer candidates have shown positive results in clinical trials, they are awaiting further evaluation in larger and longer-term studies. None of the placebo-controlled, blind trials, except Prasinezumab, have demonstrated efficacy. These novel disease-modifying therapy approaches can potentially change the landscape of PD treatment and improve the quality of life for PD patients.