Novel Use of a Bet Bromodomain Protein Inhibitor (JQ1) for the Treatment of Sickle Cell Anemia and Thalassemia

SUMMARY

• Embryonic and fetal hemoglobin have a higher affinity for oxygen than their adult counterpart, and as such, gene editing techniques to revert red blood cells to produce infant or fetal hemoglobin are being explored for the treatment of sickle cell anemia. Problematically, these techniques require the use of toxic and side-effect ridden chemotherapy to deplete unmodified red blood cells. 
• It is known that transcription factor binding (GATA1) induces the forced looping responsible for the shift in red blood cell production of infant and fetal hemoglobin to adult hemoglobin and that BET Bromodomain proteins are required to facilitate GATA1 binding. The inventors therefore hypothesized that BET Bromodomain inhibitors could prevent GATA1 binding and revert red blood cell expression of fetal hemoglobin. 
• The invention is a method of using a BET protein inhibitor for the treatment of sickle cell anemia. This treatment strategy induces red blood cell expression of embryonic and fetal hemoglobin genes, and by inducing increased overall production of hemoglobin. This treatment strategy is safer than gene editing in that it does not require red blood cell depletion, and does not make irreversible genetic modifications to the patient.
• In in vitro proof-of-concept experiments erythroleukemia cell lines (K562, HEL), cells were treated with the BET inhibitor JQ1 at 200nM for 5 days. Treated cells showed an increase in hemoglobin accumulation, and a significant increase in the transcription of embryonic and infant hemoglobin genes (HBG1, HBG2) as compared to the adult hemoglobin gene (HBB). JQ1 treatment did not noticeable impact cell viability.

FIGURE

ADVANTAGES

ADVANTAGES

• No red blood cell depletion during treatment (no chemotherapy) 
• Treatment can be immediately stopped (not possible with gene editing)
• JQ1 already in clinical trials for other indications

APPLICATIONS

• Treatment of Sickle Cell Anemia
• Treatment of Thalassemia
• Research tool (red blood cell culture)

PUBLICATIONS

• Cao JZ, Bigelow K, Wickrema A, Godley LA. BET inhibitors enhance embryonic and fetal globin expression in erythroleukemia cell lines. Haematologica 2021;106(12):3223-3227; https://doi.org/10.3324/haematol.2021.278791.

October 3, 2019

In vitro proof of concept

Patent Pending

Licensing,Co-development

Lucy Godley