Editing the Question on Gene Therapy from Can We to When Should We?

Editing the Question on Gene Therapy from Can We to When Should We?

This is a continuation of sorts from my prior post here: "Time for a Revision on Gene Editing for Cholesterol?"

One of my heroes in science is Linus Pauling, winner of two unshared Nobel Prizes. He was awarded the 1954 Nobel Prize in Chemistry in part for his work on sickle cell anemia, defining it as a molecular disease (https://en.wikipedia.org/wiki/Sickle_Cell_Anemia,_a_Molecular_Disease). Now, seven decades later, the Food & Drug Administration is poised to approve a gene editing based therapy for this disease, representing a major and important advance for patients with this painful and life limiting condition. This is but one of many gene therapy treatments which are approved or are in trials. We are in truly exciting times!

It is now clear that modern medical science has the capability of developing gene therapies for many serious conditions. I would posit that a timely question now is when and how should we use this tool? To answer this question, I’ll consider a few case examples: sickle cell anemia, Fabry disease, and heterozygous familial hypercholesterolemia (HeFH). These are three distinct genetic diseases with important implications (all three happen to affect the heart directly or indirectly, my personal favorite organ).

The first principle of selecting a disease for gene therapy has to be the severity of disease. There could come a time in the future when we are so comfortable with the safety of gene therapy that we would consider it for mild conditions. We are far from that state today. We should instead focus our work on severe genetic conditions which cause significant reduction in quality or quantity of life.

Second, the availability and effectiveness of existing therapies is a critical consideration. If a disease can be well managed by safe, widely available therapies, the ethics and importance of permanent genetic changes simply to increase convenience and adherence are more challenging. That is not to say that treatments need to be perfect. The standard has to be to compare to the potential impact of the gene therapy. If a disease’s impact can be 90% mitigated by existing therapy, should we focus on gene therapies targeting a similar level of efficacy for this early stage in their development? Conversely, a disease where most patients have only modest response to existing therapy but gene based therapy could be expected based on mechanism and animal studies to offer much greater efficacy might be reasonable.

For the third point, I’d like to dive more into the types of mechanisms where a gene therapy might be more effective than other types of medicines. There are certain diseases where people have tried to make a small molecule and failed. For some conditions, like Fabry disease, a replacement for a defective enzyme can be infused and is effective at preventing complications, even if it doesn’t always get to the origin that normally makes it. However, an infused protein drug (e.g. monoclonal or synthetic protein replacement) may not be effective for other conditions because the site where it would need to act is intracellular. In sickle cell disease, for example, infusing normal hemoglobin into the blood stream would not be effective – it has to be inside of red blood cells to safely perform its oxygen carrying function. Getting synthetic proteins inside of cells in a living human is a difficult task.

In some of these cases, an RNA-based drug may be an alternative – reprogramming cells to turn on or off expression of a native or engineered gene. The variant hemoglobin inside red blood cells would need to be suppressed, replaced with expression of normally functioning hemoglobin. This could theoretically be done with an RNA therapeutic, if there were a good way to target the RNA to the appropriate bone marrow cells that produce red blood cells. That type of targeting remains challenging and thus permanent editing is emerging as a reasonable clinical option for some patients. In this approach, progenitor cells are engineered to produce normal hemoglobin and introduced to the patient, after using chemotherapy to eliminate the patient’s own stem cells carrying the sickle cell mutation.

So what about HeFH? This is a bad disease but also an example of a condition which doesn’t meet either of the other two conditions. Patients experience heart attacks and strokes, often at a young age. Fortunately, there are three classes of oral medicines with proven benefit not just for lowering LDL but reducing heart attacks and strokes (statins, ezetimibe, and bempedoic acid). Another drug target, PCSK9, can be reduced with monoclonal antibodies infused at home every few weeks or with an RNA drug infused in the clinic twice per year. Oral tablets targeting this pathway are also in advanced stages of human testing. This same gene is being targeted in gene editing therapies by Verve Therapeutics. Their drug lowers cholesterol similarly to monoclonal antibodies and RNA drugs targeting PCSK9. What should the safety standard be for a permanent gene editor with unproven long-term toxicities? I believe it should be very high. There is little reason to continue to pursue this target at this time when 2 of 10 individuals in an early-stage trial had severe cardiac complications.

There may come a time when gene editing is so mature, with a strong, established safety record that pursuing an irreversible gene editing drug primarily for dosing convenience would make sense. That time is not now.