A new study offers cause for optimism
The genetic editing tool CRISPR-Cas9 has revolutionised biomedical science in the last few years. It uses a chemical process borrowed from bacteria, and allows scientists to accurately and simply cut lengths of DNA out of a cell and replace it with something different.
The mRNA vaccines which are playing a key role in fighting Covid would not have been possible without CRISPR. It is being used to make better, more pest-resistant crops and disease-immune pigs and chickens. In Britain, we have pioneered the use of CRISPR to edit faulty genes in the mitochondria of fertilised embryos, so that families can avoid passing down devastating mitochondrial diseases. One of the pioneers of CRISPR, Berkeley’s Jennifer Doudna, deservedly won a Nobel in 2020 for it.
But the dream would be using CRISPR to cure genetic diseases in adults. The trouble is that there are trillions of cells in an adult human, and that the faulty code that causes a genetic disease — whether that’s Huntington’s, or cystic fibrosis, or sickle-cell anaemia — is in every single one. So while it’s fairly straightforward to edit the genes in an early-stage embryo of perhaps a few dozen cells, doing so in an adult is much more complicated: you would need to do it in the entire body, or at least in large parts of organs or tissues.
So I think we’re allowed to be tentatively, cautiously excited about this study, on six patients with a deadly genetic liver disease, transthyretin amyloidosis. The disease is caused by a faulty gene which mangles the production of a particular protein, making it fold incorrectly and interfere with liver function. The six were injected with a single dose of a drug which contains mRNA instructions to, essentially, build the CRISPR components in the cell: two proteins which tell the cell to cut a particular stretch of DNA out of the genome and then sew it back together. In three of the six patients, it reduced production of the faulty protein by 80%. (Science magazine has done a really good write-up here.)
It’s not the first time CRISPR has been used to treat adult diseases: earlier this year, two patients, one with sickle-cell anaemia and one with β-thalassemia, both genetic blood diseases, had their stem cells taken out of their marrow, edited with CRISPR, and re-transfused into the body. But injecting it as a drug, rather than taking all the relevant tissue out and editing it, has the potential to be much more widely used. There was a successful recent effort to treat a kind of blindness by injecting a CRISPR mRNA drug into the eye, but the eye is small and simple; the liver is not. (Although it does have its own advantages, in that the liver is good at cleaning up all the leftover rubbish from the lipid nanoparticles which deliver the RNA, as Derek Lowe explains here.)
I don’t want to overstate things. This is an early trial, on a tiny number of patients. And there’s a long way to go to make sure it’s safe and effective: CRISPR is astonishingly accurate, but gene editing can still go wrong and have off-target effects, and it needs to be carefully examined. Plus, as mentioned, the liver is a particularly good target for these drugs; it will be more difficult making one that works for, say, the lungs in cystic fibrosis. Also, the diseases treated so far have had simple one-gene causes; genetic diseases that are caused either by one of many possible genes, or an interaction of many genes, will be less amenable.
But the key technologies involved — CRISPR, mRNA and big data/machine learning — are improving at such a rate that I would be amazed if this doesn’t become affordable and effective within a few decades. Millions of people worldwide suffer from one form or another of genetic disease that could be treated with drugs like this. I think you’re allowed to be a bit excited.