General Updates | Proof-of-concept: using epigenome editing in SCD and beta-thalassemia

So, the idea started because actually there are some approaches where some drugs, epigenetic drugs, have been used and showed that when using, for instance, drugs that lead to demethylation, this can lead to a re-expression of fetal hemoglobin, which is sufficient then to treat sickle cell in this patient. However, the drugs by themselves are not really precise, of course. So we are not targeting a precise region, but they have a broad effect. So in addition to re-expression of fetal hemoglobin, they will also target other regions of the genes that we don’t know, which can lead to unwanted effects and drawbacks. And so this is why they have been also approved for the treatment of some cancer types. But for sickle cell disease and beta-thalassemia, the effect is too broad to be approved for clinical treatment, so starting from this point we started to develop epigenome editing, where we can target and do the same thing that epigenetic drugs do, but in a specific region, so without touching all the epigenome of the cells that we are targeting. And so this is the proof. Now, then we started, and indeed, we recently published a paper where we showed that actually epigenome editing can be really precise and lead to an effective reactivation of fetal hemoglobin.

So what we did, it was first to analyze the different epigenetic background between adult and fetal cells. So we compared which were the DNA methylation status and the histone modification that were present in the promoter of the gamma globin genes. And starting from this point and starting when we found the differences that we observed in these two samples, in these two cell types, what we did, it was to design and to use an epigenome editor that were already published, actually, which can target either the DNA modification or the histone modification, combine the two together, and modify the hematopoietic stem and progenitor cells that then were differentiated through the erythroid lineage up to red blood cells. And at that point we measured like gamma globin re-expression, fetal hemoglobin, and what we saw was indeed that we increased the percentage of fetal hemoglobin expressed in these cells up to a level that it was clinically relevant. Then we moved to perform an in-vivo study. So we modified hematopoietic and progenitor cells. We injected them in immunodeficient mice. And 16 weeks after, we checked again the expression of fetal hemoglobin in order to see for how long this could be maintained. Because one of the problems with epigenome editing is that since it’s an epigenome, and so it’s something that needs to be inherited from cell to cell in each division, one of the limits for the moment is the maintenance through the different generations, let’s say cell generations. And so we want to see how much it can stay, this epigenetic modification. And we went up to 16 weeks with our mice experiment, where we observed still an expression of fetal hemoglobin, which, however, it was reduced compared to the input cells. So now the idea from our work is to try to improve our tool in order to see if this can further maintain the expression over time.

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