Targeting α-Synuclein Aggregation in Parkinson's Disease: A Narrative Review of Current Gene Therapy Strategies.
Targeting α-Synuclein Aggregation in Parkinson's Disease: A Narrative Review of Current Gene Therapy Strategies.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Mathura, IN · Author affiliation
Department of Pharmacology, Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India.Location evidence
Gajraula, IN · Author affiliation
Department of pharmacology, College of Pharmacy, Shri Venkateshwara University, Gajraula, UP-244236, India.Location evidence
Rajpura, IN · Author affiliation
Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab-140401, India.Location evidence
IN · Author affiliation · country only
Department of Microbiology, School of Applied & Life Sciences, Uttaranchal University, Dehradun-248007, Uttarakhand, India.Location evidence
Bhilai, IN · Author affiliation
Kamla Institute of Pharmaceutical Sciences, Shri Shankaracharya professional University, Bhilai Chhattisgarh, India.Location evidence
Rājkot, IN · Author affiliation
Marwadi University Research Center, Marwadi University, Rajkot, 360003, Gujarat, India.Location evidence
Chennai, IN · Author affiliation
Centre for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, Tamil Nadu, India.Location evidence
Villeurbanne, FR · Author affiliation
Société Francophone de Nutrithérapie et de Nutrigénétique Appliquée, Villeurbanne, France.Location evidence
Saint-Étienne, FR · Author affiliation
International Institute of Nutrition and Micronutrition Sciences, Saint-Étienne, France.Location evidence
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Original abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the accumulation of misfolded α-synuclein (α-syn) aggregates, leading to dopaminergic neuronal loss and motor dysfunction. Current pharmacological treatments primarily provide symptomatic relief and have a limited impact on disease progression. This article presents a narrative review of emerging gene therapy approaches aimed at modulating α-syn expression, aggregation, and clearance as potential disease-modifying strategies for PD. Gene-based interventions include viral vector-mediated gene delivery, antisense oligonucleotides, RNA interference, and gene-editing technologies. Preclinical studies and early-phase clinical trials suggest that these approaches may reduce α-syn burden, improve motor outcomes, and support dopaminergic neuron preservation. Adeno-associated viral and lentiviral vectors have demonstrated promise for targeted central nervous system delivery, although challenges related to dosage optimization, regional specificity, long-term safety, and immune responses remain. Complementary strategies focusing on enhancing molecular chaperone activity and activating autophagy-lysosomal pathways have also shown potential in facilitating α-syn clearance. Despite encouraging progress, several limitations hinder clinical translation, including off-target effects, immune activation, and the need to preserve physiological α-syn functions essential for neuronal homeostasis. Future success will depend on precise molecular targeting, optimized delivery platforms, and rigorous safety evaluation through well-designed clinical trials. This narrative review summarizes current advances, key limitations, and future directions in α-syn-targeted gene therapy, highlighting its potential role in advancing PD treatment beyond symptomatic management toward disease modification.