H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark
Chunsheng Chen
Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA
Aurelie Fricot
INSERM UMR 1163, CNRS ERL 8254, Imagine Institute, Laboratory of Excellence GR-Ex, Paris Descartes - Sorbonne Paris Cité University, Paris, France
Caroline Carvalho
INSERM UMR 1163, CNRS ERL 8254, Imagine Institute, Laboratory of Excellence GR-Ex, Paris Descartes - Sorbonne Paris Cité University, Paris, France
Julia Nguyen
Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA
Phong Nguyen
Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA
Anna Parachikova
H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark
Fuad Abdulla
Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA
Gregory M. Vercellotti
Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA
Olivier Hermine
INSERM UMR 1163, CNRS ERL 8254, Imagine Institute, Laboratory of Excellence GR-Ex, Paris Descartes - Sorbonne Paris Cité University, Paris, France
Dave Edwards
Kinexum, 8830 Glen Ferry Drive, Johns Creek, GA, USA
Jean-Antoine Ribeil
Departments of Biotherapy, Necker Children’s Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris Descartes- Sorbonne Paris Cité University, Paris, France
John D. Belcher
Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA
Thiago T. Maciel
INSERM UMR 1163, CNRS ERL 8254, Imagine Institute, Laboratory of Excellence GR-Ex, Paris Descartes - Sorbonne Paris Cité University, Paris, France
The most common treatment for patients with sickle cell disease (SCD) is the chemotherapeutic hydroxyurea, a therapy with pleiotropic effects, including increasing fetal hemoglobin (HbF) in red blood cells and reducing adhesion of white blood cells to the vascular endothelium. Hydroxyurea has been proposed to mediate these effects through a mechanism of increasing cellular cGMP levels. An alternative path to increasing cGMP levels in these cells is through the use of phosphodiesterase-9 inhibitors that selectively inhibit cGMP hydrolysis and increase cellular cGMP levels. We have developed a novel, potent and selective phosphodiesterase-9 inhibitor (IMR-687) specifically for the treatment of SCD. IMR-687 increased cGMP and HbF in erythroid K562 and UT-7 cells and increased the percentage of HbF positive erythroid cells generated in vitro using a two-phase liquid culture of CD34+ progenitors from sickle cell blood or bone marrow. Oral daily dosing of IMR-687 in the Townes transgenic mouse SCD model, increased HbF and reduced red blood cell sickling, immune cell activation and microvascular stasis. The IMR-687 reduction in red blood cell sickling and immune cell activation was greater than that seen with physiological doses of hydroxyurea. In contrast to other described phosphodiesterase-9 inhibitors, IMR-687 did not accumulate in the central nervous system, where it would inhibit phosphodiesterase-9 in neurons, or alter rodent behavior. IMR-687 was not genotoxic or myelotoxic and did not impact fertility or fetal development in rodents. These data suggest that IMR-687 may offer a safe and effective oral alternative for hydroxyurea in the treatment of SCD.
