One of our greatest opportunities in modern medicine is to develop therapies by targeting the body's very own genetic material. For illnesses characterized by loss-of-function phenotypes, we are tasked with increasing gene expression. Other conditions stem from aberrant or excessive gene expression, for which we would like to reduce messenger RNA (mRNA) or protein levels, or both, depending on the mechanism of disease. With these, the issue is twofold: how do we repress the expression of unwanted genes, and how do we formulate the therapeutic to be both safe and effective? Much progress has been made in this arena, resulting in the development of strategies employing antisense oligonucleotides (ASOs) or short interfering RNAs (siRNAs) for knockdown of undesirable genes. These techniques are a promising step forward but are not without caveats. Traditional nucleic acid approaches frequently encounter problems with metabolic stability, allele specificity, and tissue delivery.
展开▼
