When youre trying to cure a genetic disease with a genetically modified virus, you dont have to get a perfect score.
You dont have to cure everyone in the trial.
You dont even really have to cure them– Just make their lives a little easier, making it so that they can skip a few invasive procedures, or make it so that you can back off on some more aggressive traditional therapies.
Teeny-tiny wins are still WINS.
Not because we will take what we can get, but because we can modify those tiny wins and turn them into bigger and better wins.
The scientists in this paper took six Hemophilia B patients, and treated them with an Adeno-Associated Virus-8 (two at low, medium, and high doses of virus) that contained a functional copy of the Factor IX gene.
Four of them of them bumped up their Factor IX production enough to go off pharmaceutical Factor IX treatment all together (even with one of the dudes being a marathon runner!), and the two others went from needing treatments several times a week, to only needing a treatment once every couple weeks or so.
These six patients do not have normal levels of Factor IX, even after the gene therapy treatment. Two got to reduce their number of trips to the hospital. And even the ones that got to stop the pharmaceutical treatments, they are nowhere near normal levels, theyre just at ‘good enough!’ levels. Not a 100% win, here.
But it is a win scientists can work with.
For example, these initial patients had to be injected with a ton of the gene therapy virus. Which means that they developed anti-GMO-virus immune responses. Which means you will have a lot of trouble trying to treat them again– this is pretty much a ‘youve got one shot’ therapy.
Ideally, we would like to be able to inject folks with a tiiiiiiiny amount of virus. A tiny amount of extremely efficient viruses, so they get in and do their job before your immune system even knows its there. Maybe meaning you could try second, third, fourth doses to improve delivery.
So HOW do we do that? HOW do we make a tiny win better?
Okay, the functional copy of Factor IX was delivered to patients in a virus called AAV8. The actual structure of the virus is called ‘capsid’ (analogous to these guys in retroviruses). AAV8 capsids are just proteins, so theyre made of amino acids. Some of the amino acids exposed on the outside of the virus are tyrosines. Tyrosines get tagged by your cells to get sent to the proteasome for degradation (totally normal function, way to get rid of old proteins). Which means lots of GMO viruses got degraded before they had a chance to deliver their cargo– a functional copy of Factor IX.
Lets get rid of some/all of the tyrosines and see if more viruses can deliver the cargo before they get degraded!
And in preliminary studies (mouse model, delivering a fluorescent reporter, not Factor IX) it worked!
Mutating a related virus, AAV2, to get rid of some of those exposed tyrosines bumped up how many cells expressed the green fluorescent reporter. They got it as high as 29-fold higher.
Using the units in that previous paper, ‘normal’ Factor IX levels are ~100 IU/dL. The lowest responders were at 1 to 2 IU/dL. If this new ‘GET RID OF THE TYROSINES!!’ idea translates to humans and Hemophilia B, the next round of gene therapy patients might get 29 IU/dl. Patients only needed a few IU/dl to get off the pharmaceutical Factor IX, and 29 IU/dL is way beyond that. Maybe 29 IU/dL means they will only need prophylactic Factor IX for major injuries and surgeries.
We can treat genetic diseases with GMO viruses. And we are only going to get better at it from now on.