Advancing fetal hemoglobin to the clinic using highly predictive in vivo strategies

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Project Summary Abstract Elevated fetal hemoglobin levels lessen the severity of sickle cell disease (SCD) and increase the lifespan of patients. Effective treatment of the large numbers of SCD patients projected in the U.S. and worldwide in the coming years would be best accomplished with an affordable, easily-administered, orally-available drug therapy designed to increase Fetal Hemoglobin (HbF) levels to a target >30% distributed throughout a large percentage of erythrocytes. Hydroxyurea (HU), currently the sole FDA-approved drug for SCD, is only effective in approximately 50% of patients and the HbF remains heterogeneously distributed among erythrocytes resulting in a large fraction lacking the protective effects of HbF. A logical approach to increase HbF that has been successfully pursued by our laboratory is to intervene with the epigenetic mechanism executing the switch from HbF to HbA expression in adults using pharmacological inhibitors of enzymes that catalyze repressive epigenetic modifications associated with γ-globin gene silencing. Our laboratory has developed and utilized an in vivo baboon model for over thirty years to investigate globin gene regulation and the in vivo activity of HbF-inducing drugs. Simian primates such as the baboon are widely acknowledged as the best animal models for testing the ability of new drugs to increase γ-globin expression because the activity of HbF-inducing agents is predictive of effects in man due to conservation of the structure and developmental stage-specific regulation of the β-like globin genes in simian primates. Initial studies from our laboratory demonstrating that DNA methyltransferase (DNMT) inhibitors increased HbF in baboons were followed by a number of clinical trials that confirmed their effectiveness in SCD patients and validated use of the baboon model. Recently we have shown that the LSD1 inhibitor RN-1 increased γ-globin expression in the sickle cell disease mouse model and in baboons and that long term treatment of baboons was well tolerated. In this proposal we will 1) investigate a combinatorial drug regimen targeting both DNMT1 and LSD1 for effects on HbF induction and reduction of potentially adverse hematological side-effects, 2) continue to advance new highly specific “third generation” LSD1 inhibitors with reduced ability to cross the blood brain barrier with the goal of increasing HbF to therapeutic levels, maximizing F cell numbers, and raising the therapeutic index, and 3) investigate new compounds that expand the BFU-E subpopulation permissive for γ-globin expression, alone and in combination with inhibitors of epigenetic-modifying enzymes, for additional stimulation of HbF induction. We envision that the results of these studies will directly impinge in the design of new clinical trials to increase HbF for the therapy of sickle cell disease. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page