| Attribute | Value |
|---|---|
| Event | Movement Disorders Society (MDS) Congress 2026 |
| Location | COEX Convention Center, Seoul, Korea |
| Date | October 4-8, 2026 |
| Focus | Disease-modifying therapies, neuroprotection, and neurorestoration |
| Chair | MDS Neuroprotection Study Group |
Parkinson's disease (PD) affects over 10 million people worldwide, making it the second most common neurodegenerative disease after Alzheimer's disease. While dopaminergic replacement therapies (levodopa, dopamine agonists, MAO-B inhibitors) effectively manage motor symptoms, none have demonstrated unequivocal disease-modifying effects. The field has therefore shifted toward targeting the underlying pathogenic mechanisms with neuroprotective and neurorestorative strategies designed to slow, halt, or reverse dopaminergic neuron loss in the substantia nigra pars compacta[1].
This page provides a comprehensive review of the major therapeutic categories advancing through clinical development for neuroprotection and neurorestoration in PD, with emphasis on approaches to be featured at MDS 2026.
Neuroprotective strategies in PD address the core pathogenic processes that drive dopaminergic neuron degeneration. Each therapeutic approach targets one or more of these interconnected mechanisms:
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent one of the most advanced and promising classes of disease-modifying agents for PD. Originally developed for type 2 diabetes mellitus, these agents activate GLP-1 receptors in the central nervous system, triggering neuroprotective signaling cascades that enhance neuronal survival, reduce neuroinflammation, and improve mitochondrial function[2].
GLP-1R activation triggers multiple intracellular signaling pathways:
Exenatide (Bydureon): The landmark Phase II randomized controlled trial (Athauda et al., Lancet 2017) demonstrated that weekly subcutaneous exenatide (2 mg) for 48 weeks significantly improved MDS-UPDRS motor scores compared to placebo, with benefits persisting 12 weeks after washout. This provided the first compelling evidence of disease modification in PD[2:1].
Semaglutide: The NOVELTY trial (Azencott et al., J Parkinsons Dis 2023) is evaluating semaglutide in early-stage PD patients, leveraging its superior BBB penetration compared to exenatide[3].
Lixisenatide: Currently in Phase III trials for PD, lixisenatide offers a shorter half-life and potentially better tolerability profile[4].
Neurotrophic factors are endogenous proteins that support the survival, differentiation, and function of specific neuronal populations. In PD, the nigrostriatal pathway shows marked deficiency in neurotrophic support, making replacement therapy a logical disease-modifying strategy[5].
GDNF is the most potent dopaminergic neurotrophic factor known, binding to GFRα1 receptors and activating RET tyrosine kinase on dopaminergic neurons. It promotes survival, stimulates axonal sprouting, and enhances dopamine release through PI3K/Akt, MAPK/ERK, and PLCγ pathways[1:1].
Clinical Development:
BDNF activates TrkB receptors on dopaminergic neurons, promoting PI3K/Akt signaling and synaptic plasticity in the striatum. Strategies include AAV-BDNF gene therapy, small molecule TrkB agonists (e.g., 7,8-dihydroxyflavone), and exercise-induced BDNF upregulation.
Alpha-synuclein (SNCA) is the primary protein constituent of Lewy bodies, the pathological hallmark of PD. The prion-like spread of misfolded alpha-synuclein from neuron to neuron is thought to drive disease progression along Braak staging, making aggregation inhibitors a direct disease-modifying strategy[8].
Small Molecule Inhibitors: Compounds such as ambroxol (a GCase chaperone), synucleozid, and MPL-3628 aim to prevent alpha-synuclein misfolding or disrupt existing aggregates. Phase II trials for ambroxol in GBA-PD have shown promise in increasing GCase activity and reducing alpha-synuclein burden.
Immunotherapies: Both active (alpha-synuclein vaccines) and passive (monoclonal antibodies targeting alpha-synuclein epitopes) immunotherapy approaches are in clinical development. Cinpanemab (BIIB054) and semorinemab target extracellular alpha-synuclein to prevent cell-to-cell propagation.
、表格式聚合破坏剂: Novel compounds designed to disassemble pre-formed aggregates are in preclinical development.
Mitochondrial dysfunction is a central feature of PD pathophysiology, evidenced by familial PD genes PINK1, PARK2 (parkin), and DJ-1 that regulate mitophagy. Complex I deficiency is consistently observed in substantia nigra neurons from PD patients[9].
The autophagy-lysosome pathway is critical for clearing damaged mitochondria, protein aggregates, and iron-laden organelles. Impaired autophagy contributes to alpha-synuclein accumulation and mitochondrial dysfunction in PD[10].
mTOR-Independent Activation: Novel compounds like SMER28 and calpastatin inhibitors activate TFEB to enhance lysosomal biogenesis without suppressing mTORC1.
