RNA-targeted RNA interference therapy

We hope to someday understand enough about what goes wrong with the cells of the aging body that we might rationally intervene to prevent their decline. When that revolution comes (it is not yet come), we will be challenged with the task of specifically altering a significant proportion of cells in their tissue contexts, in living humans, with very nearly zero side effects.

Some of the candidate therapeutic materials will be small molecules of a sort that wouldn’t surprise a 20th-century pharmacologist, but others will be more exotic. In particular, I expect that small interfering RNAs (siRNAs) will do a lot of the heavy lifting in therapies that target specific genes. Once siRNAs are inside a cell, they can negatively regulate gene expression with breathtaking specificity (especially if multiple sequences are employed, drastically diminishing off-target effects while increasing the efficiency of repression)…but presumably, since one is aiming for zero side effects, one wants to deliver them only to the cells of interest, conferring an additional layer of specificity.

The solution also comes from the RNA world: A study by McNamara et al. cunningly employs chimeric RNAs to accomplish both specific delivery and specific gene repression. One part of the drug molecule is an aptamer (an RNA “bred” to bind specifically to a target protein), and the other part is the precursor of an siRNA. The aptamer directs the drug to the correct cells (in this case, tumor cells expressing a prostate-cancer-specific surface protein); once inside, the siRNA precursor is free to be processed and to inhibit gene expression (in this case, of prostate-cancer-specific survival genes):

Technologies that mediate targeted delivery of small interfering RNAs (siRNAs) are needed to improve their therapeutic efficacy and safety. Therefore, we have developed aptamer-siRNA chimeric RNAs capable of cell type–specific binding and delivery of functional siRNAs into cells. The aptamer portion of the chimeras mediates binding to PSMA, a cell-surface receptor overexpressed in prostate cancer cells and tumor vascular endothelium, whereas the siRNA portion targets the expression of survival genes. When applied to cells expressing PSMA, these RNAs are internalized and processed by Dicer, resulting in depletion of the siRNA target proteins and cell death. In contrast, the chimeras do not bind to or function in cells that do not express PSMA. These reagents also specifically inhibit tumor growth and mediate tumor regression in a xenograft model of prostate cancer. These studies demonstrate an approach for targeted delivery of siRNAs with numerous potential applications, including cancer therapeutics.

This paper addresses a cancer model, as opposed to an aging model, but the approach is quite general: All one needs is a surface marker specific to the cell type of interest (against which one would design the aptamer moiety) and a mission for the siRNA moiety to perform once the RNA is inside the cell, (e.g., inhibition of the master regulator of senescent cells’ bad attitude, once we figure out what it is). The former requirement underscores the value of identifying cell-surface biomarkers specific to age-related damage; the latter is the implicit subject of any number of ongoing research projects.

That the whole drug consists entirely of RNA, rather than some sort of proprietary heterocycle, is icing on the cake: even tricked out with backbone modifications for stability etc., drugs like these will be easy and cheap to synthesize and standardize.