SBIR-STTR Award

Sickle cell disease (SCD) and beta-thalassemia are mostly inherited beta-hemoglobinopathies that lead to chronic anemia. Both diseases are characterized by insufficient or defective expression of the beta chain of adult hemoglobin (Hb), leading to insufficient oxygen delivery to peripheral tissues. Inadequate oxygen levels in tissues causes the episodic vasoocclusive crises that cause ischemic pain and damage, often necessitating blood transfusions. It has been recognized for decades that a means to mitigate the pathophysiology of these diseases, and in particular SCD, is to substitute the mutant adult Hb with fetal Hb (HbF). HbF is normally not expressed during adulthood due to silencing. The ability to induce fetal hemoglobin expression during adulthood has recently been achieved by pharmacological means, and led to the approval of hydroxyurea (HU) to treat patients with SCD. Although HU is the current standard of care for SCD, it has an unclear mechanism of action, and the use of HU is hindered by dose-limiting toxicity and the fact that many SCD patients respond poorly or not at all. Furthermore, HU displays little efficacy for beta-thalassemia. Therapeutic options to treat beta-hemoglobinopathy remain a large, unmet medical need worldwide. FibroGen has proprietary libraries of prolyl hydroxylase (PH) inhibitors that activate the transcription factor hypoxia-inducible factor, which may play a role in regulating expression of the gamma-globin gene that comprises HbF. Preliminary data shows that PH inhibitors lead to increased HbF expression in vitro and are additive to the HbF-inducing effects of HU. We propose to screen our existing libraries of PH inhibitors to identify and optimize the pharmacophore associated with induction of HbF expression. The ultimate goal is to select and test lead candidates in non-human primates for induction of HbF in vivo. Ultimately, this will enable identification of an HbF-inducing compound that can be tested alone or in combination with HU to mitigate the pathophysiology associated with SCD and other beta-hemoglobinopathies.

Thesaurus Terms:
drug design /synthesis /production, enzyme inhibitor, gene induction /repression, hemoglobin F, hemoglobinopathy, oxygenase blood disorder chemotherapy, chemical structure function, combinatorial chemistry, erythropoiesis, gamma globulin, hemoglobin A, hydroxyurea, molecular site, sickle cell anemia, thalassemia, transcription factor tissue /cell culture

Beta-hemoglobinopathies are diseases characterized by defective or insufficient expression of the beta-chain of adult hemoglobin, and lead to the anemia associated with sickle cell disease (SCD) and beta-thalassemia. One approach to treat beta-hemoglobinopathies, and in particular SCD, involves the elevation of fetal hemoglobin (HbF) expression in patients. The rationale for this approach came from observations that patients with SCD that also harbor secondary genetic mutations for persistent HbF expression into adulthood exhibit reduced pathophysiological symptoms associated with SCD. Hydroxyurea (HU) is currently the only FDA-approved therapy for SCD and reduces the number of clinical crisis and incidence of episodic pain. However, the use of HU therapy is hindered by dose-limiting toxicity and poor response rate of many patients with SCD, highlighting an unmet medical need for better therapeutic options to treat this disease. The work proposed within this application leverages FibroGen's technology platform aimed at therapeutic HIF stabilization, and in our anemia program we have developed a series of orally bioavailable HIF prolyl hydroxylases inhibitors (PHI) that elevate circulating, endogenous EPO levels and potently stimulate erythropoiesis with repeated intermittent dosing. In the phase I SBIR program, we demonstrated that erythropoietic PHI are also capable of inducing HbF in human bone marrow-derived CD34+ cells undergoing erythroid expansion ex vivo. The primary goal of the proposed phase 2 SBIR plan is to obtain proof-of- concept that orally bioavailable, erythropoietic PHI can elevate HbF protein expression in anemic non-human primates, either alone or in combination with HU. Enhancing HbF expression is long recognized as an important protective mechanism against SCD. The ability to activate the HbF expression program by PHI may prove to be a powerful approach in the therapeutic treatment of SCD and beta-hemoglobinopathies.

Thesaurus Terms:
blood disorder chemotherapy, combination therapy, drug screening /evaluation, gene induction /repression, hemoglobin F, hydroxyurea, nonhuman therapy evaluation, sickle cell anemia, stimulant /agonist anemia, dosage, erythropoietin, gene mutation Macaca fascicularis, blood cell count, blood chemistry, enzyme linked immunosorbent assay, hematology, laboratory mouse, phlebotomy, polymerase chain reaction