Medical breakthroughs this week (including a better, potentially curative, sickle cell therapy)
Progress in medicine is fast. I track it here, with the most important advances from each week — let’s go!
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1. A more delicate (potentially curative) therapy for sickle cell disease
About 500,000 people are born each year with sickle cell anemia. It’s a genetic condition that causes red blood cells to become misshapen — sickled. It’s also a fascinating evolutionary trade-off: one mutant copy helps protect against malaria; two cause sickle cell disease. These cells block vessels, potentially leading to multi-organ damage if untreated.
The first-ever CRISPR therapy (Casgevy) was approved for sickle cell disease in 2023, which takes patients’ hematopoetic stem cells and edits them to raise levels of fetal hemoglobin and reduce sickling. Casgevy works by disrupting expression of a gene called BCL11A — which encodes a transcription factor that suppresses fetal hemoglobin by repressing two genes, HBG1 and HBG2.
Casgevy isn’t perfect, though: the CRISPR approach introduces double-strand breaks, which can be the substrates of genome rearrangement (this sounds about as bad as it is).
This week, Beam Therapeutics report in the New England Journal of Medicine a more delicate approach: base editing of individual sites in the promoters of HBG1 and HBG2 — to prevent binding of BCL11A. It’s a more native strategy that avoids double-strand breaks, and — so far — it works beautifully:
Some patients even overshot into high hemoglobin (which was not obviously harmful) and the result was an operational success, too: there were no manufacturing failures to derail treatment — often a scourge of hematopoietic stem cell therapies.
This still is not a simple cure, though. One patient sadly died, which was attributed to idiopathic pneumonia, probably caused by the busulfan conditioning that’s a requirement of the hematopoietic stem cell transplant.
That problem is important in its own right — and Beam are already thinking about it in waves: Wave 1 (this one): ex vivo base editing of a patient’s own hematopoietic stem cells to raise fetal hemoglobin. Wave 2: replacing busulfan with gentler, targeted conditioning to make the transplant process safer. Wave 3: in vivo editing of hematopoietic stem cells, aiming to avoid transplantation and conditioning entirely.
