What you're seeing here is a key moment for the gene editing tool CRISPR-Cas9.
That's because the doctors are injecting a patient with an experimental drug
that will edit their DNA inside their body.
CRISPR-Cas9 holds a lot of promise, but up till now, all the treatments
in human clinical trials have been ex vivo.
They have relied on taking cells out of the body in order to edit them.
Like in a treatment for sickle cell anemia, researchers removed cells from the bone marrow
of a young woman in Mississippi, modified them to turn on the production of fetal hemoglobin,
and then infused the cells back in.
But for many inherited diseases, like brain, muscle or kidney disease,
you just don't have cells that you can take out and put back in.
Which is why the first in vivo trial, called BRILLIANCE, is so important.
So let's take a look at how the in vivo gene editing drug works.
CRISPR-Cas9 technology is adapted from bacteria and archae,
specifically from a defense system used to detect and destroy phages.
And it's really appealing to researchers because it's cheap, precise, and highly adaptable.
It's also elegant.
Its basic principles are fairly straightforward, although there are many modifications of this
and many layers of additional technologies now being deployed.
But at its core it's a combination of the Cas9 enzyme, which is really good at cutting DNA,
and a guide RNA which directs the Cas9 enzyme to a specific location
in the genome This guide RNA is designed to be unique to each application.
It contains a 20 base pair sequence called a "spacer region" that's designed
to be a homologous base pair match to the cell's DNA.
As this whole complex bounces around the cell,
the Cas9 attaches to the cell's double helix at short sequences called PAM.
The specific PAM sequence depends on the Cas enzyme being used.
Each time this unwinds the double helix just a little bit,
allowing the guide RNA to check if there's a match.
If not, the complex moves off.
But if those base pairs do match, the guide RNA will continue to anneal to the target DNA.
Once the Cas9 detects that every base pair of the spacer region is a match
to the cell's DNA, it cleaves the double helix.
And this by itself can be enough to knockout, or disable, the gene.
Scientists can also provide a repair template to the cell.
And this is the most basic way this technology works,
but CRISPR-Cas systems are being rapidly developed, so it can also do lots more.
Now let's take a look at a CRISPR-Cas9 treatment in practice.
The in vivo trial I mentioned earlier is testing a drug for Leber congenital amaurosis type 10,
a disease that affects photoreceptor cells in the retina
and causes severe, early-onset vision loss.
To get the drug into the eye, doctors performed a sub-retinal injection.
So the procedure itself involves a surgery to perform that subretinal injection
where the surgeon makes three tiny incisions in the eye
so they can put instruments inside the eye to remove the vitreous gel,
which is needed so that the very fine cannula that's used
to make the subretinal injection can be passed across the eye, placed very delicately
under the retina to inject this small amount of gene editing drug.
That drug contains an adeno-associated virus vector.
This virus is the delivery system for CRISPR-Cas9.
So the researchers put the sequence encoding the Cas9 protein
and two guide RNAs inside the virus, and the virus carries it like cargo to the cells.
The target is a mutation in photoreceptor cells, in the CEP290 gene.
So the most common mutation in the CEP290 gene that's associated
with severe early onset vision loss is an intronic mutation that results in the inclusion
of a cryptic exon, an abnormal exon in the gene so the gene doesn't function.
Introns are noncoding parts of sequences that get removed during RNA splicing.
Exons get left in.
And that one wrong letter means that not all of the intron gets removed.
So it's a great target for early CRISPR therapeutic because all we need
to do is cut out the mutation in the intron.
And that, the researchers hope, will restore gene function to the cells.
They're looking to enroll 18 patients, with results starting to trickle in in 2021.
But while they're gonna be paying close attention to the efficacy
of the medicine, the primary outcome is safety.
And a lot of uncertainty still remains about CRISPR-Cas systems more generally.
But one thing is clear: we are finally at a point where the promise
of CRISPR-Cas9 is beginning to be tested out in the real world.