Tuesday, November 10, 2009

Combining Forces to Understand RNAi Therapeutics Inside Out

This entry is first a PR on a business development of the blog itself, but also reflects what should be the next major value-driver in RNAi Therapeutics after the liver: solid cancers.

Solid cancers are a very attractive target for RNAi Therapeutics because of its unmet needs and because of the so called Enhanced Permeability and Retention (EPR) effect of solid tumors which means that it should be possible to target them with siRNA-containing nanoparticles. Getting there, of course, is only half the story. The particles need to navigate their way through the extracellular matrix of tumors, latch onto the cancer cells, be taken up, and then finally be released into the cytoplasm. This requires a good understanding of nanoparticle-related chemistry and physiology, the biology of the extracellular matrix of cancer tissues, and cancer cell membrane biology.

Enter Tobias Wolfram. I have known Tobias since my days studying biology in Heidelberg (10 years ago now!) and have since been impressed by his enzyclopaedic knowledge of not only biology, but also history, psychology, economics and what not. He spent much of his time as a teenager with science projects and in molecular biology labs and won national prizes, at a time I did not even know that PCR existed. Since then he has become a truly multi-discliplinary scientist spanning the subjects of biology, chemistry, and material physics. Right now, he is at the Max-Planck-Institute for Metals Research in Stuttgart, the home of German engineering, where Tobias employs precisely engineered nanometer-patterned substrates for studying the interaction of cells with the extracellular matrix and their use for cell-based diagnostics. I visited him there two weeks ago to talk about working more closely together on the topic of RNAi trigger delivery.

In an experiment, we have decided to combine his expertise in getting molecules to cells with my understanding of the molecular biology of RNAi inside cells, to hopefully provide more insightful blog entries on the topic of RNAi Therapeutics delivery, with an initial emphasis on solid cancers. With Calando, Alnylam, and Silence Therapeutics having active programs in solid cancers, we will, over the next couple of weeks, start by taking a look at each of the applied technologies.

4 comments:

GS said...

I wasnt aware of EPR, interesting, thanks.

When you talk about the challenge of getting triggers actually into target cells - something I fully appreciate - can I ask what your views are on how possible this is?

Presumably pre-clinical experiments can be very informative, since the physiology in humans is the same in many respects.
Can triggers be delivered to target cells in larger organisms without for example having to administer worryingly high doses?
(I'm primarily referring to systemic dosing here)

I look forward to hearing your combined views on the candidates targeting solid tumours.

Anonymous said...

Love the blog, but the white letters on black is limiting my ability to read it. Any way to invert it??

Anonymous said...

Great blog - but I agree with the text color. My workaround: click a letter and the press control-A to select all the text. This is how I read it to avoid going blind.

Dirk Haussecker said...

Thank you for letting me know about your reading difficulties. I will see whether other color modes will work, too. My only concern is that by switching, some of the older blog entries will become difficult to read.

GS- "Can triggers be delivered to target cells in larger organisms without for example having to administer worryingly high doses?" It depends on your target. Adding targeting ligands should in many cases allow for lowering the dose to be administered for reaching a target organ/tissue/cell types, but at the cost of more complicated formulation and the risk of running into immune issues.

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