Drug development: Arrive and shine

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Drug development: Arrive and shine
Drug development: Arrive and shine

Arrive and shine

Eating he althy, exercising, not smoking - all this helps a lot, but sometimes it is not enough to protect the stressed body from accumulating blood lipids and prevent arteriosclerosis and heart disease. In these cases, small RNA drugs could soon be in their prime. Oh, these annoying little, subtle differences: unfortunately, a promise does not equal fulfillment, individual cells do not equal whole organisms and humans are not mice. And that is why interventions that appear promising on paper in real life often fail unpredictably; in cell cultures, wonderfully effective medicinal miracle weapons are dull or even sometimes harmful in the living organism. And some drugs that stabilize blood levels in rodents, dry out tumors or compensate for gene failures are ineffective in human test series.

Whenever a promising, innovative, clever new approach is found and presented after a long analysis, with which a disease can perhaps be combated, the much longer phase of boring routine work begins: Many tests here, there is still more filing to be done, namely adapting the fundamentally effective substance to the requirements of biological and medical reality. Attempts to use this technology to actually cure diseases are now also in this phase – a few years after so-called RNA interference caught the glaring light of the expectant public.

In the laboratory and in the test tube, RNAi has been working extremely well for a long time. It can be used to switch off genes in a targeted manner and without great effort: the injection of short RNA strands into a cell blocks those genes whose sequence matches that of the injected RNAs. This works because the cells' enzyme apparatuses recognize the introduced RNA, trim it down to the right length and pass around all the resulting "siRNA" snippets as a template for comparison within the cell. If the cell's own messenger RNAs are found with a matching base sequence, then the template and mRNA are degraded - and the proteins whose construction instructions are contained in the mRNAs are therefore no longer produced.

Wonderful. So, in order to lower the cholesterol levels of people at risk of heart attack, for example, would only an RNAi against, for example, the body's own metabolic producers of the "bad" cholesterol, be packed in pills and administered in the correct dose? That's true in principle, but as always, the devil is in the details. Tracy Zimmermann and her colleagues at the biopharmaceutical company Alnylam tell us more about it.

They are working on one day switching off a specific protein (apolipoprotein B, or ApoB for short) in a specific human tissue cell type (in the liver) without side effects. This would probably have encouraging consequences: ApoB, mainly produced in the cells of the liver and upper small intestine, is crucial for the secretion and production of "low-density lipoproteins" (low density Lipoproteins, LDL) with – the so-called "bad cholesterol". And the less LDL in relation to the "good" cholesterol transport form HDL, the lower the susceptibility to heart disease, according to medical doctrine.

In mice, switching off ApoB via RNAi works quite well – with the help of targeted injections of the RNA drug into the liver cells. Zimmermann and colleagues went two steps further – they packaged the RNAi dose in a special lipid envelope and tested it on the laboratory's second most human-like organism – a clan of long-tailed macaques (Macaca fascicularis). The packaging of the RNAs allowed the dose to simply be injected into the monkeys' tail veins and let it find its way to the liver on its own.

This was spectacular: after 48 hours, the liver cells of the monkeys – depending on the dose used – reduced their ApoB production by an average of eighty percent for up to eleven days. Other cell types were unimpressed. The LDL levels in the blood of the treated animals plummeted accordingly.

The researchers are pleased that a possible application in humans has come a step closer. Successful lipid packaging – code name SNALP for stable ucleic acid lipid p articles – could also benefit other drugs that are supposed to develop their effect specifically in the liver. So even if it doesn't hurt to keep your cholesterol levels low in the tried and tested way for now – the jump of RNAi from the laboratory bench into higher medical spheres could be imminent.

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