Role of Gene Therapy in SCD Management

Biree Andemariam, MD: Let’s have a discussion about gene therapy. Matt, what’s the role of gene therapy in the management of sickle cell disease? If you had a crystal ball, how will it may stand in the future? For the future to occur, for whatever you describe, what needs to happen between now and then?

Matthew M. Heeney, MD: The role of gene therapy is experimental. There are no FDA-approved gene therapy curative options for sickle cell disease. But the hope is that toward the end of this year, the first lentiglobin, or betibeglogene autotemcel, will be approved or move toward approval by the FDA. The decision for this treatment will become a reality soon. To give a brief overview of the gene-therapy approaches, there’s a gene addition approach, which adds the normal or a modified normal β-globin to replace or add to the sickle cell β-globin. There is an approach that adds back a γ-globulin to try to induce more fetal hemoglobin production productions. These are all lentiviral-based gene addition approaches. Another major approach is to try to harness the effect of BCL11A. BCL11A is a transcription factor that represses γ-globin or fetal hemoglobin in the physiologic switch from γ-globin to β-globin or from fetal to adult hemoglobin. There are a number of ways to do this.

Another gene-addition approach is to add an RNAi [RNA interference] knockdown. This knocks down the expression of BCL11A and therefore the repressed γ-globin. Another method of trying to eliminate BCL11A is through gene-editing approaches. These can be through zinc finger nuclease or CRISPR-Cas9, which attach the intronic enhancer that’s specific to erythroid expression of BCL11A. There are ongoing trials of that mechanism, which is exciting. Hopefully we’ll see results soon.

The next approach is base editing, in which you’re trying to change a single base. This can have benefits to induce fetal hemoglobin by activating some of the hereditary persistence of fetal hemoglobin promoters in the γ-globin gene. Another approach is to focus on the sickle cell mutation itself. Instead of returning or correcting the sickle cell mutation, this induces a different change at that site, to change the patient from expressing sickle cell hemoglobin to hemoglobin G-Makassar. This is felt to be a benign variant but also a potentially curative approach.

Finally, gene correction is probably the holy grail. I just noticed that the first patient has been enrolled on a trial to look at this homology-directed repair to try to correct the sickle cell mutation. There are a number of flavors of gene therapeutic approaches. It’s not entirely clear which 1 will be most effective. All will require myeloablative-conditioning chemotherapy, which may have its own complications in sickle cell disease. It seems as if we don’t know where we’re going to go. I joke that this is like different [formats for watching] movies. We used to watch Betamax, VHS, DVD, and Blu-ray. They’re all great for watching a movie with your family. They may all have efficacy, but it’s hard to know what’s going to be the next Netflix, which is going to put them all out of business. Some of us who still have a Blockbuster card. It’s not understood, but there’s a great deal of hope that they all may be somewhat effective.

The second part of your question is how this is going to make inroads on the unmet needs. At no time soon are the 100,000 patients with sickle cell disease in the United States are going to be cured by gene therapy. This requires a huge amount of resources and a huge amount of specialty care. There may be an ability to have centers of excellence with a hub-and-spoke model, but it’s going to take years to treat a significant number of patients. Most of the burden of the disease is in parts of the world where there’s no hope of gene therapy making inroads in the decades ahead. I still think there’s a lot to be learned from it. It’s very exciting. For some patients, it may prove to be a curative option, particularly those who don’t have a donor who could have a matched-sibling transplant or 1 of the alternative donor transplants that Elna discussed earlier. There’s a lot of excitement, but it’s tempered by the fact that it’s very experimental.

Transcript edited for clarity