Orphan drugs for sickle vaso-occlusion: dawn of a new era of targeted treatment

Abstract

Abstract:While an orphan disease in the USA, sickle cell disease (SCD), a group of genetic disorders of hemoglobin structure and function, is a major public health problem in much of the rest of the world, particularly sub-Saharan Africa. The pathophysiology of SCD stems from the formation of sickle hemoglobin polymers that deform the erythrocyte into a characteristic sickle shape, the rapidity of which is regulated by its intracellular hemoglobin concentration. Subsequent vaso-occlusion is dependent on adhesion of sickled erythrocytes, and perhaps other cellular elements, including leucocytes and platelets, to abnormal vascular endothelium using a number of receptor-ligand pairs. This propensity for vaso-occlusion may be enhanced by altered vascular tone from excessive amounts of vaso-constrictive factors or diminished amounts of vasodilatory factors. Acute pain is the hallmark symptom caused by sickle polymer formation and subsequent vaso-occlusion, and is represented in the endpoints of most previous and current clinical trial designs. Numerous failures of prior investigational agents have frustrated clinicians and patients alike. Hydroxyurea is currently the only US Food and Drug Administration-approved drug for SCD and reduces the frequency of vaso-occlusive complications in many individuals. A considerable therapeutic need remains as hydroxyurea usage is currently not approved for all types of SCD, is not always clinically effective, and requires frequent monitoring. Recent improvements in our understanding of SCD pathophysiology have generated many new therapeutic targets and associated investigational agents. For example, a number of more specific fetal hemoglobin inducers and several therapies to reduce sickle polymer formation are being tested in preclinical and early phase clinical trials. Several agents that target receptor-ligand interactions which mediate cellular adhesion to vascular endothelium have shown considerable promise and are entering Phase III trials, but present some continuing challenges in clinical trial design and conduct. Gene therapy trials are poised to start and offer the potential for curative therapy.

Sickle Cell Disease: Advances in Treatment

“…For this reason, hydroxyurea has been the standard of care for patients with sickle cell disease since the late 1980s. 28,29,[75][76][77][78] Until 2008-2013, no other drugs carried such promise or were on the horizon. While the efficacy of hydroxyurea is principally attributable to its ability to turn on production of hemoglobin F, other salutary effects include its reduction of the expression of adhesion molecules on red blood cells and the decrease in neutrophil, monocyte, platelet, and reticulocyte numbers that may translate into decreased blood viscosity, fewer deleterious cell-cell interactions, and a reduction in hemolysis.…”

“…While the efficacy of hydroxyurea is principally attributable to its ability to turn on production of hemoglobin F, other salutary effects include its reduction of the expression of adhesion molecules on red blood cells and the decrease in neutrophil, monocyte, platelet, and reticulocyte numbers that may translate into decreased blood viscosity, fewer deleterious cell-cell interactions, and a reduction in hemolysis. [76][77][78] The drug has been quite effective in bringing about a reduction in the number of vaso-occlusive pain or acute chest syndrome episodes, the number of hospitalizations, and the number of transfusions required by patients. 79,80 Most important, the demonstration of a definite survival advantage for those taking the drug would seem to be a persuasive finding for healthcare providers and patients and an inducement to take it.…”

On the Binding Free Energy and Molecular Origin of Sickle Cell Hemoglobin Aggregation

“…Thus, delaying or preventing the formation of such precursors could represent a potential SCD therapeutic route. Nonetheless, in spite of intensively studied, − there is no covalent or noncovalent antisickling drug able to inhibit erythrocyte sickling, and the only preventive therapeutics available consists in the administration of hydroxyurea, , which increases the levels of fetal hemoglobin that does not polymerize. , More recently, successful gene therapy results were reported for a single SCD patient and l -glutamine has been recently approved for the treatment of SCD. ,, Another important aspect of SCD concerns the differences between the disease symptoms (e.g., pain crisis frequency and severity) among genetically identical patients, suggesting that in addition to the concentration of HbS and other Hb forms, other variations in the erythrocytes’ environment (e.g., pH, osmolality) may be important to the polymerization process. ,,, …”

Protein Aggregation-Inhibition: A Therapeutic Route from Parkinson's Disease to Sickle Cell Anemia

“…Many small molecules 18,139,[242][243][244][245][246][247][248][249] including some amino acids 140,139,250,138,251 , were long found to decrease the deoxy-HbS aggregation in vitro by increasing the solubility of HbS. While these molecules, many reported in the 1970s and 1980s, failed their purpose as effective drugs for the treatment of SCD it is of interest to contrast some of these molecules with those proposed more recently to address SCD and other proteinopathies such as PD.…”