Antisense oligonucleotides are the most direct means to target rna in a selective manner and have become an established platform technology for drug discovery. Development of novel antisense oligonucleotides for the. Carlsbad, ca usa pk and pd properties of antisense oligonucleotides. Antisense oligonucleotides and other genetic therapies made. Antisense oligonucleotides are short stretches of synthetic, chemically modified nucleic acids designed to hybridize to complementary mrna sequences and block. Objectives we recently identified microrna181a5p mir181a5p as a critical mediator involved in the destruction of lumbar facet joint fj cartilage. Tc, cfb, hbk, and ees are employees of ionis pharmaceuticals. Indeed, existing pipelines for the development of aso therapies for spinocerebellar ataxias, huntington disease, alzheimer disease. Antisense therapy is a form of treatment for genetic disorders or infections. Natural oligonucleotides are decomposed rapidly in biological systems, which. This would be achieved by the binding of the antisense oligonucleotide to the mrna from which that protein is normally synthesized.
Guidelines for antisense oligonucleotide design and insight. Oligonucleotides incorporating 2omethoxyethyl moemodified nucleotides, can support most, if not all antisense mechanisms of action. Antisense oligonucleotides asos are short, synthetic, singlestranded oligodeoxynucleotides that can alter rna and reduce, restore, or modify protein expression through several distinct mechanisms. The antisense approach relies on aons to efficiently bind to target sequences and depends on aon length, sequence content, secondary structure, thermodynamic properties, and target. Antisense oligonucleotides microsynth ag microsynth ch. Efficient delivery of antisense oligonucleotides using bioreducible. The antisense principle is based on a specific recognition of certain dna and rna regions by an antisense oligonucleotide, which inhibits the translation by a selective pairing of the sense with.
Antisense oligonucleotide in lnagapmer design targeting. The use of antisense oligonucleotides was first identified over twenty years ago as a method to arrest gene expression levels, both in vitro and in. The recurring issues of target accessibility, probe design, offtarget effects and the proper use of chemical modifications are solved in the antisense architect which uses design heuristics that allows for the rational design of antisense oligonucleotides. This experiment was first done by zamecnik and stephenson in 1978 6 and continues to be a useful approach, both for laboratory experiments and potentially for clinical applications. Despite the success of lowdensity lipoprotein cholesterol ldlclowering drugs in reducing adverse cardiovascular disease. We wish to thank dr liebling for the relevant comments1 regarding our recent article in annals of the rheumatic diseases entitled microrna181a5p antisense oligonucleotides attenuate osteoarthritis in facet and knee joints. New chemical modifications are urgently required to enhance their druglike properties. Aug 01, 2006 the feasibility of this gene downregulation strategy was further demonstrated by identifying antisense oligonucleotides that direct degradation of mrnas encoding target proteins involved in alzheimer disease, including presenilin 1, part of the.
Normally, antisense oligonucleotides contain 15 to 22 monomers and are often called oligos. Mar 27, 2020 antisense oligonucleotides asos have the potential to reduce, restore, or modify rna and protein expression. Antisense oligonucleotides are used to hybridize to a specific rna molecule in vivo and thereby to inhibit its subsequent use. Antisense oligonucleotides for neurodegeneration science. Pk and pd properties of antisense oligonucleotides. Antisense oligonucleotide an overview sciencedirect topics. The concept underlying antisense technology is relatively straightforward. Sep 08, 2011 a new way to block protein function is to prevent the translation of mrna into protein. Recent years have seen a reemergence of antisense oligonucleotides asos as valuable tools to inform on disease mechanisms and as powerful therapeutics for disease intervention. Antisense oligonucleotide therapies for neurodegenerative.
