The ultimate goal of this research is to provide safe, effective, accessible and durable disease modification for sickle cell anemia (SCD) and ?-thalassaemia (CA) that will improve multi-organ pathophysiology and reduce early death. Incontrovertible data from both basic and clinical research studies over the past 40 years support the premise that inducing fetal ?-globin (HBG) gene repression would be therapeutic in human patients. The two specific aims of this proposal focus on the manipulation and specific targeting of the transcriptional regulatory machinery that represses HBG genes during development.
Our first aim i s devoted to the discovery and validation of new epigenetic modifying enzymes that elicit ?-globin repressive activity in adult erythroid progenitor cells, and we describe several promising new candidate enzymes that we propose to investigate for potential drug targeting.
Our second aim i s to refine structure-based inhibitors of the epigenetic modifying enzyme LSD1 (KDM1a), which (we showed in a proof of concept study) could constitute an ideal target for therapeutic intervention for the treatment of these diseases. Through structure-aided design coupled to iterative enzyme inhibition and cell-based HbF induction assays, we are currently refining and testing fourth and fifth generation inhibitors (designed at the University of Michigan). These compounds have evolved to the point that they are proposed to be highly specific for LSD1 (with IC50s < 90 nM), are reversible, exhibit no behavioral or cardiac side effects and can be orally administered. We have already developed LSD1 inhibitors that were partially successful in preclinical animal studies, and here we propose to develop novel compounds with minimal undesirable on target effects. We propose to follow up these preclinical studies, in collaboration with investigators in project 2, by analysis of the effects of the best of these novel inhibitors in baboons, and if those are successful, in collaboration with project 3, in human clinical trials. The projected impact for patients suffering from ?-globinopathies is that these proposed HbF-inducing therapies will be sufficiently efficacious to counter the devastating complications of these diseases such as stroke and acute chest syndrome, and with accessibility and safety parameters that will permit universal application as well as life-long use.
