Current antisense oligonucleotides designed for drug therapy rely on Watson-Crick base pairing for the specificity of interactions between antisense and target molecules. To improve cellular uptake and oligonucleotide spatial and temporal activity, a range of techniques and transporters have been developed. ASOs are single-stranded chemically modified nucleic acid polymers, typically in the range of 1825 bases in length. This change enables enhanced binding affinity to the target mRNA and is considerably less toxic than the 2-O methyl (OMe) modification. Small Drugs, Huge Impact: The Extraordinary Impact of Antisense Oligonucleotides in Research and Drug Development. With efficient anti-leukemic activity and a low toxicity profile in phase 1 clinical trials, this liposomal formulation is now being assessed in combination treatments (phase 2) and in a pending phase 1 study in solid tumors. By controlling protein expression via RNA interference, previously undruggable proteins that were unaffected by conventional small molecules can now be affected. Indeed, existing pipelines for the development of ASO therapies for spinocerebellar ataxias, Huntington disease, Alzheimer disease, amyotrophic lateral sclerosis, Parkinson disease, and others, and increased focus by the pharmaceutical industry on ASO development, strengthen the outlook for using ASOs for neurodegenerative diseases. Crit. Satake N., Duong C., Yoshida S., Oestergaard M., Chen C., Peralta R., Guo S., Seth P.P., Li Y., Beckett L., et al. This makes ASOs more versatile than siRNA or microRNA because ASOs, in addition to reducing protein expression, can also enhance target translation. Federal government websites often end in .gov or .mil. ASOs with these structures hybridize to target RNAs with affinities like their corresponding LNAs and have improved liver toxicity and increased resistance to nuclease degradation compared with the LNA chemistry. doi: 10.1164/rccm.200304-505SO. Overall world revenue for Antisense Oligonucleotide Therapeutics Market, 2022 to 2032 in terms of value the market will surpass US$19 billion in 2022, our work calculates. ; writingreview and editing, M.G. (A) Grb2 is an adaptor protein that binds to phosphorylated receptor tyrosine kinases and mediates the activation of Ras via the recruitment of guanine exchange factor SOS. Gryaznov, S. M., Lloyd, D. H., Chen, J. K., Schultz, R. G., DeDionisio, L. A., Ratmeyer, L., and Wilson, W. D. Oligonucleotide N3>P5 phosphoramidates. Baker et al. Thus, BP1001 is uniquely different from other liposomal oligo formulations, which typically utilize positively charged lipids to bind to the negatively charged oligonucleotides [135,136]. BP1001 is unique because it is uncharged and is essentially non-toxic, as demonstrated in preclinical and clinical studies. Copyright 2022 by the American Association for Cancer Research. Chemical structures of the oligonucleotides. Iversen P.L. Scientists can easily arrange those building blocks in an antisense, or opposing, fashion to repress any sequence of RNA and prevent the production of harmful proteins. Another advantage of these therapies is that due to their straightforward design and production, the time between their conceptualization and clinical use is reduced. Eteplirsen, an ASO that has a PMO oligomer structure, interacts with the DMD pre-mRNA at exon 51 resulting in exon 51 exclusion. In antisense technology, single-stranded DNA or RNA molecules are used to target a specific sense mRNA. Because I'm focusing in this blog post on antisense oligonucleotides, meaning, those designed to be reverse-complementary to a targeted gene, I won't spend much time on aptameric mechanisms of action, meaning, things that oligonucleotides can do by directly binding proteins rather than by binding RNA in a sequence-dependent manner. The two generated fragments are then degraded by exonucleases. Pulst serves on the editorial boards of Journal of Cerebellum, NeuroMolecular Medicine, Experimental Neurology, Neurogenetics, Nature Clinical Practice, and Neurology: Genetics; holds patents for Nucleic acids encoding ataxin-2 binding proteins; Nucleic acid encoding Schwannomin-binding proteins and products related thereto; Transgenic mouse expressing a polynucleotide encoding a human ataxin-2 polypeptide; Methods of detecting SCA-2 nucleic acids; Nucleic acid encoding SCA-2 and products related thereto; Schwannomin-binding-proteins; and Compositions and methods for SCA; has received publishing royalties for The Ataxias (Churchill Livingston, 2007), Genetics in Neurology (ANN Press, 2005), Genetics of Movement Disorders (Academic Press, 2003), Neurogenetics (Oxford University Press, 2000), and Molecular Genetic Testing in Neurology, 2nd to 5th (AAN Press, 1996); serves or has served as a consultant for Ataxion Therapeutics; has received research support from the NIH (RC1NS068897, RC4NS073009, R21NS081182, R21NS079852, and R01NS33123) and the National Ataxia foundation; and has received license fee payments for technology or inventions from the Cedars-Sinai Medical Center. government site. Azad R.F., Driver V.B., Tanaka K., Crooke R.M., Anderson K.P. Oligonucleotides are unmodified or chemically modified single-stranded DNA molecules. and transmitted securely. Although it is recognized that the 2 stereoisomers (Rp and Sp) differ in their binding affinity and susceptibility to degradation,22,24 there are tradeoffs between the two, and it is still debated whether stereopure isomers can be more potent than stereorandom ASOs. Giles, R. V., Spiller, D. G., Grzybowski, J., Clark, R. E., Nicklin, P., and Tidd, D. M. Selecting optimal oligonucleotide composition for maximal antisense effect following streptolysin. Multiorgan failure and cardiac arrest pose a greatest risk of death for ATTR patients. 