What is oligonucleotide therapeutics?
Oligonucleotide therapeutics are short, single- or double-stranded DNA or RNA molecules consisting of strands of 10-50 nucleotides. By targeted modulation of gene expression oligonucleotides provide the chance of targeting diseases at their molecular level.
How many oligonucleotide drugs have been approved?
Oligonucleotides have been under development for several decades. Development started with antisense oligonucleotides and aptamers, followed by siRNAs. In total, the U.S. Food and Drug Administration (FDA) has approved eleven oligonucleotide drugs.
How do oligonucleotide therapies work?
Antisense oligonucleotides (AS ONs) are synthetic DNA oligomers that hybridize to a target RNA in a sequence-specific manner. They have successfully been employed to inhibit gene expression, modulate splicing of a precursor messenger RNA, or inactivate microRNAs.
What are the potential limitations issues of using unmodified antisense oligonucleotide as a drug in the synthesis delivery and targeting processes?
Unmodified oligonucleotides can be toxic by means of intracellular degradation into nucleotides, since even small changes in intracellular pools of free nucleotides have been shown to alter DNA synthesis.
What is the difference between oligonucleotide and nucleotide?
is that nucleotide is (biochemistry) the monomer comprising dna or rna biopolymer molecules each nucleotide consists of a nitrogenous heterocyclic base (or nucleobase), which can be either a double-ringed purine or a single-ringed pyrimidine; a five-carbon pentose sugar (deoxyribose in dna or ribose in rna); and a …
How are oligonucleotides manufactured?
The oligonucleotide manufacturing process consists of five major steps, (1) synthesis, (2) cleavage and deprotection (C&D), (3) purification, (4) desalting and concentration and (5) lyophilization, as shown in Fig. 1. Additional steps can be added depending on the type of oligonucleotide being manufactured.
Is a chemically synthesized oligonucleotide?
Oligonucleotide synthesis is the chemical synthesis of relatively short fragments of nucleic acids with defined chemical structure (sequence). Typically, synthetic oligonucleotides are single-stranded DNA or RNA molecules around 15–25 bases in length.
What is ribozyme therapy?
Abstract. RNA enzymes – ribozymes – are being developed as treatments for a variety of diseases ranging from inborn metabolic disorders to viral infections and acquired diseases such as cancer. Ribozymes can be used both to downregulate and to repair pathogenic genes.
Are all oligonucleotides primers?
Oligonucleotides made up of 2′-deoxyribonucleotides are the molecules used in polymerase chain reaction (PCR). These are referred to as primers and are used to massively amplify a small amount of DNA.
What is the phosphoramidite method?
Phosphoramidite chemistry is the gold standard method for DNA synthesis that has been used in the industry for almost 35 years. Since its discovery, its simplicity and high efficiency have allowed large volumes of oligonucleotide sequences to be synthesized up to 200 base pairs in length.
Where do oligonucleotides come from?
In nature, oligonucleotides are usually found as small RNA molecules that function in the regulation of gene expression (e.g. microRNA), or are degradation intermediates derived from the breakdown of larger nucleic acid molecules.
What is not included in an oligonucleotide therapy?
What is not included? • Nucleosides/nucleoside analogs • Long sequences of coding genetic material (e.g. gene therapy) • Non-nucleic acid transcriptional regulators (e.g. nuclear hormones, small molecule transcriptional regulators) The Major Classes of Oligonucleotide Therapeutics
How are antisense oligonucleotides used in RNA interference?
The two major therapeutic approaches in this field are the antisense oligonucleotides (ASOs) that inhibit mRNA translation and the oligonucleotides, which function via RNA interference (RNAi) pathway ( Chan et al., 2006; Chery, 2016 ).
How are chemical changes used to improve oligonucleotides?
A portfolio of chemistries can be used to confer drug-like properties onto the oligonucleotide as a whole, with minor chemical changes often translating into major improvements in clinical efficacy. One outstanding challenge in oligonucleotide chemical development is the optimization of chemical architectures to ensure long-term safety.
What is the length of an antisense oligonucleotide?
Generally, the length of an ASO is approximately 20 nucleotides and the ASO is selected to target either the methionine (AUG) initiation codon (to block translation) or splice sites (to block splicing) ( Chan et al., 2006; Chery, 2016 ).
