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User:HAL333/Parkinson's research

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Research

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Astronaut Alexander Gerst conducting Parkinson's research aboard the International Space Station in 2018

As of 2022, no disease-modifying drugs (drugs that target the causes or damage) are approved for Parkinson's, so this is a major focus of Parkinson's research.[1][2] Active research directions include the search for new animal models of the disease and studies of the potential usefulness of gene therapy, stem cell transplants, and neuroprotective agents.[3] To aid in earlier diagnosis, research criteria for identifying prodromal biomarkers of the disease have been established.[4]

Gene therapy

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Gene therapy typically involves the use of a noninfectious virus[5] to shuttle genetic material into a part of the brain. Approaches have involved the expression of growth factors to prevent damage (Neurturin – a GDNF-family growth factor), and enzymes such as glutamic acid decarboxylase (GAD – the enzyme that produces GABA), tyrosine hydroxylase (the enzyme that produces L-DOPA) and catechol-O-methyl transferase (COMT – the enzyme that converts L-DOPA to dopamine). No safety concerns have been reported but the approaches have largely failed in phase two clinical trials.[3] The delivery of GAD showed promise in phase two trials in 2011, but while effective at improving motor function, was inferior to DBS. Follow-up studies in the same cohort have suggested persistent improvement.[6]

Some therapies seek to upregulate expression of DOPA decarboxylase and other enzymes in the dopamine synthetic pathway to increase overall dopamine production.[7] Others target GBA1 mutations, which are believed to result in lysosome dysfunction, altered protein homeostasis, and ultimately alpha-synuclein aggregation.[8]

The three most studied gene targets are alpha-synuclein (AS), glucocerebrosidase (GBA1), and leucine-rich repeat most studied gene targets, alpha-synuclein (AS), glucocerebrosidase (GBA1), and leucine-rich repeat kinase-2 (LRRK2).[9]

Neuroprotective treatments

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A vaccine that primes the human immune system to destroy alpha-synuclein, PD01A, entered clinical trials and a phase one report in 2020 suggested safety and tolerability.[10][11] In 2018, an antibody, PRX002/RG7935, showed preliminary safety evidence in stage I trials supporting continuation to stage II trials.[12]

Cell-based therapies

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Researchers at Argonne National Laboratory examining induced pluripotent stem cells
Researchers at Argonne National Laboratory examine induced pluripotent stem cells (iPSCs) for use in Parkinson's and other diseases: the action potentials of one such iSPC differentiated into a dopaminergic neuron are visible at right

In contrast to other neurodegenerative disorders, many Parkinson's symptoms can be attributed to the loss of a single cell type: mesencephalic dopaminergic (DA) neurons. Consequently, DA neuron regeneration is a promising therapeutic approach.[13] Although most initial research sought to generate DA neuron precursor cells from fetal brain tissue,[14] pluripotent stem cells—particularly induced pluripotent stem cells (iPSCs)—have become an increasingly popular tissue source.[15][16]

Both fetal and iPSC-derived DA neurons have been transplanted into patients in clinical trials.[17][18] Although some patients see improvements, the results are highly variable. Adverse effects, such as dyskinesia arising from excess dopamine release by the transplanted tissues, have also been observed.[19][20]

Pharmaceutical

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Antagonists of adenosine receptors (specifically A2A) have been explored for Parkinson's.[21] Of these, istradefylline has emerged as the most successful medication and was approved for medical use in the United States in 2019.[22] It is approved as an add-on treatment to the levodopa/carbidopa regime.[22]

Diagnostic methods

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[23]

Works cited

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References

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  1. ^ Mari Z, Mestre TA (2022). "The Disease Modification Conundrum in Parkinson's Disease: Failures and Hopes". Frontiers in Aging Neuroscience. 14: 810860. doi:10.3389/fnagi.2022.810860. PMC 8920063. PMID 35296034.
  2. ^ McFarthing K, Rafaloff G, Baptista M, Mursaleen L, Fuest R, Wyse RK, Stott SR (24 May 2022). "Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2022 Update". Journal of Parkinson's Disease. 12 (4): 1073–1082. doi:10.3233/JPD-229002. PMC 9198738. PMID 35527571.
  3. ^ a b Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. (March 2017). "Parkinson disease". Nature Reviews. Disease Primers. 3 (1): 17013. doi:10.1038/nrdp.2017.13. PMID 28332488. S2CID 11605091.
  4. ^ Heinzel S, Berg D, Gasser T, Chen H, Yao C, Postuma RB (October 2019). "Update of the MDS research criteria for prodromal Parkinson's disease". Movement Disorders. 34 (10): 1464–1470. doi:10.1002/mds.27802. PMID 31412427. S2CID 199663713.
  5. ^ Sudhakar V, Richardson RM (January 2019). "Gene Therapy for Neurodegenerative Diseases". Neurotherapeutics. 16 (1): 166–175. doi:10.1007/s13311-018-00694-0. PMC 6361055. PMID 30542906.
  6. ^ Hitti FL, Yang AI, Gonzalez-Alegre P, Baltuch GH (September 2019). "Human gene therapy approaches for the treatment of Parkinson's disease: An overview of current and completed clinical trials". Parkinsonism & Related Disorders. 66: 16–24. doi:10.1016/j.parkreldis.2019.07.018. PMID 31324556. S2CID 198132349.
  7. ^ Axelsen 2018, pp. 196–198.
  8. ^ Abeliovich 2021, pp. 183–184.
  9. ^ Polissidis 2020, pp. 3.
  10. ^ Volc D, Poewe W, Kutzelnigg A, et al. (July 2020). "Safety and immunogenicity of the α-synuclein active immunotherapeutic PD01A in patients with Parkinson's disease: a randomised, single-blinded, phase 1 trial". The Lancet. Neurology. 19 (7): 591–600. doi:10.1016/S1474-4422(20)30136-8. PMID 32562684. S2CID 219947651.
  11. ^ "World's first Parkinson's vaccine is trialled". New Scientist. London. 7 June 2012. Archived from the original on 23 April 2015.
  12. ^ Jankovic J, Goodman I, Safirstein B, et al. (October 2018). "Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti-α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial". JAMA Neurology. 75 (10): 1206–1214. doi:10.1001/jamaneurol.2018.1487. PMC 6233845. PMID 29913017.
  13. ^ Parmar 2020, pp. 103.
  14. ^ Parmar 2020, pp. 103–104.
  15. ^ Parmar 2020, pp. 106.
  16. ^ Henchcliffe 2018, pp. 134.
  17. ^ Parmar 2020, pp. 106, 108.
  18. ^ Schweitzer 2020, pp. 1926.
  19. ^ Parmar 2020, pp. 105, 109.
  20. ^ Henchcliffe 2018, pp. 132.
  21. ^ Jenner P (2014). "An overview of adenosine A2A receptor antagonists in Parkinson's disease". International Review of Neurobiology. 119: 71–86. doi:10.1016/B978-0-12-801022-8.00003-9. ISBN 978-0128010228. ISSN 2162-5514. PMID 25175961.
  22. ^ a b Office of the Commissioner (20 February 2020). "FDA approves new add-on drug to treat off episodes in adults with Parkinson's disease". FDA. Retrieved 23 February 2020.
  23. ^ Polissidis 2020, pp. 2.