Targeted Therapeutics for Treating Sickle Cell Disease and β-thalassemia - (HJF 596-21)

Novel therapeutics for sickle cell disease and β-thalassemia are available for licensing and collaboration. This technology was developed by scientists from the Uniformed Services University of the Health Sciences (USU) and assigned to HJF.

Applications and Advantages

Novel therapeutic targets for sickle cell disease and β-thalassemia.
Several proprietary compounds, owned by commercial entities, are in clinical studies for different indications.

Innovation Description

This technology relates to novel methods for treating β-globinopathies, including sickle cell disease (SCD) and β-thalassemia, by inducing the expression of embryonic and fetal hemoglobins using small molecule compounds or RNAi technology. The inventor was the first to discover MEN1, KMT2A, and BMI1, which encode three transcriptional regulators, as novel regulators of embryonic and fetal hemoglobin repression. The inventor further discovered that small molecule inhibitors for MENIN (which block the interaction between MEN1 and KMT2A) and BMI1 can increase the expression of embryonic and fetal hemoglobin. In addition, knocking-down the expression of these three transcription factors using RNAi technology increased the levels of embryonic and fetal hemoglobins. These results were verified in primary human CD34⁺ hematopoietic stem and progenitor cells.

Several proprietary MENIN and BMI1 inhibitor compounds, owned by commercial companies, are in clinical studies for other indications, including malignant diseases and diabetes.

test results

Figure 1 PTC596 and MI-3454 significantly increased fetal hemoglobin expression levels in human erythroid cells. Human CD34⁺ HSPCs treated with BMI1 inhibitor PTC596 (PTC) or MENIN inhibitor MI-3454 (MI) at indicated concentrations or vehicle (DMSO) were induced to undergo erythroid differentiation. Cells were harvested after 14 days of differentiation for real-time RT-PCR analysis of human g-globin mRNA levels. Relative expression levels were calculated by normalizing to GAPDH mRNA levels in the same sample and also to treated with DMSO.