Therapies to activate alternate endogenous genes to relieve effects of mutant genes in genetic disorders or to augment beneficial signaling pathways in hematology oncology conditions
Sickle Cell Disease and β-Thalassemia
Abnormal or deficient hemoglobin, the major protein in red blood cells, causes severe anemia and organ damage in β-thalassemia and sickle cell anemia (β-hemoglobinopathies). Another type of hemoglobin, HbF, a form expressed in all humans before birth, functions well, but is silenced during infancy. When re-activated, HbF can replace the function of abnormal “adult” genes, reversing or reducing the pathology in the β-hemoglobinopathy blood diseases, which are orphan conditions in the US and EU, and prevalent in SE Asia and southern China.
Deficiencies of blood cells (cytopenias) are a major cause of morbidity following chemotherapy, transplantation, in genetic disorders, and of mortality following acute accidental radiation exposures. Therapeutics which are oral are needed to stimulate hematopoietic recovery from radiation-induced marrow damage, increase survival from radiation exposure in disaster conditions, and reduce infections and bleeding in other cytopenias.
Phoenicia scientists discovered a panel of small molecules (Hemokines™) that stimulate hematopoiesis in human progenitor cultures, in multi-lineage-hematopoietic cell lines, and in 3 species (including irradiated mice in a collaboration with AFFRI, in dogs, and baboons) with oral dosing. With completed studies, a selected candidate can be developed to an IND in one year.
Supported by the Heart, Lung and Blood Institute, and the National Institute of Diabetes, Digestive and Kidney Disorders
RAS-Targeted Cancer Therapy
Targeting cancer therapeutics towards specific mutations or abnormalities in tumor cells which are not found in normal tissues offers advantages of high selectivity for the tumor and low secondary toxicities. At least 30% of all human malignancies have activating mutations in the p21Ras genes, and another 60% display other activating mutations or over-activity of p21 Ras-signaling pathways. Phoenicia scientists previously discovered that over-activity of p21Ras signaling sensitizes tumor cells to apoptosis induced by suppression of PKCϬ activity, which is not toxic to normal cells. This “Ras-mediated apoptosis”, is being exploited for cancer therapy.
We characterized Ras-mediated apoptosis molecularly, demonstrated its selectivity, identified the specific target PKC isozyme (PKCϬ), and lead compounds for inducing cell death in tumors containing activated Ras or Ras pathways, and obtained intellectual property protection on Ras-mediated apoptosis as a therapeutic approach.
Phoenicia identified highly-potent PKCϬ inhibitors and licensed IP for optimal inducers of Ras-mediated apoptosis for pharmaceutical application to Viacell.
Supported by the National Cancer Institute
Chronic Wounds Therapy
Refractory wounds or ulcerations of the extremities which do not heal with 3-6 months of standard measures are a major medical condition affecting millions. Non-healing wounds affect 6.5 million patients, with an annual healthcare cost of $25 billion in the US. These numbers are likely to rise with the aging population and the increasing incidence of diabetes. Refractory leg ulcers associated with hemolytic anemias are particularly debilitating and troubling to patients with sickle cell disease and thalassemia.
Phoenicia scientists observed that a parenteral drug being given for a separate action dramatically accelerated healing of refractory sickle cell and thalassemic leg ulcers. This Program studied topical preparations in animal models of wound healing. We are interested in refining this therapy and assisting clinical collaborations for this debilitating complication of hemolytic anemias.
