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Research

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See also: Parkinson's disease clinical research

There are currently no disease modifying drugs for Parkinson's disease. A number of approaches have reached clinical trials in recent years including cell therapies, gene therapies and neuroprotective agents. Rapid progress in genetics has enabled the development of a number of new animal models for Parkinson's disease and induced pluripotent stem cell therapies recently reached phase I clinical trials.

Animal models

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PD is not known to occur naturally in any species other than humans, animal models reflect some features of the disease and are used in research to develop and test treatments. The appearance of parkinsonism in a group of drug addicts in the early 1980s who consumed a contaminated batch of the synthetic opiate MPPP led to the discovery of the chemical MPTP as an agent that causes parkinsonism in non-human primates as well as in humans.[1] Other predominant toxin-based models employ the insecticide rotenone, the herbicide paraquat and the fungicide maneb.[2] Models based on toxins are most commonly used in primates. Transgenic rodent models that replicate various aspects of PD have been developed.[3] The use of neurotoxin 6-hydroxydopamine, creates a model of Parkinson's disease in rats by targeting and destroying dopaminergic neurons in the nigrostriatal pathway when injected into the substantia nigra.[4] Whilst previously animal models focused entirely on developing symptoms, animal models focused on the causative agents of Parkinson's such as alpha-synuclein dysfunction have been developed. These rely on genetic modification to express proteins such as alpha-synuclein. Various protein modifications enable modelling of parkinsonism. These animal models may more faithfully recapitulate the pathology of parkinson's disease and are widely used to understand the disease mechanisms. They also allow for the development of disease modifying therapies that focus on alpha-synuclein for instance.

Stem Cell Models

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Stem cell models of Parkinson's, typically differentiated (or changed) into dopaminergic neurons derived from patients and embryos play an increasingly important role in pre-clinical research. The first robust models for pluripotent stem cell differentiation into dopaminergic neurons were described in 2011. [5]

Gene therapy

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Gene therapy typically involves the use of a non-infectious virus (i.e., a viral vector such as the adeno-associated virus) to shuttle genetic material into a part of the brain. The gene used leads to the production of an enzyme that helps to manage PD symptoms or protects the brain from further damage.[6][7] In 2010 there were four clinical trials using gene therapy in PD.[6] There have not been important adverse effects in these trials although the clinical usefulness of gene therapy is still unknown.[6] One of these reported positive results in 2011,[8] but the company filed for bankruptcy in March 2012.[9]

Neuroprotective treatments

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Several chemical compounds, such as GDNF (chemical structure pictured) have been proposed as neuroprotectors in PD, but their effectiveness has not been proven.

Investigations on neuroprotection are at the forefront of PD research. Several molecules have been proposed as potential treatments.[6] However, none of them have been conclusively demonstrated to reduce degeneration.[6] Agents currently under investigation include, antiglutamatergics, monoamine oxidase inhibitors (selegiline, rasagiline), promitochondrials (coenzyme Q10, creatine), calcium channel blockers (isradipine) and growth factors (GDNF).[6] Reducing alpha-synuclein pathology is a major focus of preclinical research.[10] A vaccine that primes the human immune system to destroy alpha-synuclein, PD01A (developed by Austrian company, Affiris), entered clinical trials and a phase 1 report in 2020 suggested safety and tolerability.[11][12] In 2018, an antibody, PRX002/RG7935, showed preliminary safety evidence in stage I trials supporting continuation to stage II trials.[13]

Cell-based therapies

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

Since early in the 1980s, fetal, porcine, carotid or retinal tissues have been used in cell transplants, in which dissociated cells are injected into the substantia nigra in the hope that they will incorporate themselves into the brain in a way that replaces the dopamine-producing cells that have been lost.[6] More recently, these sources of tissues have been largely replaced by induced pluripotent stem cell derived dopaminergic neurons as this is thought to represent a more feasible source of tissue. There was initial evidence of mesencephalic dopamine-producing cell transplants being beneficial, double-blind trials to date have not determined whether there is a long-term benefit.[14] An additional significant problem was the excess release of dopamine by the transplanted tissue, leading to dyskinesia.[14] In 2020, a first in human clinical trial reported the transplantation of induced pluripotent stem cells into the brain of a person suffering from Parkinson's disease. [15]

Other

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Repetitive transcranial magnetic stimulation temporarily improves levodopa-induced dyskinesias.[16] Its usefulness in PD is an open research topic.[17] Several nutrients have been proposed as possible treatments; however there is no evidence that vitamins or food additives improve symptoms.[18] There is no evidence to substantiate that acupuncture and practice of Qigong, or T'ai chi, have any effect on the course of the disease or symptoms.[19][20][21] Fava beans and velvet beans are natural sources of levodopa and are eaten by many people with PD; their intake is not free of risks as life-threatening adverse reactions have been described, such as the neuroleptic malignant syndrome.[22]

