Gene Patching by Oligonucleotide Crossover

During replacement gene therapy, we normally think of replacing the whole defective gene with a complete functional copy. However, some genetic defects consist of just a single base change, or perhaps a cluster of closely linked base alterations. In this case, the defective gene could be “patched” rather than replaced. This may be done by crossing over with a relatively short double-stranded oligonucleotide, which carries the wild-type sequence.

The crossover frequency may be improved by using an RNA-DNA hybrid oligonucleotide. Such hybrids are known to take part in crossover formation more readily than double-stranded DNA. In addition, designing hairpin bends protects the ends of the oligonucleotide and prevents degradation by exonucleases. This technique is still in the experimental phase.

Gene Patching by oligonucleotids

FIGURE: Patching Defective Gene by Oligonucleotide Crossover
A special gene-patch oligonucleotide can be synthesized to provide a corrected copy of a short specific region of a defective gene. The oligonucleotide is designed to promote a crossover in the defective region of the gene.

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