36


August/September 2010


Oligonucleotides: The Next Big Challenge


For Analytical Chemistry Chromatographic Society Symposium at GSK Ware 27 and 28th October 2010


by George Okafo1 & Chris Bevan2 ,* 1Scinovo, GSK, Ware, SG12 0DP - 2 The Chromatographic Society, c/o Meeting Makers, Jordanhill Campus, 76 Southbrae Drive, Glasgow, G13 1PP *Corresponding author: chromsoc@meetingmakers.co.uk


Research and development of oligonucleotides as therapeutic medicines is experiencing exponential growth and interest within academia, the biotechnology and pharmaceutical industries [1] by several key historical events including:


1. The regulatory approval of the first antisense oligonucleotide (ASO) for cytomegalovirus infection Vitravene® (1998)[2]


,


2. Approval of Macugen®, an aptamer for treatment of wet macular degeneration (2005) [3]


3. The discovery by Drs Andrew Fire and Craig Mello of gene silencing by RNA interference (RNAi) (published 1998, Nobel Prize, 2006).[4]


RNAi technology has been used to validate gene targets, and both RNAi and ASO technologies have been used to interfere with targets that are considered non-druggable by traditional small molecule interventions [5]


. The early Nobel Prize-winning work by Fire and Mello


demonstrated that some genes in C.elegans can be switched off by the introduction of double stranded small interfering RNA (siRNA) to block the normal translation of a specific messenger RNA to the protein product [4] to mammalian cells and the molecular process characterized.


Oligonucleotide therapeutics


Oligonucleotide therapeutics can be divided into a number of different classes based on mechanism of action;


1. siRNA’s and microRNA ( miRNA) use RNA interference to degrade messages via a phylogenetically conserved regulatory mechanism[6][7]


Anti-sense oligonucleotides (ASO) working either through steric hindrance or RNA degradation via RNAase H degradation of double stranded RNA.[8]


(miRNA) to down-regulate the production of a harmful protein [7] ,


others stimulate the body’s immune system (sequence dependant ASO and siRNA) [10]


or work by interacting with a specific gene sequence to restore function to a defective protein ( exon skipping ASO) [11]. As


Receptor or soluble mediator antagonism using single stranded oligonucleotide ligands such as aptamers and speiglemers.[9] Each oligonucleotide class has a different mechanism of action; some work by blocking a specific gene (siRNA, ASO) [6] [8]


or family of genes


scientific knowledge of oligonucleotides grows coupled with increased evidence of clinical efficacy of these compounds as drugs, the pharmaceutical industry has considered it worth investing billions of dollars to develop oligonucleotide-like drugs to treat diseases ranging from viral infections [12]


, immuno-inflammation [13] and certain cancers


(acute myeloid luekeamia) [14] to rare diseases like Duchenne muscular dystrophy [11], thrombic thrombocytopenic purpura [15] caused by genetic mutations.


, thought to be . This early identification of the process has been extended . This has largely been driven


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