Most people have never heard of siRNA, but it’s going to change the face of medicine.
worksinprogress.co/issue/the-kill
Much drug development today involves developing chemicals to fit into proteins and block them. But this almost never turns out as planned: many drug candidates get broken down in the body, interfere with other proteins and cause toxic side effects, or fail to be absorbed at all.
The majority of proteins are considered undruggable, because they lack a pocket for drugs to bind, or they are ‘intrinsically disordered’, without coherent structure.
What if, instead of trying to block the protein, you could simply switch it off?
In a new article, Jacob Witten explains the magic button to silence genes.
siRNA, or ‘small interfering RNA’, is a short strand of RNA that blocks the production of proteins. As a brief refresher, proteins in the body are produced through the sequence: DNA --> mRNA --> protein. siRNA molecules bind to the intermediate mRNA and target it for destruction, meaning the protein isn’t produced.
It’s a precision medicine: siRNA targets matching mRNA sequences like a barcode, so you can pick a gene of your choice, synthesize siRNA to match, deliver it to the right cells, and silence the protein. And a single dose can last months.
Several siRNA drugs have already been developed: patisiran for hereditary transthyretin amyloidosis, inclisiran for high cholesterol, and fitusiran for hemophilia, are just a few examples.
So far, all of them target the liver, which is an easy organ to deliver drugs to. But the principle can be applied to other organs too, and scientists are developing ‘molecular address labels’ to do it.
And while some of these diseases are caused by a single gene, not all are. High cholesterol, for example, is a complex disease, but it can be targeted with siRNA drugs as well, because the disease’s pathway hinges on a critical protein, PCSK9.
siRNA is exciting because it makes it possible to circumvent the problem of otherwise ‘undruggable’ proteins. And, unlike current gene-editing therapies, it can be given to people off the shelf, without needing to extract cells from the body, edit and replace them. But it’s still going to depend on having the right hypotheses of which genes to target and delivering the drugs safely to the right organs.
We now have a kill switch for harmful genes.
Read the full article here:
worksinprogress.co/issue/the-kill
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One of the best things about being an editor is being able to bring pieces into existence.
This idea we featured in our 'list of pieces we'd like to commission' last year (worksinprogress.news/p/more-article) and got a great pitch from , who works on RNA therapies himself!
After reading about the horrors biochemists had to go through in 'The Billion-Dollar Molecule', this method seems much more elegant:
It seems like there are so many promising things happening in medicine rn!
"Yet the broader point still stands: siRNA delivery beyond the liver is a matter of when, not if. If biologists can identify proteins that are critical to the progression of a disease, those diseases can become treatable or preventable." 
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