Path: /therapeutics/psp-therapeutic-ideas
Title: PSP Therapeutic Ideas
Tags: section:treatments, kind:treatment, disease:psp
| Progressive Supranuclear Palsy Treatment | |
|---|---|
| Disease | Progressive Supranuclear Palsy (PSP) |
| Pathology | 4R-tauopathy, neurofibrillary tangles, tufted astrocytes |
| Subtypes | Richardson syndrome (classic), PSP-Parkinsonism, PSP-PAGF, Corticobasal syndrome |
| Key Targets | Tau protein, neuroinflammation, synaptic dysfunction |
| Treatment Focus | Disease-modifying, symptomatic, neuroprotective |
Progressive Supranuclear Palsy (PSP), also known as Steele-Richardson-Olszewski syndrome, is a rare, rapidly progressive neurodegenerative disorder classified as a 4R-tauopathy[1]. Unlike Parkinson's disease, PSP shows minimal and transient response to dopaminergic medications, and disease progression is more rapid with a median survival of 6-9 years from symptom onset. Current therapeutic approaches focus on symptomatic management of motor, ocular, and cognitive symptoms, with emerging disease-modifying therapies targeting the underlying tau pathology.
Tau immunotherapy aims to reduce extracellular tau propagation and enhance clearance of toxic aggregates:
Small molecules designed to prevent or reverse tau aggregation:
Targeting enzymes responsible for tau hyperphosphorylation:
Targeting oxidative stress pathways:
Response in PSP is typically poor and short-lived:
| Agent | Mechanism | Phase | Status |
|---|---|---|---|
| Gantenerumab | Anti-tau antibody | 2 | Completed |
| Tilavonemab (ABBV-8E12) | Anti-tau antibody | 2 | Completed |
| Lunemastemab (ABBV-8E12) | Anti-tau antibody | 2 | Completed |
| TRx0237 (LMTX) | Tau aggregation inhibitor | 3 | Completed |
| Sodium selenate | Tau dephosphorylation | 2 | Completed |
| Davunetide | Microtubule stabilizer | 3 | Completed |
| Lithium | GSK-3β inhibitor | 2 | Completed |
| Coenzyme Q10 | Mitochondrial support | 2 | Completed |
Critical need for biomarkers to enable earlier diagnosis and monitor treatment response:
PSP has a median survival of 6-9 years from symptom onset, with more rapid progression than Parkinson's disease[25]. Treatment goals focus on:
Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Archives of Neurology. 1964. ↩︎
Budur K, Kumar S, Guss J, et al. Efficacy and safety of ABBV-8E12 in progressive supranuclear palsy. Neurobiology of Aging. 2019. ↩︎
Ostrowitzki S, Deptula D, Thurfjell L, et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Archives of Neurology. 2011. ↩︎
Florian H, Wang D, Arnold SE, et al. Tilavonemab for the treatment of progressive supranuclear palsy. Alzheimer's & Dementia: Translational Research & Clinical Interventions. 2021. ↩︎
Wischik CM, Staff RT, Akaida T, et al. Tau aggregation inhibitor therapy: an exploration of efficacy and disease modification in Alzheimer's disease and primary tauopathies. Alzheimer's Research & Therapy. 2015. ↩︎
Taniguchi S, Suzuki N, Masuda M, et al. Phenylthiazolylhydrazide derivatives as inhibitors of tau fibril formation. Journal of Biological Chemistry. 2005. ↩︎
Xu J, Kao SY, Lee FJ, et al. Dopamine-dependent neurotoxicity induced by MPTP is attenuated by green tea polyphenol (-)-epigallocatechin-3-gallate. Journal of Neurochemistry. 2002. ↩︎
Engel T, Goñi-Oliver P, Lucas JJ, et al. Chronic lithium administration to FTDP-17 tau and GSK-3β overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert. Journal of Neurochemistry. 2006. ↩︎
Zheng YL, Kesavapany S, Gravell M, et al. A CDK5-derived peptide inhibits Cdk5/p25 activity and improves neuronal viability in oxidatively stressed cultured neurons. Journal of Neuroscience. 2005. ↩︎
Deng G, Wang J, Liu W, et al. Sulforaphane exerts neuroprotective effects via Nrf2/HO-1 signaling in a rat model of Parkinson's disease. Brain Research Bulletin. 2020. ↩︎
Stamelou M, Reuss A, Pilatus U, et al. Short-term effects of coenzyme Q10 in progressive supranuclear palsy: a randomized, placebo-controlled trial. Journal of Affective Disorders. 2008. ↩︎
Wu HY, Tang EK, Lin CY, et Szeto PP. Mitochondria-targeted peptide SS-31 attenuates neuronal injury via mitochondrial protective effect after spinal cord injury. Neuroscience. 2016. ↩︎
Tobinick EL. Perispinal etanercept for neuroinflammatory disorders. Drug Discovery Today. 2009. ↩︎
Griciuc A, Tanzi RE. The role of microglial TREM2 and AD risk genes in Alzheimer's disease. Neuron. 2021. ↩︎
Kompoliti K, Goetz CG, Litvan I, et al. Pharmacological therapy in progressive supranuclear palsy. Archives of Neurology. 1998. ↩︎
Truong DD, Bhidayasiri R. Botulinum toxin therapy for cervical dystonia in progressive supranuclear palsy. Parkinsonism & Related Disorders. 2006. ↩︎
Hallett M, Eidelman O, Walz B, et al. Botulinum toxin for blepharospasm and hemifacial spasm. Physical Medicine and Rehabilitation Clinics. 2004. ↩︎
Liepelt I, Gaenslen A, Godau J, et al. Rivastigmine for the treatment of dementia in progressive supranuclear palsy. Movement Disorders. 2010. ↩︎
Schrag A, Sheikh S, Quinn NP, et al. A comparison of depression, anxiety, and health status in patients with progressive supranuclear palsy and multiple system atrophy. Movement Disorders. 2010. ↩︎
Tarditi M, Caricasole A, Marconi R. Gene therapy for neurodegenerative diseases: the role of AAV vectors. Molecular Therapy. 2022. ↩︎
Tsai CP, Lee JK, Lee CT. Mesenchymal stem cells in the treatment of neurodegenerative disorders. Stem Cell Research & Therapy. 2018. ↩︎
Bäckström DC, Eriksson Domellöf M, Zetterberg H, et al. Neurofilament light chain in cerebrospinal fluid and prediction of progression in patients with prodromal and manifest Alzheimer's disease. JAMA Neurology. 2016. ↩︎
Morris ME, Iansek R, Kirkwood B. A randomized controlled trial of movement strategies compared with exercise for people with Parkinson's disease. Movement Disorders. 2009. ↩︎
Langmore SE, Terpenning MS, Schatz A, et al. Predictors of aspiration pneumonia: how important is dysphagia?. Dysphagia. 2002. ↩︎
Wenning GK, Geser F, Krismer F, et al. [The natural history of multiple system atrophy: a prospective European cohort study](https://doi.org/10.1016/S1474-4422(13). Lancet Neurology. 2013. ↩︎