番茄社区

At December's American Society of Hematology (ASH) virtual meeting, researchers presented that provides proof of concept for technology that targets the root cause of sickle cell disease and beta-thalassemia.

In this exclusive 番茄社区 video, , Director of the Adult Blood and Marrow Transplantation Program at NewYork-Presbyterian/Columbia University Medical Center in New York City, discusses the importance of this technology and how it might be implemented into practice.

Following is a transcript of his remarks:

It's a pleasure to talk to you about the recent ASH plenary presentation by Dr. Haydar Frangoul about initial data on the CRISPR technology for patients with transfusion-dependent beta-thalassemia and sickle cell disease. So both obviously are very serious diseases which require an allogeneic bone marrow transplant to cure them. And recent developments over the last years really have ushered in a new era with genetically engineering the hematopoietic stem cell of patients who were affected with those disorders.

In principle, there are at least two approaches how to do this. One would be what's called gene addition therapy, that you introduce a new gene into the hematopoietic stem cells to produce a new type of hemoglobin to compensate for the genetic defects in both diseases. You could either also do what is called gene correction therapy to actually completely correct the affected DNA sequence, or what is being done here and which was presented at the ASH plenary session and is now being , is to modulate the expression and to turn on the production of the gamma chain to produce fetal hemoglobin in those patients by targeting the transcription factor BCL11A.

And the technology, how this was done, was through the CRISPR-Cas9 approach by gene editing that transcription factor that basically gets turned off, and so that you get a continuous expression of the fetal hemoglobin. And the first experience in patients both with transfusion-dependent beta-thalassemia and also sickle cell disease were presented at that meeting.

And the astonishing findings really are that, first of all, you really do get a significant induction and expression of the fetal hemoglobin to a very high level. And also that the initial patients which are represented, that you do really not only get expression of a fetal hemoglobin, but this also translates into clinical benefit as measured by a reduction of hemolysis, which is key. And, also in terms of controlling in the setting of sickle cell disease, reduction of vaso-occlusive crises, which obviously is I think, a major breakthrough.

What is however noteworthy is that these are of course early days, follow-up was short. So the first patient was transplanted no more than a year ago. More patients are being accrued. And so the critical issue, which we will need to be followed, and so far, there is no evidence that any off target gene editing occurs. But that obviously is, from our perspective, the major safety issue which will need to be followed carefully over time. But so far there's no evidence that this actually occurs.

So I think that this will be a treatment option which really has the potential of completely doing away with the need for allogeneic bone marrow transplant, which is obviously associated with much higher risk of toxicities, due to the fact that you introduce the donor immune system, which has the chance of attacking the recipient and causing graft-versus-host disease. And so using the patient's own stem cells completely overcomes this risk.

The big hurdle, I think, which once this has been shown to be really effective, the next step is really to overcome the need of using chemotherapy to get the engraftment of the stem cells. So at the moment it was being done with busulfan, which obviously is a standard chemotherapy drug with all the long-term consequences of giving a higher myeloablative dose of busulfan which leads to impairment of fertility, which obviously for the young patients who are included in those studies, is a major issue.

And, I think also quite interesting to see over the next year when a new non-genotoxic conditioning agent are being introduced, as they are already -- and there's very promising preclinical data, and now emerging clinical data, that this will be possible by using antibodies which targets the stem cell of the recipient, and then allow engraftment of either gene edited autologous stem cells, or potentially even if you consider allo-transplant, get stem cells in without the need for myeloablating the recipient with these toxic doses of chemotherapy or even potentially radiation. So I think this is really an enormously exciting area for curing a number of potential genetic diseases, which originate in the hematopoietic system.

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