EMERGING DISEASE-MODIFYING THERAPIES FOR EARLY PARKINSON’S DISEASE: A COMPREHENSIVE NARRATIVE REVIEW

Abstract

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor manifestations, primarily resulting from dopaminergic neuronal loss in the substantia nigra and widespread molecular dysfunction. Current pharmacological therapies, including levodopa and dopamine agonists, provide symptomatic benefit but fail to alter disease progression. Over the last decade, growing insights into α-synuclein pathology, mitochondrial dysfunction, neuroinflammation, lysosomal impairment, and genetic susceptibility have driven intense interest in disease-modifying therapies (DMTs) aimed at slowing or halting neurodegeneration in early-stage PD.

Objective: This narrative review aimed to synthesize and critically evaluate contemporary preclinical and clinical evidence on emerging disease-modifying strategies for early Parkinson’s disease, with emphasis on their mechanistic rationale, translational progress, and therapeutic potential.

Methods: A comprehensive literature search was conducted using PubMed, Scopus, and ClinicalTrials.gov to identify English-language studies published between January 2015 and September 2025. Preclinical studies, early- and late-phase clinical trials, and registered interventional studies investigating disease-modifying approaches in early PD were included. Data were qualitatively synthesized according to therapeutic mechanism, development stage, and reported outcomes.

Results: The review identified more than 120 relevant publications and over 40 registered interventional trials evaluating disease-modifying strategies. α-synuclein–targeted immunotherapies accounted for approximately one-third of clinical candidates, with multiple Phase II trials reporting acceptable safety and biomarker engagement but limited functional efficacy. Genetic and lysosomal modulators targeting LRRK2 and GBA represented nearly 25% of ongoing trials, showing consistent target engagement and favorable tolerability. Mitochondrial enhancers and anti-inflammatory agents demonstrated neuroprotective signals in preclinical models and early clinical phases. Regenerative approaches, including gene therapy and stem cell transplantation, were evaluated in fewer but rapidly expanding early-phase studies, with initial evidence of feasibility and biological activity.

Conclusion: Emerging disease-modifying therapies reflect a decisive shift toward mechanism-based intervention in Parkinson’s disease. Although most strategies remain in early clinical development, accumulating quantitative and biological evidence supports their potential, particularly when applied early and guided by biomarkers and precision medicine frameworks.