Antisense RNA Therapies

If I'm going to discuss the future power-house technology of RNA interference (RNAi) in the context of fighting cancer, I should probably also mention closely related research into antisense RNA therapies - so says Charles Dorman in an email:

You've mentioned RNAi to cure cancer. Maybe I just missed it, but I haven't seen you mention [antisense RNA (aRNA)] applied to cancer. These articles are old, but this company has gotten its glioma drug through Phase III trials and has many more in the pipeline:

http://www.biospace.com/news_story.aspx?StoryID=19879020&full=1
http://www.engelpub.com/News/index.cfm?articleid=342460&categoryid=21

The results of its Phase IIb glioma trial was that 72 of 75 patients taking their drug were still alive at the time that the whole control group had died -- achieved essentially without side effects.

Both antisense and RNAi therapies are - comparatively speaking, at least in comparison to other technologies readily available today - precision methods of silencing the expression of particular problem genes. This could be thought of as a very limited way of reprogramming the biochemical engine in the nucleus of your cells.

One could say an antisense therapy is more of less half of an RNAi therapy, a comment that makes much more sense after reading this article:

When antisense RNA (aRNA) is introduced into a cell, it binds to the already present sense RNA to inhibit gene expression. So what would happen if sense RNA is prepared and introduced into the cell? Since two strands of sense RNA do not bind to each other, it is logical to think that nothing would happen with additional sense RNA, but in fact, the opposite happens! The new sense RNA suppresses gene expression, similar to aRNA. While this may seem like a contradiction, it can be easily resolved by further examination. The cause is rooted in the prepared sense RNA. It turns out that preparations of sense RNA actually contain contaminating strands of antisense RNA. The sense and antisense strands bind to each other, forming a helix. This double helix is the actual suppressor of its corresponding gene. The suppression of a gene by its corresponding double stranded RNA is called RNA interference (RNAi), or post-transcriptional gene silencing (PTGS). The gene suppression by aRNA is likely also due to the formation of an RNA double helix, in this case formed by the sense RNA of the cell and the introduced antisense RNA.

The Wikipedia entry might be a more gentle introduction:

Antisense therapy is a theoretical form of treatment for genetic disorders. When the genetic sequence of a particular gene is known to be causative of a particular disease, it is possible to synthesize a strand of nucleic acid (DNA, RNA or a chemical analogue) that will bind to the messenger RNA produced by that gene, effectively turning that gene "off".

This synthesized nucleic acid is termed an "anti-sense" oligo because its base sequence is complementary to the gene's messenger RNA (mRNA), which is called the "sense" sequence (so that a sense segment of mRNA " 5'-AAGGUC-3' " would be blocked by the anti-sense mRNA segment " 3'-UUCCAG-5' ").

In essence, you can accomplish a great deal by interfering in the messenger RNA that genes use to accomplish their job of creating proteins. The comments I made in relation to the future of RNA intereference apply just as much here.

Cancer must be dealt with if we are to enjoy much longer, healthier lives, but let's tie this to another topic of great interest to those who follow healthy life extension research. You may recall that researchers have recently discovered that the Lamin-A mutations underlying the accelerated aging of progeria - mutations that lead to malformed cell nuclei and resultant failure of function - are also a part of "normal" aging:

In cells taken from the elderly, the nuclei tend to be wrinkled up, the DNA accumulates damage, and the levels of some proteins that package up DNA go askew ... The team suggests that healthy cells always make a trace amount of an aberrant form of lamin A protein, but that young cells can sense and eliminate it. Elderly cells, it seems, cannot. Critically, blocking production of this deviant protein corrected all the problems with the nucleus. ... You can take these old cells and make them young again.

So then, there is the possibility that any successful therapy for progeria will also be of use to repair these age-related cellular defects. At PubMed, we can find a full text paper reporting on research using antisense RNA technologies:

The fact that the antisense [RNA] reduced prelamin A levels in cells and improved nuclear shape is exciting, raising the possibility that systemic administration of these antisense compounds might ameliorate disease phenotypes in Zmpste24-/- mice or newly created mice with a targeted Hutchinson-Gilford mutation in [Lamin-A].

The next ten years in applied genetics are going to be most interesting.

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