NLRP3 Inhibition: Dapansutrile (OLT1177) reduces neuroinflammation-driven impairment of autophagy through caspase-1 inhibition.
TFEB Activation: Small molecules promoting transcription factor EB nuclear translocation enhance expression of autophagy-lysosome genes.
Oxidative stress is a consistent finding in PD substantia nigra, with elevated lipid peroxidation, protein oxidation, and DNA damage. The NRF2-KEAP1 pathway regulates antioxidant response element (ARE)-driven gene expression[11].
Cell replacement therapy aims to replace lost dopaminergic neurons through transplantation of stem cell-derived or fetal tissue-derived cells into the striatum and substantia nigra[kriks2023].
iPSC-Derived Dopaminergic Neurons: Induced pluripotent stem cells (iPSCs) from patient or donor sources are differentiated into dopaminergic progenitor cells and transplanted. Major trials include:
Allogeneic vs. Autologous: Allogeneic approaches offer faster production but require immunosuppression. Autologous iPSCs avoid immune rejection but are logistically complex and expensive.
Tissue Engineering: Approaches combining dopaminergic neurons with supportive biomaterials and neurotrophic factor-secreting cells to enhance survival and integration.
Gene therapy enables sustained, localized expression of therapeutic proteins in the brain, overcoming the BBB delivery challenge for proteins like GDNF. AAV vectors are the preferred platform due to their favorable safety profile and long-term expression[12].
| Therapy | Target | Mechanism | Stage | Trial ID |
|---|---|---|---|---|
| AB-1005 (Neuromyx) | GDNF | AAV2-GDNF putaminal delivery | Phase II | NCT04815625 |
| AXO-Lenti-PD (Oxford) | TH, AADC, GCH1 | Lentiviral triple gene therapy | Phase I/II | NCT03758718 |
| AAV-GAD (Voyager) | GAD | AAV-GAD thalamic delivery | Phase I | NCT05688436 |
| PTB-siRNA (NIR Therapeutics) | PTB | RNA interference for neuron reprogramming | Preclinical | — |
The multifaceted pathogenesis of PD suggests that combining neuroprotective agents with different mechanisms may provide synergistic benefits. Promising combinations include:
Key biomarkers for patient stratification and monitoring include:
The BBB remains the primary challenge for neuroprotective agents. Emerging delivery approaches:
The following sessions at MDS 2026 are directly relevant to neuroprotection and neurorestoration:
The neuroprotective and neurorestorative therapeutic landscape for Parkinson's disease is more advanced and diverse than ever before. GLP-1 receptor agonists have demonstrated disease-modifying potential in Phase II trials and are advancing to Phase III. Neurotrophic factor gene therapy, particularly AAV-GDNF (AB-1005), represents a maturing platform with compelling biomarker evidence. Cell replacement therapy with iPSC-derived dopaminergic neurons has entered clinical trials, while combination approaches and biomarker-driven patient selection promise to optimize outcomes.
The convergence of these strategies toward multi-target neuroprotection — addressing alpha-synuclein aggregation, mitochondrial dysfunction, neuroinflammation, and neurotrophic deficiency simultaneously — represents the most promising path toward genuine disease modification in Parkinson's disease.
Barker RA, et al. GDNF and the treatment of Parkinson's disease. Nat Rev Neurol. 2020. ↩︎ ↩︎ ↩︎ ↩︎
Athauda D, et al. Exenatide and the treatment of patients with Parkinson's disease. Lancet. 2017. ↩︎ ↩︎
Azencott CA, et al. Semaglutide in Parkinson's disease: rationale and design of the NOVELTY trial. J Parkinsons Dis. 2023. ↩︎
Foltynie T, et al. GLP-1 as a disease-modifying treatment for Parkinson's disease: from science to practice. Nat Rev Neurol. 2019. ↩︎
Sidorova Y, et al. Neurotrophic factor-based therapies for Parkinson's disease. Nat Rev Neurol. 2024. ↩︎
Whone A, et al. Randomized trial of AAV-GDNF in Parkinson disease. Ann Neurol. 2019. ↩︎
Hovde S, et al. AB-1005 gene therapy for Parkinson's disease. Brain. 2024. ↩︎
Ljungberg T, et al. Alpha-synuclein aggregation inhibitors for Parkinson's disease. Neurobiol Dis. 2021. ↩︎
Schapira AHV, et al. Targeting mitochondria for neuroprotection in Parkinson's disease. Nat Rev Neurol. 2019. ↩︎
Devos D, et al. Targeting autophagy for neuroprotection in Parkinson's disease. Nat Rev Neurol. 2023. ↩︎
Zhang Y, et al. NRF2 activators and neuroprotection in Parkinson's disease. Free Radic Biol Med. 2022. ↩︎
Muzina M, et al. AAV gene therapy for Parkinson's disease: current pipeline and future directions. Mol Ther. 2024. ↩︎