There are a lot of unexplored consequences of potentially editing out a gene as important as PCSK9. Some of the compounds it is making are essential to brain and liver development. They'll have to study that for years.
Lipid nanoparticle delivery vehicle is really simplifying a lot of therapeutics. Looking forward to seeing Moderna and Acuitas continue to build out the platform for more targeted or effective actuator delivery.
So the actual tech here is:<p>* mRNA and lipid nano particles to get the mRNA into cells<p>* 2 pieces of mRNA. One codes for the change to break the gene for the protein being targeted and another to create a enzyme to edit the first piece into the genome<p>* both bits of mRNA need to be in the cell, then the enzyme and gene are created and the enzyme edits in the gene<p>So any cell where this works correctly (and its descendents) no longer produces the protein. It appears that about 60% of cells get hit successfully (based on a 60% drop on the protein level).<p>They only targeted liver cells. That's good because the liver tends to soak up foreign materials from blood. But edits were found at low levels in other organs (spleen etc). That shouldn't make much difference as the protein in question is only produced in the liver. But beware I guess as a multi-use protein could be altered in multiple organs.<p>Also, it looks like the edit was very accurate and didn't break other genes at anything like the rate it broke the target.<p>This is pretty incredible stuff. The biochemical equivalent of keyhole surgery.
"Tissue studies showed that the base editing took place <i>almost</i> entirely in the liver.. Modified sequences could be detected in the spleen and adrenal glands, and <i>hardly anywhere else</i>. Similarly, liver samples showed very low levels of <i>off-target editing</i> in their DNA sequences.."<p><i>Yikes</i> there is a lot of important information being glossed over here
> The actual therapy is a long mRNA encoding the sequence of the base editor (with all the appropriate modifications to make it express well – this is very much like making an mRNA vaccine, just with a very different payload. The mRNA vaccines just make an antigen protein, but this one will of course produce a functional enzyme that is itself capable of modifying DNA. That mRNA and the guide mRNA (to tell the newly produced enzyme where to go) are encapsulated in a lipid nanoparticle formulation (again, similar to the vaccines and the existing RNAi therapies).<p>This is mind blowing stuff. I wish our best and brightest put their mind on this rather than working on online ads
So, if I understand the article, the possible medical effect of this specific thing is to change LDL cholesterol levels.<p>Doesn't seem like that would solve any huge health problem, but the proof of concept that you can edit DNA in the liver fairly freely should be enormously fruitful
My biggest worry with this would be the low level of off target edits and the number of recombination events that yielded an unwelcome product. Looks like those were very low, but with an N of 4, hard to know long term. The reason being that when you screw around with DNA you can get cancer. This has been an issue in a variety of cases with gene therapy, though is clearly getting much better. This is really cool though, exciting times!
It's hard to judge even as a PoC in a sample of 4 and just one gene. I hope the research will expand into statistically substantial samples and various different genes.
Oddly worded intro given human trials are "primate" trials. I'd be interested to see if there are different rules for using CRISPR on any person who could reproduce, vs those who can't.