Huge potential for gene therapy

Huge potential for gene therapy:

Huge potential for gene therapy

Scientists have taken an important step towards a new way of treating disease by switching off key genes.

The research, tested in mice by biotechnology company Alnylam Pharmaceuticals, blocks cells' ability to manufacture proteins.

It resulted in cholesterol levels being almost halved - and it is hoped the same approach could eventually treat many diseases from diabetes to cancer.

Details are published in the journal Nature.

This is huge! Drudge siren time. The genetic material is delivered via an injection into the blood! Having diseased genetics used to mean grin and bear it and hope the insurance  company doesn't find out. Now we may actually be able to use genetic testing for something positive like cure or treat the genetic disease via injection.

Here's the first paragraph of the Nature article:

Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs [Rich: You wouldn't know the significance from the article title would you?]

RNA interference (RNAi) holds considerable promise as a therapeutic approach to silence disease-causing genes, particularly those that encode so-called 'non-druggable' targets that are not amenable to conventional therapeutics such as small molecules, proteins, or monoclonal antibodies. The main obstacle to achieving in vivo gene silencing by RNAi technologies is delivery. Here we show that chemically modified short interfering RNAs (siRNAs) can silence an endogenous gene encoding apolipoprotein B (apoB) after intravenous injection in mice. Administration of chemically modified siRNAs resulted in silencing of the apoB messenger RNA in liver and jejunum, decreased plasma levels of apoB protein, and reduced total cholesterol. We also show that these siRNAs can silence human apoB in a transgenic mouse model. In our in vivo study, the mechanism of action for the siRNAs was proven to occur through RNAi-mediated mRNA degradation, and we determined that cleavage of the apoB mRNA occurred specifically at the predicted site. These findings demonstrate the therapeutic potential of siRNAs for the treatment of disease.

Here's how it's done (click on image for larger picture):

Figure 1 Silencing genes the RNAi way. a, For a gene to be expressed, its DNA sequence must be copied (transcribed) into messenger RNA (mRNA); this must in turn be translated into a protein sequence. b, RNAi works by either destroying the mRNA (bottom) or preventing it from being translated (not shown). In Soutschek and colleagues' modification of the general RNAi approach, short interfering RNAs (siRNAs) are synthesized, chemically modified and labelled on the 'sense' strand (blue) with cholesterol. The siRNAs are then injected intravenously into mice, where the cholesterol group enables the siRNAs to be taken up into tissues. There, the sense strand is destroyed by the inherent RNAi pathway, leaving the antisense strand (red) to bind to a complementary sequence in a target mRNA. Recruitment of a protein complex, the RNA-induced silencing complex (RISC), enables the mRNA to be cleaved.

Update: Not everything is rosy in RNAi land. Note this news story in yesterday's Science magazine:

RNAi's tendency to influence genes and proteins that it's not designed to target is provoking questions and controversy, as scientists labor to solve the problem

A promising new approach to manipulating genes is showing blemishes as it moves from its glamorous early days to a more nuanced adolescence. The technique, RNA interference (RNAi), shuts down genes; this braking effect helps reveal a gene's function and could potentially be used to treat a host of diseases. But a growing number of researchers are learning that RNAi, which was hailed for its laserlike specificity by scientists and the press (including Science, which anointed it 2002's Breakthrough of the Year), comes with some unintended baggage. In particular, it can hijack genes and proteins it wasn't designed to target--a potential problem for both basic genetics studies and RNAi-based therapies, some of which are just beginning human testing.

Even experts concerned about these so-called off-target effects hasten to point out that RNAi's future remains bright. But the issue is stirring controversy in the field. Biologists are struggling to determine--and agree upon--just how widespread off-target effects are, why they occur, and what can be done to avoid them. Some are feverishly working to circumvent the problem, with early hints of success.