Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2017 Jun 23

PMID 28641106

Citations 154

Authors

Kathleen M Schoch

Timothy M Miller

Affiliations

Soon will be listed here.

Abstract

Multiple neurodegenerative diseases are characterized by single-protein dysfunction and aggregation. Treatment strategies for these diseases have often targeted downstream pathways to ameliorate consequences of protein dysfunction; however, targeting the source of that dysfunction, the affected protein itself, seems most judicious to achieve a highly effective therapeutic outcome. Antisense oligonucleotides (ASOs) are small sequences of DNA able to target RNA transcripts, resulting in reduced or modified protein expression. ASOs are ideal candidates for the treatment of neurodegenerative diseases, given numerous advancements made to their chemical modifications and delivery methods. Successes achieved in both animal models and human clinical trials have proven ASOs both safe and effective. With proper considerations in mind regarding the human applicability of ASOs, we anticipate ongoing in vivo research and clinical trial development of ASOs for the treatment of neurodegenerative diseases.

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References

Geary R, Norris D, Yu R, Bennett C . Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides. Adv Drug Deliv Rev. 2015; 87:46-51. DOI: 10.1016/j.addr.2015.01.008. View

Lagier-Tourenne C, Baughn M, Rigo F, Sun S, Liu P, Li H . Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci U S A. 2013; 110(47):E4530-9. PMC: 3839752. DOI: 10.1073/pnas.1318835110. View

Butovsky O, Jedrychowski M, Cialic R, Krasemann S, Murugaiyan G, Fanek Z . Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann Neurol. 2014; 77(1):75-99. PMC: 4432483. DOI: 10.1002/ana.24304. View

Hua Y, Vickers T, Okunola H, Bennett C, Krainer A . Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. Am J Hum Genet. 2008; 82(4):834-48. PMC: 2427210. DOI: 10.1016/j.ajhg.2008.01.014. View

Siemers E, Sundell K, Carlson C, Case M, Sethuraman G, Liu-Seifert H . Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer's disease patients. Alzheimers Dement. 2015; 12(2):110-120. DOI: 10.1016/j.jalz.2015.06.1893. View

Porensky P, Mitrpant C, McGovern V, Bevan A, Foust K, Kaspar B . A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse. Hum Mol Genet. 2011; 21(7):1625-38. PMC: 3298284. DOI: 10.1093/hmg/ddr600. View

Farr S, Erickson M, Niehoff M, Banks W, Morley J . Central and peripheral administration of antisense oligonucleotide targeting amyloid-β protein precursor improves learning and memory and reduces neuroinflammatory cytokines in Tg2576 (AβPPswe) mice. J Alzheimers Dis. 2014; 40(4):1005-16. PMC: 4136536. DOI: 10.3233/JAD-131883. View

Rubinsztein D . Lessons from animal models of Huntington's disease. Trends Genet. 2002; 18(4):202-9. DOI: 10.1016/s0168-9525(01)02625-7. View

McMahon B, Stewart J, Fauq A, Younkin S, Younkin L, Richelson E . Peptide nucleic acids targeted to the amyloid precursor protein. J Mol Neurosci. 2003; 20(3):261-5. DOI: 10.1385/JMN:20:3:261. View

10.

Henry S, Stecker K, Brooks D, Monteith D, Conklin B, Bennett C . Chemically modified oligonucleotides exhibit decreased immune stimulation in mice. J Pharmacol Exp Ther. 2000; 292(2):468-79. View

11.

Dickson A, Osman E, Lorson C . A negatively acting bifunctional RNA increases survival motor neuron both in vitro and in vivo. Hum Gene Ther. 2009; 19(11):1307-15. PMC: 2940461. DOI: 10.1089/hum.2008.067. View

12.

Liu Y, Pattamatta A, Zu T, Reid T, Bardhi O, Borchelt D . C9orf72 BAC Mouse Model with Motor Deficits and Neurodegenerative Features of ALS/FTD. Neuron. 2016; 90(3):521-34. DOI: 10.1016/j.neuron.2016.04.005. View

13.

Polydoro M, de Calignon A, Suarez-Calvet M, Sanchez L, Kay K, Nicholls S . Reversal of neurofibrillary tangles and tau-associated phenotype in the rTgTauEC model of early Alzheimer's disease. J Neurosci. 2013; 33(33):13300-11. PMC: 3742920. DOI: 10.1523/JNEUROSCI.0881-13.2013. View

14.

Stanek L, Yang W, Angus S, Sardi P, Hayden M, Hung G . Antisense oligonucleotide-mediated correction of transcriptional dysregulation is correlated with behavioral benefits in the YAC128 mouse model of Huntington's disease. J Huntingtons Dis. 2014; 2(2):217-28. DOI: 10.3233/JHD-130057. View

15.

Vassar R . BACE1 inhibitor drugs in clinical trials for Alzheimer's disease. Alzheimers Res Ther. 2015; 6(9):89. PMC: 4304279. DOI: 10.1186/s13195-014-0089-7. View

16.

Arnold W, Porensky P, McGovern V, Iyer C, Duque S, Li X . Electrophysiological Biomarkers in Spinal Muscular Atrophy: Preclinical Proof of Concept. Ann Clin Transl Neurol. 2014; 1(1):34-44. PMC: 3914317. DOI: 10.1002/acn3.23. View

17.

Geary R, Watanabe T, Truong L, Freier S, Lesnik E, Sioufi N . Pharmacokinetic properties of 2'-O-(2-methoxyethyl)-modified oligonucleotide analogs in rats. J Pharmacol Exp Ther. 2001; 296(3):890-7. View

18.

ORourke J, Bogdanik L, Yanez A, Lall D, Wolf A, Muhammad A . C9orf72 is required for proper macrophage and microglial function in mice. Science. 2016; 351(6279):1324-9. PMC: 5120541. DOI: 10.1126/science.aaf1064. View

19.

Kumar V, Farr S, FLOOD J, Kamlesh V, Franko M, Banks W . Site-directed antisense oligonucleotide decreases the expression of amyloid precursor protein and reverses deficits in learning and memory in aged SAMP8 mice. Peptides. 2001; 21(12):1769-75. DOI: 10.1016/s0196-9781(00)00339-9. View

20.

Mougenot A, Nicot S, Bencsik A, Morignat E, Verchere J, Lakhdar L . Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol Aging. 2011; 33(9):2225-8. DOI: 10.1016/j.neurobiolaging.2011.06.022. View