The role of the gut–brain axis and the gut flora in Parkinsons became a topic of study in the 2010s, starting with work in germ-free transgenic mice, in which fecal transplants from people with PD had worse outcomes. Some studies in humans have shown a correlation between patterns of dysbiosis in the gut flora in the people with PD, and these patterns, along with a measure of severity of constipation, could diagnose PD with a 90% specificity but only a 67% sensitivity. As of 2017 some scientists hypothesized that changes in the gut flora might be an early site of PD pathology, or might be part of the pathology.[23][24]

Adenosine receptors (specifically A2A) have been explored as an avenue for novel drugs for Parkinson's.[25] Of these, istradefylline was approved for medical use in the United States in 2019 as an add-on treatment to the levodopa/carbidopa regime.[26]

  1. ^ Langston JW, Ballard P, Tetrud JW, Irwin I (February 1983). "Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis". Science. 219 (4587): 979–80. Bibcode:1983Sci...219..979L. doi:10.1126/science.6823561. PMID 6823561.
  2. ^ Cicchetti F, Drouin-Ouellet J, Gross RE (September 2009). "Environmental toxins and Parkinson's disease: what have we learned from pesticide-induced animal models?". Trends in Pharmacological Sciences. 30 (9): 475–83. doi:10.1016/j.tips.2009.06.005. PMID 19729209.
  3. ^ Harvey BK, Wang Y, Hoffer BJ (2008). Transgenic rodent models of Parkinson's disease. Acta Neurochirurgica Supplementum. Vol. 101. pp. 89–92. doi:10.1007/978-3-211-78205-7_15. ISBN 978-3-211-78204-0. PMC 2613245. PMID 18642640. {{cite book}}: |journal= ignored (help)
  4. ^ Blum D, Torch S, Lambeng N, Nissou M, Benabid AL, Sadoul R, Verna JM (October 2001). "Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease". Progress in Neurobiology. 65 (2): 135–72. doi:10.1016/S0301-0082(01)00003-X. PMID 11403877.
  5. ^ Kriks, Sonja; Shim, Jae-Won; Piao, Jinghua; Ganat, Yosif M.; Wakeman, Dustin R.; Xie, Zhong; Carrillo-Reid, Luis; Auyeung, Gordon; Antonacci, Chris; Buch, Amanda; Yang, Lichuan (2011-11-06). "Floor plate-derived dopamine neurons from hESCs efficiently engraft in animal models of PD". Nature. 480 (7378): 547–551. doi:10.1038/nature10648. ISSN 0028-0836. PMC 3245796. PMID 22056989.
  6. ^ a b c d e f g Obeso JA, Rodriguez-Oroz MC, Goetz CG, Marin C, Kordower JH, Rodriguez M, Hirsch EC, Farrer M, Schapira AH, Halliday G (June 2010). "Missing pieces in the Parkinson's disease puzzle". Nature Medicine. 16 (6): 653–61. doi:10.1038/nm.2165. PMID 20495568.
  7. ^ Feng LR, Maguire-Zeiss KA (March 2010). "Gene therapy in Parkinson's disease: rationale and current status". CNS Drugs. 24 (3): 177–92. doi:10.2165/11533740-000000000-00000. PMC 2886503. PMID 20155994.
  8. ^ LeWitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW, Eskandar EN, Kostyk SK, Thomas K, Sarkar A, Siddiqui MS, Tatter SB, Schwalb JM, Poston KL, Henderson JM, Kurlan RM, Richard IH, Van Meter L, Sapan CV, During MJ, Kaplitt MG, Feigin A (April 2011). "AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial". The Lancet. Neurology. 10 (4): 309–19. doi:10.1016/S1474-4422(11)70039-4. PMID 21419704.
  9. ^ "Neurologix Files to Liquidate Under Chapter 7 Bankruptcy". Archived from the original on 7 January 2014.
  10. ^ Dimond PF (16 August 2010). "No New Parkinson Disease Drug Expected Anytime Soon". GEN news highlights. GEN-Genetic Engineering & Biotechnology News. Archived from the original on 31 October 2010.
  11. ^ Volc, Dieter; Poewe, Werner; Kutzelnigg, Alexandra; Lührs, Petra; Thun-Hohenstein, Caroline; Schneeberger, Achim; Galabova, Gergana; Majbour, Nour; Vaikath, Nishant; El-Agnaf, Omar; Winter, Dorian (2020-07-01). "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. ISSN 1474-4422.
