Objective: Achieve disease modification in idiopathic Parkinson’s Disease through miR-27 targeting using Antisense Oligonucleotides

Background: There are currently no disease-modifying therapies for Parkinson’s Disease (PD). Therefore, new approaches that can stop or slow disease progression are of critical medical need to improve the lives of PD patients.

RNA drugs such as Antisense Oligonucleotides offer several advantages over small molecule drugs: 1) Interfere with targets previously deemed undruggable; 2) Modulate multiple pathways through interference of microRNA (miRNA); 3) ASOs have excellent pharmacokinetic and -dynamic properties in the CNS, enabling long drug dosing intervals.

MiRNAs are pleiotropic non-coding RNAs that negatively regulate their target mRNAs. MiR-27 is a family of miRNAs consisting of miR-27a and miR-27b, which is highly expressed in the Substantia Nigra and Thalamus [1,2] ; and expression of miR-27b has been shown to be increased in PD patients [3,4].

Interestingly, miR-27 has been shown to regulate disease pathways deeply implicated in PD pathogenesis: Mitochondrial dysfunction, inflammation and oxidative stress. Therefore, miR-27 targeting holds the potential to deliver long-lasting disease modification through the targeting of multiple pathways.

Method: ASO library design and in vitro screening, ICV administration of ASOs in mice, iPSC-derived neuronal cultures.

Results: We first screened our ASO library targeting miR-27 in PC-12 cells with a Luciferase reporter in vitro to identify ASO candidates with the highest potency and efficacy. Next, we performed a dose-range finding study in vivo, and assessed brain levels of ASO, miR-27 and downstream targets one week post-injection. We were able to confirm the knockdown of miR-27 over 95% when compared to PBS control. Finally, we confirmed translatability to a human setting by measuring efficient ASO uptake, miR-27 knockdown and target de-repression in iPSC-derived neurons from healthy patients.

Conclusion: We have identified anti-miR27 ASOs with excellent on-target efficacy and potency. Thus, we have identified compounds to move forward to our preclinical Proof-of-Concept studies. We will use our candidate ASOs in the MitoPark mouse and the AAV rat a-synuclein model.

References: [1] Cardo, L. F., Coto, E., Ribacoba, R., Menéndez, M., Moris, G., Suárez, E., & Alvarez, V. (2014). MiRNA profile in the substantia nigra of Parkinson’s disease and healthy subjects. Journal of Molecular Neuroscience : MN, 54(4), 830–836. https://doi.org/10.1007/S12031-014-0428-Y
[2] Kim, J., Inoue, K., Ishii, J., Vanti, W. B., Voronov, S. V., Murchison, E., Hannon, G., & Abeliovich, A. (2007). A microRNA feedback circuit in midbrain dopamine neurons. Science, 317(5842), 1220–1224. https://doi.org/10.1126/SCIENCE.1140481/SUPPL_FILE/KIM.SOM.PDF
[3] Fazeli, S., Motovali-Bashi, M., Peymani, M., Hashemi, M. S., Etemadifar, M., Nasr-Esfahani, M. H., & Ghaedi, K. (2020). A compound downregulation of SRRM2 and miR-27a-3p with upregulation of miR-27b-3p in PBMCs of Parkinson’s patients is associated with the early stage onset of disease. PLOS ONE, 15(11), e0240855. https://doi.org/10.1371/JOURNAL.PONE.0240855
[4]Chen, L., Yang, J., Lü, J., Cao, S., Zhao, Q., & Yu, Z. (2018). Identification of aberrant circulating miRNAs in Parkinson’s disease plasma samples. Brain and Behavior, 8(4), e00941. https://doi.org/10.1002/BRB3.941

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MDS Abstracts - https://www.mdsabstracts.org/abstract/targeting-mir-27-with-antisense-oligonucleotides-for-disease-modification-in-parkinsons-disease/