Proof of Concept for siRNA in Melanoma

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Image: Flickr - shikeroku
By far the majority of marketed drugs modulate the activity of proteins. Since the discovery of RNA interference (RNAi) over 10 years ago, a major goal has been to develop agents which will selectively block the synthesis of target proteins. Small interfering RNAs (siRNAs) occur naturally and are believed to have evolved as a defence mechanism against viral infection but synthetic siRNAs could potentially be used to silence any target gene. Although the idea is not conceptually difficult and many cancer-associated genes have been silenced in laboratory experiments, there have been a number of obstacles in developing RNAi for clinical use, not least of which is how to deliver the siRNAs to the target cells.

A team led by scientists and clinicians at the California Institute of Technology (Caltech) has now published the results of a small phase I clinical trial in patients with skin cancer showing that targeted nanoparticles can traffic into tumours and deliver siRNAs in a dose-dependent fashion when administered intravenously. The siRNA-containing nanoparticles used in the study are being developed by Calando Pharmaceuticals, Inc. and the technique used for detecting and imaging the nanoparticles inside cells from tumour biopsies was developed at Caltech. Although phase I studies are primarily designed as safety studies, the team was able to demonstrate that, in one patient who received the highest dose of nanoparticles, the target mRNA (M2 subunit of ribonucleotide reductase (RRM2)) had been cleaved at the predicted position and that protein levels had also been reduced.

Although more trials will be needed to show that such treatment is safe and effective, the study provides the first evidence that nanoparticles and RNAi can be combined to reduce expression of cancer-associated genes in human patients.

The results are published in the journal Nature.

Malaria Uses Cholesterol Receptor to Enter Liver Cells

mosquitoMalaria is a global health problem and causes 2 – 3 million deaths each year. Mosquito bites allow malaria parasites to enter the bloodstream. Within 30 minutes, the parasites are transported to the liver where they enter cells and start to reproduce rapidly. Following release from hepatocytes, the parasites re-enter the bloodstream and infect red blood cells, triggering the pathology that is associated with malaria.

The receptor on human liver cells that allows the malaria parasites to enter hepatocytes has been identified as the scavenger receptor (SR-B1). This receptor normally transfers cholesteryl esters and other lipids from high density lipoprotein (HDL) in the bloodstream into liver cells. A new study shows that, in cell culture experiments as well as experiments in mice, blocking the SR-B1 receptor dramatically reduced the ability of the malaria parasite to infect liver cells. The researchers used RNA interference (RNAi), monoclonal antibodies, and small molecule inhibitors to demonstrate the importance of the SR-B1 receptor for entry of malaria parasites into hepatocytes. The study demonstrates that blocking the SR-B1 receptor may offer a new approach to the prophylaxis of malaria.

Targeting host mechanisms promises better protection against the emergence of resistant strains of the malaria parasite but, in this case, should be balanced against the atherosclerotic potential of long term blockade of the SR-B1 receptor.