Breaking or fixing? A tale of two approaches for hemoglobinopathies

Painting by Hertz Nazaire

Covid19 is affecting everyone, but it has hit the sickle cell (SCD) community particularly hard. According to STAT News the pandemic has temporarily stopped clinical trials and the introduction of new drugs, besides directly impacting SCD patients who are at high risk for severe complications from Sars-Cov2 infection and may need hospital assistance for SCD pain crises.

Hopefully there is some evidence that things are getting going again this autumn. Europe granted gene-editing therapy CTX001 Priority Medicines Designation for severe SDC and the start-up Graphite Bio is planning CRISPR-based clinical trials for hemoglobinopathies in 2021.

Matthew Porteus, a cofounder of both CRISPR Therapeutics and Graphite Bio, explained the differences between the approaches of the two companies at the International CRISPR and Gene Editing Symposium – Looking Beyond the Bench.

The first one is a “break thing” strategy, where fetal hemoglobin production resumes after taking a genetic brake off. The other approach aims to “fix things” by correcting the mutation causing SCD or by precisely integrating a genetic cassette to treat beta-thalassemia where the problem is too much alpha-globin and too little beta-globin.

“My feeling as a clinician is that we want as many different approaches available for patients and physicians to allow them to choose,” says Porteus. When asked about Victoria Gray, the first sickle cell patient treated with the “break things” approach, the Stanford scientist replied that she is doing well.

“I know what is publicly disclosed, but it’s exciting. The amount of fetal hemoglobin is at a level that should prevent having any symptoms. The durability remains to be seen because it is still early. There is another thing that we need to see. Many people in the world have a high level of fetal hemoglobin, which is the basis for this strategy. They are generally healthy, but we don’t know if there is any subtle issue with having a high level of fetal hemoglobin that we are not aware of”.

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