Mount Sinai Center for Translational Medicine and Pharmacology

Evaluating JAK2 Inhibitors

The program is evaluating the effectiveness of JAK2 inhibitors in slowing or stopping disease progression in order to develop a more effective JAK2 inhibitor. Specific goals are to assess the effectiveness of therapeutic agents targeted directly to malignant myeloproliferative disorders; to explore inflammatory signaling and dysregulated gene expression in malignant mylofibrosis stem cells; and to investigate novel therapeutic agents, including biomarker studies. These studies are being conducted by Huihui Li, PhD, a K01 awardee.

Iron Metabolism

Under the leadership of Dr. Ginzburg, this area of the Hematology Program focuses on understanding the mechanistic underpinnings and bringing discoveries to clinical care to help patients with disordered production of red blood cells (erythropoiesis), among other conditions. We have demonstrated that compensatory mechanisms in the iron regulation pathway can be effectively targeted to ameliorate diseases of erythropoiesis. Currently, the program is spearheading a comprehensive exploration of the role of iron metabolism dysregulation in the pathophysiology of polycythemia vera, myelodysplastic syndromes, β-thalassemia, bone homeostasis, and Alzheimer’s disease, using both mouse models and patient samples.

Monoferric N Relative to Monoferric C

Using newly generated transgenic mice, the program demonstrates the disparate effects of monoferric N relative to monoferric C transferrin on erythropoiesis and iron metabolism. Preliminary data suggest similar beneficial effects when monoferric N (but not monoferric C) mutant transferrin mice are crossed with β-thalassemic mice. These studies represent a significant advance in our understanding of how apo-transferrin may ameliorate ineffective erythropoiesis in β-thalassemia and enable additional targeted development of treatment options for patients with erythropoiesis disorders. In collaboration with the Mount Sinai Bone Program, we have found that erythroferrone (ERFE), the erythroid regulator of hepcidin that is implicated in causing iron overload in β-thalassemia patients and in mice, has a significant osteoprotective effect. These findings are critical as ERFE-related therapeutics are being developed for patients with β-thalassemia, many of whom exhibit thinning of cortical bone and decreased bone mineral density.

Treatment for Polycythemia Vera

Another ongoing project involves looking at the use of hepcidin-mimetic rusfertide and activin receptor ligand traps to treat polycythemia vera patients. This translational work builds on research demonstrating the effectiveness of hepcidin-mimetics in a mouse model of polycythemia vera. This agent has received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA) and is poised for FDA approval as the first agent of its kind for the treatment of a malignant disease. Upon approval, this approach will represent a promising treatment for these patients.

Sickle Cell Disease

Under the leadership of Dr. Glassberg, this is an offshoot program of the Mount Sinai Center for Sickle Cell Disease, which pursues several avenues of research to improve the lives of patients with the disease. The network of labs funded by this Center studies biomarkers for disease severity and vaso-occlusion, novel agents for the prevention and treatment of complications, the role of the gut microbiome in driving organ injury, and in vivo gene therapy cures using lipid nanoparticle delivery of CRISPR gene editing systems on collaboration with the Biopharmaceutical and Nanomedicine Development Core. The Center also oversees large-scale, multi-site research projects, including a 10-center, 1,000-patient, observational study called REAL Answers, where investigators use a technique called target-trial emulation to determine which new sickle cell medications work best, in which combinations, and for which patients. The overall goal is to advance sickle cell science to facilitate personalized treatment regimens now, and cure the disease in the future.

Role of Gut Microbiota in Organ Damage Among Sickle Cell Patients

This program is investigating the hypothesis that organ damage from sickle cell disease, while long believed to be a consequence of the sickling of red blood cells, may be independently caused by gut microbiota. We are inspired by data showing that the disruption of microbiota with broad-spectrum antibiotics led to improvements in chronic organ damage and sepsis survival in sickle cell disease. We therefore aim to identify specific types of gut microbiota and microbial-related mechanisms that are involved in triggering chronic inflammation and organ damage in sickle cell disease. Additionally, we aim to manipulate dietary elements, such as iron, to relieve dysbiosis and lower the disease burden.