Alpha Synuclein Aggregation Inhibitors is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
| Alpha-Synuclein Aggregation Inhibitors | |
|---|---|
| Category | Disease-Modifying Therapy |
| Target Diseases | Parkinson's Disease, Dementia with Lewy Bodies, Multiple System Atrophy, Pure Autonomic Failure |
| Mechanism | Inhibit α-synuclein nucleation, aggregation, and fibril formation |
| Development Stage | Clinical trials (Phase I-III) |
Alpha-synuclein (α-syn) aggregation inhibitors represent the most promising disease-modifying approach for synucleinopathies. These small molecules and biological agents target the pathological aggregation of α-syn from soluble monomers into toxic oligomers and fibrils that form Lewy bodies and glial cytoplasmic inclusions. By preventing or reversing aggregation, these therapies aim to slow or halt disease progression[1].
The aggregation of α-syn follows a nucleation-dependent polymerization pathway:
Different α-syn strains (oligomorphs) may explain the clinical heterogeneity of synucleinopathies:
Green tea polyphenol that directly binds α-syn and prevents aggregation. Clinical trials in PD showed reduced α-syn oligomers but inconsistent clinical outcomes[3].
Status: Phase II completed
Natural anthrax that stabilizes native α-syn conformation and inhibits fibril formation. Poor blood-brain barrier (BBB) penetration limits efficacy[4].
Status: Preclinical/Phase I
Nicotine reduces α-syn aggregation through α7-nAChR activation. Observational studies suggest reduced PD risk in smokers, but clinical trials showed limited efficacy[5].
Status: Phase II (repurposing)
Affitope PD01A/PD03A (Affiris)
ACI-35 (AC Immune/Liioni)
Prasinezumab (RO7046015/PRX002) (Roche)
Cinmeron (ABBV-0805) (AbbVie/Cellular Dynamics)
Lunembrezumab (BIIB054) (Biogen)
| Drug | Company | Mechanism | Phase | Status |
|---|---|---|---|---|
| Prasinezumab | Roche | Passive immunization | IIb | Ongoing |
| ABBV-0805 | AbbVie | Passive immunization | I | Completed |
| BIIB054 | Biogen | Passive immunization | II | Completed |
| Affitope PD01A | Affiris | Active immunization | II | Ongoing |
| ACI-35 | AC Immune | Active immunization | Ib | Completed |
| Anle138b | MODAG | Oligomer modulator | I/II | Completed |
The study of Alpha Synuclein Aggregation Inhibitors has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
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[2] Peelaerts W, Bousset L, Van der Perren A, et al. α-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature. 2015;522(7556):340-344.
[3] de la Mata M, Cotán J, Oropesa-Ávila M, et al. Epigallocatechin-3-gallate as a potential therapeutic agent for neurodegenerative diseases. Adv Nutr. 2015;6(5):565-568.
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[8] Schneeberger A, Mandler M, Mattner F, Schmidt W. Affinity of α-synuclein vaccines in Parkinson's disease. J Parkinsons Dis. 2012;2(4):275-282.
[9] Bucchieri F, Farina C, Frossi B, et al. ACI-35 liposomal vaccine induces robust anti-α-syn antibodies in Parkinson's disease. NPJ Parkinsons Dis. 2020;6:25.
[10] Pagano G, Taylor KI, Anzures-Cabrera J, et al. Prasinezumab for early-stage Parkinson's disease: a randomized, double-blind, Phase II trial. Nat Med. 2022;28(10):2106-2112.
[11]</sup] Weintraub D, Raza S, Siderowf AD, et al. ABBV-0805, a monoclonal antibody against α-synuclein, in healthy volunteers. Mov Disord. 2022;37(9):1889-1896.
[12] Berg D, et al. BIIB054 (cinmeron) in Parkinson's disease: Phase II SENSIP trial. Lancet Neurol. 2021;20(12):938-950.
[13] Fairfoul G, McGuire LI, Pal S, et al. Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies. Ann Neurol. 2016;80(5):730-740.