Gene therapy is part of an increasingly large collection of research fields: those with a huge, useless backlog of innovations. Gene therapy researchers have spent decades developing amazing, world-changing therapies with absolutely no ability to use those therapies outside of a test tube, or at best a cloned rodent. Now, with the advent of advanced gene-editing tech, we can apply them, and dozens of genetically inherited diseases could soon be curable as the result. The latest example is hemophilia, and the incredible recent progress toward a cure (or cures) show just how much potential the field really has.
Hemophilia is a disease defined by insufficient clotting of the blood, and in extreme cases it can lead to excessive bleeding with as little as a small bruise. One of the two main types of the disease is called hemophilia B, caused by a deficiency in a particular clotting protein, called Factor IX. Injections that can currently provide a synthetic version to replace factor IX can be ruinously expensive — one patient told Technology Review his treatments cost three quarters of a million dollars per year.
One of the main centers making progress in this field is called Spark Therapeutics, which recently announced findings in four human patients: the patients given gene therapy treatment showed naturally produced (“endogenous”) factor IX production to about 30% that of a healthy person. That’s far from what we would call a healthy level, but it does provide a huge proportion of the most important therapeutic effects of the injections — namely, it stops bleeding from truly incidental trauma like bruises and sprains.
A simplified schematic of the CRISPR system. RNA guides Cas9 in cutting at the CRISPR sequences.
Though the treatment is in no way a pass to a totally normal life — at least, not yet — it does allow patients to forego their injections without taking on any unreasonable risk during the basic activities of life. That’s the threshold of a cure; not a perfect cure, mind, but a cure nonetheless, and there’s every reason to believe the effectiveness could improve in the future.
It’s a breakthrough that has the potential to affect the lives of millions of men — men because, as a recessive, X chromosome-linked disease, hemophilia A and B are both found virtually entirely in the male population. Women, with their second X chromosome, have a second chance to get a healthy version of the gene and thus have a much smaller chance of getting the associated disease. About 1 in 5,000 males is born with Hemophilia A, which has to do with the function of the protein factor VIII, and 1 in 30,000 is born with hemophilia B, due to defective versions of factor IX.
In fact, the challenge at this point may be as much to modulate the effect down as up, with national regulators beginning to worry that increasing the natural factor IX output could lead to accidental over-compensation, and the production of potentially fatal blood clots. Just a few years ago, the whole idea of increasing this sort of protein output through gene therapy was considered at least a bit idealistic; today, there are genuine concerns about how to keep from increasing those protein levels too far.
An adeno-associated virus much like Spark’s custom-engineered one affecting these diseased liver cells.
One big reason is that gene therapy technologies for inserting genetic material into the cells of interest are still very primitive in an objective sense; only a minority actually reach their targets, and only a minority of these actually manage to get their genetic payload into the cells. As a result, these early therapies must usually find a way to augment the baseline infection rate of their therapeutic virus. Most commonly, they infect a small proportion of cells and allow those cells to out-compete non-infected ones, simply because they’re healthier. In this case, without such an evolutionary mechanism to help them, the scientists had to go for a more extreme version of the factor IX protein.
That’s why the worry about over-clotting: the version of factor IX that is being used by the therapy was in fact found and copied from a real patient suffering from overly common blood clots. Despite the low number of cells “fixed” through insertion of the super-factor IX, its incredible level of activity, almost eight times that of the natural version, allows it to make up for its low concentration. And the team has already increased the infection rate by making their custom virus head more directly for the liver, where its therapeutic genes are actually needed. Only time will tell whether it turns out to be safer and more effective to increase the virus’ infection rate for the target cell type, or the protein’s clotting strength, or both.
Unlike real viruses, these therapeutic ones have been neutered of their replication mechanisms, meaning that the low infection rate can’t become a high one without another deliberate infusion of the virus from doctors — so it’s not likely the protein levels will run away unexpectedly. Still, it’s worth being cautious with anything derived from a quasi-living entity evolved very specifically to do things to our cells that our cells want to stop them from doing. Putting such microscopic beasts to work is a very powerful approach, but it’s one that requires great care as well.
Now read: What is gene therapy?