Future Advances in Early Phase Clinical Development for Disease Modifying Therapies for Neurodegenerative Diseases
Main Article Content
Abstract
With aging populations in many countries, the prevalence of neurodegenerative diseases is expected to increase in the upcoming decades. Currently, no disease modifying therapies for these conditions exist. Advances in genetics and proteomics have identified novel druggable targets for neurodegenerative diseases. Compounds modulating these targets have recently entered clinical trials. These compounds can be orally administered small drug molecules, intravenously dosed antibodies, intrathecally injected antisense oligonucleotides (ASOs), gene therapies, stem cells or viral vectors. For the development of these compounds to be successful, multiple challenges have to be overcome. In this review we discuss advances in drug development for each of the major neurodegenerative diseases, which, when applied to early phase drug studies, increase the chance of successful clinical development. Here we will limit ourselves to: 1) the use of biomarkers for understanding target and pathway engagement at an early stage of development, 2) novel approaches for increasing blood-brain barrier penetration and 3) advances in understanding cerebrospinal fluid flow dynamics in relation to neurodegeneration and target site distribution for intrathecally administered compounds.
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How to Cite
KREMER, Philip H.C.; GROENEVELD, Geert Jan.
Future Advances in Early Phase Clinical Development for Disease Modifying Therapies for Neurodegenerative Diseases.
Medical Research Archives, [S.l.], v. 10, n. 9, sep. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3042>. Date accessed: 21 dec. 2024.
doi: https://doi.org/10.18103/mra.v10i9.3042.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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2. Cummings J, Fox N. Defining Disease Modifying Therapy for Alzheimer’s Disease. J Prev Alzheimers Dis. 2017;4(2):109-115.
3. Plascencia-Villa G, Perry G. Status and future directions of clinical trials in Alzheimer’s disease. Int Rev Neurobiol. 2020;154:3-50.
4. McFarthing K, Buff S, Rafaloff G, Dominey T, Wyse RK, Stott SRW. Parkinson’s Disease Drug Therapies in the Clinical Trial Pipeline: 2020. J Parkinsons Dis. 2020;10(3):757-774.
5. Bonam SR, Wang F, Muller S. Lysosomes as a therapeutic target. Nat Rev Drug Discov. 2019;18(12):923-948.
6. Levine B, Deretic V. Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol. 2007;7(10):767-777.
7. Deus CM, Yambire KF, Oliveira PJ, Raimundo N. Mitochondria-Lysosome Crosstalk: From Physiology to Neurodegeneration. Trends Mol Med. 2020;26(1):71-88.
8. Cooper AA, Gitler AD, Cashikar A, et al. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science. 2006;313(5785):324-328.
9. Gitler AD, Bevis BJ, Shorter J, et al. The Parkinson’s disease protein alpha-synuclein disrupts cellular Rab homeostasis. Proc Natl Acad Sci U S A. 2008;105(1):145-150.
10. Tardiff DF, Jui NT, Khurana V, et al. Yeast reveal a “druggable” Rsp5/Nedd4 network that ameliorates α-synuclein toxicity in neurons. Science. 2013;342(6161):979-983.
11. Eguchi T, Kuwahara T, Sakurai M, et al. LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis. Proc Natl Acad Sci U S A. 2018;115(39):E9115-E9124.
12. Purlyte E, Dhekne HS, Sarhan AR, et al. Rab29 activation of the Parkinson’s disease-associated LRRK2 kinase. EMBO J. 2019;38(2). doi:10.15252/embj.2018101237
13. Steger M, Tonelli F, Ito G, et al. Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. Elife. 2016;5. doi:10.7554/eLife.12813
14. Henderson MX, Sedor S, McGeary I, et al. Glucocerebrosidase Activity Modulates Neuronal Susceptibility to Pathological α-Synuclein Insult. Neuron. 2020;105(5):822-836.e7.
15. Pierce S, Coetzee GA. Parkinson’s disease-associated genetic variation is linked to quantitative expression of inflammatory genes. PLoS One. 2017;12(4):e0175882.
16. Caggiu E, Arru G, Hosseini S, et al. Inflammation, Infectious Triggers, and Parkinson’s Disease. Front Neurol. 2019;10:122.
17. Chang D, Nalls MA, Hallgrímsdóttir IB, et al. A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat Genet. 2017;49(10):1511-1516.
18. Karch CM, Goate AM. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry. 2015;77(1):43-51.
19. Lambert JC, Ibrahim-Verbaas CA, Harold D, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 2013;45(12):1452-1458.
20. Jonsson T, Stefansson H, Steinberg S, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med. 2013;368(2):107-116.
21. Keren-Shaul H, Spinrad A, Weiner A, et al. A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell. 2017;169(7):1276-1290.e17.
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