ASH 2024 | The promise of gene therapy approaches in SCD and barriers that remain to their implementation

This is an exciting time. It has been more than 100 years since sickle cell was discovered in 1910, but in the last few years, it is exciting to see the new development from new molecules to newer approaches to allogeneic transplant and the transformative therapy of gene addition and gene editing. But the problem starts with the first – access. So I think it is, I can go on and on about these promises and how many great successes, but it means nothing if patients cannot have access. And that access is on a multi-level. It starts with patient education, it goes to community education, and third, it is the healthcare system and healthcare policy that will allow access. This is beyond just the price that is expensive. We need to have structures that can enable us to take care of these patients in a comprehensive way, to discuss all the options, educate them about the possible benefits, but also the possible side effects and how long it’s going to take to achieve this. This is not a simple injection that you could deliver in the office. We currently, with the number of patients and the capacity of the gene therapy companies, we cannot simply deliver that care to everyone. So we have to build up the system to be able to take care of them and to prioritize the patients who are in most need. So that really is the biggest challenge, access, access, access. 

Then it is really how could we improve on some of these therapies. So this therapy, specifically gene therapy, is being done through a chemotherapy conditioning regimen. So the challenge is that many patients, they may have some end-organ damage, they cannot tolerate that, or they may be concerned appropriately about the long-term side effects, increased risk of secondary cancer, increased risk of infertility, and that’s why some newer technology that was presented for the first time here at ASH is quite exciting. 

So there are some preclinical data about two newer approaches. First, it is for in vivo gene editing using some RNA. That’s quite exciting that it is enabling, with repeated treatment in some animal model, to elevate the fetal hemoglobin. And the second, that it is probably going to come sooner to clinical trial, is the newer technology of gene editing through base editing or even double editing, where you can edit the stem cell with what we call a shield against the CD117 antibodies. By using this shield, it can protect the modified hematopoietic stem cell from the effect of the antibody against the CD117. So you can give that antibody without the need of chemotherapy to deplete the bone marrow from the affected cells and allow the infusion of the modified cells without trying to get side effects from the antibody. And today, in the plenary session, it shows actually some of that initial result in the preclinical model where there is a persistently increased level of fetal hemoglobin. So I am optimistic, and I think this is a promising technology that we hope, we call it the ESCAPE trial, that could come potentially to fruition in the next year or following year.

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