Antisense oligonucleotides asos are singlestrand dnas serving as effective drugs to reduce the messenger rna. However, although antisense oligonucleotides are commonly. Micrornas mirnas are known to be important posttranscription regulators of gene expression. We combine amide coupling with standard oligonucleotide synthesis to assemble backbone chimera gapmers that trigger an efficient rnase h response while improving serum life. Antisense oligonucleotide therapy for neurodegenerative disease. Pdf on feb 21, 2019, sara karaki and others published antisense. Once the gene sequence of interest is known, an antisense oligonucleotide with the. Antisense oligonucleotides are synthesized in the hope that they can be used as therapeutic agents blocking disease processes by altering the synthesis of a particular protein. Antisense oligonucleotide therapy linkedin slideshare. The development of antisense oligonucleotide therapies spinal muscular atrophy and duchenne muscular dystrophy suggest potentially. Antisense oligonucleotides oligonucleotidebased antisense techniques represent the most common and, to date, the most successful approach to achieving suppression or elimination of a genetic message.
There are few diseasemodifying therapeutics for neurodegenerative diseases, but successes on the development of antisense oligonucleotide aso therapeutics for spinal muscular atrophy and duchenne muscular dystrophy predict a robust future for asos in medicine. Pharmacokinetics and metabolism in mice of a phosphorothioate oligonucleotide antisense inhibitor of craf1 kinase expression. This and the concomitant high nuclease resistance of lnas results in unprecedented sensitivity and specificity and makes lna oligonucleotides ideal for use in antisense applications. When the genetic sequence of a particular gene is known to cause a particular disease, it is possible to synthesize a strand of nucleic acid dna, rna or a chemical analogue that will bind to the messenger rna mrna produced by that gene and inactivate it, effectively turning that gene off. An antisense oligonucleotide therapy is one such approach which blocks the protein formation by inhibiting translation step. Many antisense oligonucleotides asos from several classes of molecules are currently in drug development. Antisense oligonucleotide therapy has gained popularity since the late 1980s. Therefore, mirnas are considered significant therapeutic targets for cancer therapy. Pdf therapeutic oligonucleotides by cooleys anemia. Antisense oligonucleotides extend survival of prioninfected mice and was published in the. Antisense oligonucleotides asos are small sequences of dna able to target rna transcripts, resulting in reduced or modified protein expression. Lna containing oligonucleotides offer substantially increased affinity for its complementary strand, compared to traditional dna or rna oligonucleotides. Antisense oligonucleotides, antisense technology bio.
Nucleic acidbased therapeutics are attracting much attention, and numerous therapeutic oligonucleotides, such as antisense oligonucleotides, sirnas, spliceswitching oligonucleotides. Antisense oligonucleotides are now entering the clinic for hardtotreat diseases. Antisense oligonucleotides for atherosclerotic disease. Hybridization of the aso to the target rna mediates rnase h cleavage of the rna, which can inhibit the function of noncoding rnas e. Biogen provides support to tmm for clinical studies. It is a potential therapy for sma, as customizing asos may change the splicing of smn2 and, therefore, produce more functional smn protein. Pdf on apr 1, 2002, nathalie dias and others published antisense. Antisense oligonucleotides block translation of the mrna or induce its degradation. Antisense oligonucleotide treatment produces a type i interferon. The antisense effect of a synthetic oligonucleotide sequence was first demonstrated in the late 1970s by zamecnik and stephenson 1. Mirnas do not act alone, but exhibit their functions by forming rnainduced silencing complex risc. Pdf antisense oligonucleotides, a novel developing targeting.
Antisense oligonucleotides represent a novel therapeutic platform for the discovery of medicines that have the potential to treat most neurodegenerative diseases. May 30, 2019 synthetic oligonucleotides, such as asos, can mediate both specific and nonspecific molecular interactions. Pdf pharmacological effects of antisense oligonucleotide inhibition of. Mechanism of action of antisense oligonucleotides asos. Their multivalent negative charge, basepairing potential, and sequence motifs can be responsible for various forms of nonspecific interactions and offtarget effects. Antisense drugs are currently in development for the treatment of amyotrophic lateral sclerosis, huntingtons disease, and alzheimers disease, and multiple research programs are underway for additional neurodegenerative diseases. Many genetic neurological diseases result from the dysfunction of single proteins. Small pieces of dna or rna that can bind to specific molecules of rna. Antisense oligonucleotides are efficient tools for the inhibition of gene expression in a sequence specific way.