2022 Sep 8:1-19. doi: 10.1007/s11427-022-2171-2. Neil E.E., Bisaccia E.K. Prakash T.P., Graham M.J., Yu J., Carty R., Low A., Chappell A., Schmidt K., Zhao C., Aghajan M., Murray H.F., et al. Chronic and acute LRRK2 silencing has no long-term behavioral effects, whereas wild-type and mutant LRRK2 overexpression induce motor and cognitive deficits and altered regulation of dopamine release, LRRK2 antisense oligonucleotides ameliorate alpha-synuclein inclusion formation in a Parkinson's disease mouse model. Once located at disease sites characterized by lower pH, such as tumors, the ACPP undergoes acid-catalyzed cleavage. Stanton R, Sciabola S, Salatto C, et al.. Chemical modification study of antisense gapmers. In this review we will specifically focus on ASOs, as they are the most clinically developed, with several drugs already approved by the U.S. Food and Drug Administration (FDA) and in clinical trials. Despite the great potential and numerous ASO drugs in preclinical research and clinical trials, there are many limitations to this technology. Yu D., Pendergraff H., Liu J., Kordasiewicz H.B., Cleveland D.W., Swayze E.E., Lima W.F., Crooke S.T., Prakash T.P., Corey D.R. In: Crooke S.T., editor. Another innovative technology currently under development is that of exosome-like nanoparticles. Formation of the ASO-mRNA heteroduplex either triggers RNase H activity, leading to mRNA degradation, induces translational arrest by steric hindrance of ribosomal activity, interferes with mRNA maturation by inhibiting splicing or destabilizes pre-mRNA in the nucleus, resulting in downregulation of target protein expression. Chi Q., Yang Z., Xu K., Wang C., Liang H. DNA Nanostructure as an Efficient Drug Delivery Platform for Immunotherapy. Stable oligonucleotides have also been produced that do not possess the natural phosphate-ribose backbone. Delivery of antisense oligonucleotides by poly(L-lysine) conjugation and liposome encapsulation. Its hydrophobic and hydrophilic nature accommodates hydrophobic cargo in between the lipid layers and hydrophilic cargo in the aqueous compartment or conjugated to the external lipid polar headgroups. Additional studies will assess the impact that this increase has on disease progression [55]. Koziolkiewicz, M., Gendaszewska, E., Maszewska, M., Stein, C. A., and Stec, W. J. FOIA Miller C.M., Wan W.B., Seth P.P., Harris E.N. The potential for antisense oligonucleotides (ASOs) to produce off-target effects has been known for decades. Linnane E., Davey P., Zhang P., Puri S., Edbrooke M., Chiarparin E., Revenko A.S., MacLeod A.R., Norman J.C., Ross S.J. Nanomed. Xiang B., Jia X.-L., Qi J.-L., Yang L.-P., Sun W.-H., Yan X., Yang S.-K., Cao D.-Y., Du Q., Qi X.-R. Liu, Y., and Bergan, R. Improved intracellular delivery of oligonucleotides by square wave electroporation. The bases in this oligonucleotide are attached to a neutral morpholino ring and nucleotides are linked via phosphoramidate bonds [51]. Stull, R. A., Taylor, L. A., and Szoka, F. C., Jr. Summerton, J., Stein, D., Huang, S. B., Matthews, P., Weller, D., and Partridge, M. Morpholino and phosphorothioate antisense oligomers compared in cell-free and in-cell systems. Dias N., Stein C.A. These oligomers can form very stable duplexes or triplexes with nucleic acids: single or double-strand DNA or RNA (25, 26). They rely on the use of synthetic lipids that, once triggered, undergo conformational changes to disrupt the liposomal membrane. Yakubov, L. A., Deeva, E. A., Zarytova, V. F., Ivanova, E. M., Ryte, A. S., Yurchenko, L. V., and Vlassov, V. V. Mechanism of oligonucleotide uptake by cells: involvement of specific receptors? N-acetyl galactosamine-conjugated antisense oligonucleotide (GSK3389404) in chronic hepatitis B patients on stable nucleos(t)ide therapy: Phase 2a, randomised, double-blind, controlled study; Related episodes. Mipomersen has been shown to lower lipoprotein (a) by 20-50% in phase 3 studies. A., Ginjaar, I. Called an antisense oligonucleotide, such therapies are particularly well suited to personalization because they are made of nucleotidesthe building blocks of our genetic code. The Cancer Gene Atlas now allows us to identify appropriate genetic targets and has propelled the development of oligonucleotide therapeutics [123,124,125]. Although there are a number of new ASO therapies for neurodegenerative diseases in preclinical development and in clinical trials, there are only 2 therapies for neurodegenerative diseases that are FDA approved: nusinersen and eteplirsen. Nishina K., Piao W., Yoshida-Tanaka K., Sujino Y., Nishina T., Yamamoto T., Nitta K., Yoshioka K., Kuwahara H., Yasuhara H., et al. Alkyl phosphotriesters of dinucleotides and oligonucleotides. J. Clin. Schttler S., Becker G., Winzen S., Steinbach T., Mohr K., Landfester K., Mailnder S.S.V., Wurm F. Protein adsorption is required for stealth effect of poly(ethylene glycol)- and poly(phosphoester)-coated nanocarriers. Vickers T.A., Crooke S.T. From the Department of Neurology (D.R.S., S.M.P. However, the optimal use of antisense oligonucleotides in the treatment of disease requires the resolution of problems relating to effective design, enhanced biological activity, and efficient target delivery. Many antisense oligonucleotides (ASOs) from several classes of molecules are currently in drug development. Maclachlan I. Liposomal formulations for nucleic acid delivery. Gambacorti-Passerini, C., Mologni, L., Bertazzoli, C., le Coutre, P., Marchesi, E., Grignani, F., and Nielsen, P. E. Summerton, J., and Weller, D. Morpholino antisense oligomers: design, preparation, and properties.
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