Wednesday, May 19, 2010

Targeting MicroRNA to Increase Good Cholesterol

In back-to-back publications in the journal Science, researchers from Boston and New York demonstrate that microRNA-33 (miR-33) is part of the complex control system regulating cholesterol metabolism (Najafi-Shoushtari et al. and Rayner et al.). The research further suggests that miR-33 is an attractive target for increasing ‘good’ HDL-cholesterol and continues to add to the intriguing possibilities how microRNAs may be exploited for the treatment of a range of major diseases.

Most pharmacologic strategies in cardiovascular risk management today aim at lowering the ‘bad’ LDL-cholesterol, including oligonucleotide therapeutics targeting ApoB and PCSK9 currently in development. It is, however, actually the ratio of the bad to good cholesterol and associated proteins in the blood that provides a better measure of the cardiovascular risk compared to the absolute levels of bad cholesterol alone.

The reason HDL-cholesterol is good for you is because it promotes reverse cholesterol transport from atheromatous plaques in blood vessels back to the liver and excretion via bile. If you come across a colleague in your workplace with an intensely red head, chances are that they have just taken niacin, the most widely used drug to increase HDL-cholesterol. Partly because of the side-effects of niacin and also to even more increase HDL levels, the medical community is extremely interested in additional drugs that can complement the LDL-lowering drugs such as statins with those that elevate HDL-cholesterol. Despite the failed high-profile billion $ gamble by Pfizer on small molecule Torcetrapib, appetite for such agents continues to be high also in the pharmaceutical industry.

Ever since the work by Brown and Goldstein, lipid metabolism has become the prime example for complex, yet robust regulatory networks in biology with lots of built-in feedbacks and redundancies. It is therefore probably not surprising that encoded within an intron (the part of an RNA transcript that is cut out during messenger RNA processing) in one of the master regulators of this network, the SREBP transcription factors, was encoded a microRNA, miR-33, that was co-expressed with SREBPs and similarly functioned in cholesterol regulation. While SREBPs contribute to the synthesis and cellular uptake of cholesterol, miR-33 redundantly works to increase cellular cholesterol levels by targeting members of the ATP-binding cassette transporter family involved in the transport of cholesterol out of cells (loading of cholesterol onto HDL apolipoproteins).

In other words, inhibiting miR-33 function should enhance cholesterol efflux from cells. This would be particularly beneficial for macrophages that by overfeeding on LDL-cholesterol play a central role in forming plaques and clogging up arteries. Indeed, the researchers were able to show that the inhibition of miR-33 with antisense would do just that: increase cholesterol efflux from macrophages. Preliminary data showing the predicted increase in HDL-cholesterol following systemic administration of miR-33 antisense molecules were presented as well.

Although encouraging, in order to firmly validate mir-33 as a therapeutic target for increasing HDL-cholesterol, a more thorough understanding of the consequences of miR-33 inhibition is required as are strategies aiming at targeting miR-33 preferentially in the atherogenic macrophages and possibly also hepatocytes. This, however, should be a quite realistic goal given that phosphorothioate antisense molecules alone as well as a number of oligonucleotide nanoparticle delivery systems are preferentially taken up by these cells anyway.

It is quite exciting to see so many microRNAs emerge as potentially high-value therapeutic targets. It is a testimony to the intense interest these small RNAs have attracted in the scientific community as they are involved in very likely almost all biological pathways. This should both help to establish microRNA Therapeutics as a vibrant industry able to stand on its own feet due to the many therapeutic opportunities, and also benefit RNAi Therapeutics by contributing to our understanding of the molecular mechanisms and functions of the natural counterparts of RNAi triggers.


Anonymous said...

Excellent analysis as usual. It will be interesting to watch the progression of microRNA research over the next few years.

In your opinion, roughly how many years will it take for a microRNA drug to be approved by the FDA?

Dirk Haussecker said...

5-7 years? Mir-122 for HCV infection looks like a strong candidate.

Anonymous said...

Is it too early to predict with any certainty if microRNA-based drugs would be more effective and safer than monoclonal antibody or small molecule drugs?

Dirk Haussecker said...

It is difficult to answer your question. For many of the diseases that microRNA therapeutics may address, there should also be valid small molecule and monoclonal antibody approaches. The profiles, however, will differ and affect how they will be used in the clinic. The ability to target networks and on an RNA level should certainly let microRNA Rx stand out in many cases.

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