Guidelines for experiments using antisense oligonucleotides. Recent studies have led to a greater appreciation of the diverse roles rnas play in maintaining normal cellular function and how they contribute to disease pathology, broadening the number of potential therapeutic targets. Antisense oligonucleotides in therapy for neurodegenerative. Antisense oligonucleotides asos are an emerging drug class. Transdermal delivery of antisense oligonucleotides with. Thus, they can target disease pathogenesis by altering the expression of mutant proteins 1 1. Antisense oligonucleotides asos are small molecules that can bind to rna to change how it is spliced. Aberrant mirna expression is associated with pathological disease processes, including carcinogenesis. Antisense technology is the process in which the antisense strand hydrogen bonds with the targeted sense strand. Antisense oligonucleotides gene silencing can be achieved by introducing into cells a short antisense oligonucleotide that is complementary to an rna target. They are being studied in the treatment of several types of cancer.
Antisenseoligonucleotides block translation of the mrna or induce its degradation. Jci antisense oligonucleotide therapy for neurodegenerative. Crooke, in encyclopedia of cancer second edition, 2002. Antisense oligonucleotides complementary to rna targets promise generality and ease of drug design. Nov, 2018 in this followup work, kapoor and his team tested locked nucleic acid antisense oligonucleotides that can target mir181a5p from mice, rats and humans. When an antisense strand binds to a mrna sense strand, a cell will recognize the double helix as foreign to the cell and proceed to degrade the faculty mrna molecule thus preventing the production of undesired. Structural modifications of antisense oligonucleotides.
Antisense oligonucleotides may be used to block the production of proteins needed for cell growth. When the genetic sequence of a particular gene is known to be causative of a particular disease, it is possible to synthesize a strand of nucleic acid dna, rna or a chemical analogue that will bind to the messenger rna mrna produced by that. Prion disease in mice treated successfully with antisense. Antisense oligonucleotides asos are dna oligos, typically 1525 bases long, designed in antisense orientation to the rna of interest. A new way to block protein function is to prevent the translation of mrna into protein. Sep 25, 2019 science translational medicine 25 sep 2019. Citations 0 references 14 researchgate has not been able to resolve any citations for. Modified antisense oligonucleotides, continuously infused intraventricularly, have been demonstrated to distribute widely throughout the cns of rodents and primates, including the regions affected in the major neurodegenerative diseases. Novel rnatargeting antisense therapy is shown to reduce. Tmm has participated in a medical advisory board for biogen and is a consultant for cytokinetics. A single antisense oligonucleotide can partake in the destruction of many mrna molecules by this mechanism. Antisense oligonucleotides for atherosclerotic disease nature. This blocks the ability of the rna to make a protein or work in other ways. Antisense oligonucleotides, micrornas, and antibodies core.
Ionis pharmaceuticals provides antisense oligonucleotides to tmm. Aptamers and antisense oligonucleotides for diagnosis and treatment of hematological diseases. Feb 27, 2009 antisense oligonucleotides aons can interfere with mrna processing through rnase hmediated degradation, translational arrest, or modulation of splicing. Oligonucleotides modified at both the 3 and 5 ends by methoxyethylphosphoramidate are protected from exonuclease digestion. Definition of antisense oligonucleotide nci dictionary of. In this study, we tested if locked nucleic acid lna mir181a5p antisense oligonucleotides aso could be used as a therapeutic to limit articular cartilage degeneration. The recent regulatory approval of asos for the pediatric motor neuron disease spinal muscular atrophy has provided a regulatory pathway for additional aso therapies in other central. Further key distinctive characteristics are nuclease resistance, lower toxicity, superior target binding specificity, as well as increased affinity towards complementary rna.