  12. ^ "World's first Parkinson's vaccine is trialled". New Scientist. London. 7 June 2012. Archived from the original on 23 April 2015.
  13. ^ Jankovic, J.; Goodman, I.; Safirstein, B.; Marmon, T. K.; Schenk, D. B.; Koller, M.; Zago, W.; Ness, D. K.; Griffith, S. G.; Grundman, M.; Soto, J.; Ostrowitzki, S.; Boess, F. G.; Martin-Facklam, M.; Quinn, J. F.; Isaacson, S. H.; Omidvar, O.; Ellenbogen, A.; Kinney, G. G. (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.
  14. ^ a b Henchcliffe, Claire; Parmar, Malin. "Repairing the Brain: Cell Replacement Using Stem Cell-Based Technologies". Journal of Parkinson's Disease. 8 (Suppl 1): S131–S137. doi:10.3233/JPD-181488. ISSN 1877-7171. PMC 6311366. PMID 30584166.
  15. ^ Schweitzer, Jeffrey S.; Song, Bin; Herrington, Todd M.; Park, Tae-Yoon; Lee, Nayeon; Ko, Sanghyeok; Jeon, Jeha; Cha, Young; Kim, Kyungsang; Li, Quanzheng; Henchcliffe, Claire (2020-05-14). "Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson's Disease". New England Journal of Medicine. 382 (20): 1926–1932. doi:10.1056/NEJMoa1915872. ISSN 0028-4793. PMC 7288982. PMID 32402162.{{cite journal}}: CS1 maint: PMC format (link)
  16. ^ Koch G (2010). "rTMS effects on levodopa induced dyskinesias in Parkinson's disease patients: searching for effective cortical targets". Restorative Neurology and Neuroscience. 28 (4): 561–568. doi:10.3233/RNN-2010-0556. PMID 20714078.
  17. ^ Platz T, Rothwell JC (2010). "Brain stimulation and brain repair – rTMS: from animal experiment to clinical trials – what do we know?". Restorative Neurology and Neuroscience. 28 (4): 387–98. doi:10.3233/RNN-2010-0570. PMID 20714064.
  18. ^ Suchowersky O, Gronseth G, Perlmutter J, Reich S, Zesiewicz T, Weiner WJ (April 2006). "Practice Parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology". Neurology. 66 (7): 976–82. doi:10.1212/01.wnl.0000206363.57955.1b. PMID 16606908.
  19. ^ Lee MS, Lam P, Ernst E (December 2008). "Effectiveness of tai chi for Parkinson's disease: a critical review". Parkinsonism & Related Disorders. 14 (8): 589–94. doi:10.1016/j.parkreldis.2008.02.003. PMID 18374620.
  20. ^ Lee MS, Ernst E (January 2009). "Qigong for movement disorders: A systematic review". Movement Disorders. 24 (2): 301–303. doi:10.1002/mds.22275. PMID 18973253.
  21. ^ Lee MS, Shin BC, Kong JC, Ernst E (August 2008). "Effectiveness of acupuncture for Parkinson's disease: a systematic review". Movement Disorders. 23 (11): 1505–15. doi:10.1002/mds.21993. PMID 18618661.
  22. ^ Raguthu L, Varanese S, Flancbaum L, Tayler E, Di Rocco A (October 2009). "Fava beans and Parkinson's disease: useful 'natural supplement' or useless risk?". European Journal of Neurology. 16 (10): e171. doi:10.1111/j.1468-1331.2009.02766.x. PMID 19678834.
  23. ^ Tremlett H, Bauer KC, Appel-Cresswell S, Finlay BB, Waubant E (March 2017). "The gut microbiome in human neurological disease: A review". Annals of Neurology. 81 (3): 369–82. doi:10.1002/ana.24901. PMID 28220542.
  24. ^ Klingelhoefer L, Reichmann H (2017). The Gut and Nonmotor Symptoms in Parkinson's Disease. Vol. 134. pp. 787–809. doi:10.1016/bs.irn.2017.05.027. ISBN 9780128126035. PMID 28805583. {{cite book}}: |journal= ignored (help)
  25. ^ Jenner, Peter (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 9780128010228. ISSN 2162-5514. PMID 25175961.
  26. ^ Commissioner, Office of the (2020-02-20). "FDA approves new add-on drug to treat off episodes in adults with Parkinson's disease". FDA. Retrieved 2020-02-23.
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