An ever increasing number of pathological conditions have been found to have genetic components. Sometimes a single defective gene (e.g. Huntingtons’s), other times more complex multigene causes are implicated. If the cause is a non-functional gene (i.e., the protein product does not work) it might help to supply the cell with a good copy of the gene in question – gene therapy. The replacement gene construct can be contained in a plasmid, which has to be delivered to the nucleus. By decorating the plasmid in a modular way with functional groups, the machinery already present in the cell may be "hi-jacked" to perform this delivery. We use simulations to optimize the composition (including the use of modified nucleotides, e.g. LNA or novel bases) and sequence of triplex forming oligonucleotides (TFOs) to bind with high affinity and specificity to double stranded DNA and function as an anchor for functional groups decorating a plasmid carrying genetic material to be introduced in the nucleus. Systematic free energy calculations are applied to sets of systems with the modified nucleotides in different positions and different sequence contexts in the TFO.

Triplex forming oligonucleotides and gene therapy

251st National Meeting (2016)

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