User:HAL333/Parkinson's research

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Research[edit]

See also: Parkinson's disease clinical research
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[edit]

Main article: Gene therapy in Parkinson's disease

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[edit]

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[edit]

Main article: Cell-based therapies for Parkinson's disease
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[edit]

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[edit]

[23]

Works cited[edit]

References[edit]

  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.
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