William G. Kaelin, Jr., MD
2019 Nobel Prize Recipient
Professor, Department of Medical Oncology, Dana-Farber
Professor of Medicine, Harvard Medical School
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EGLN/PHD siRNA Reactivated Hepatic Erythropoietin Production for Treatment of Anemia
Project Overview
- Anemia in chronic kidney disease (CKD), defined as a reduction in red blood cells (RBCs) or hemoglobin levels, results from decreased levels of erythropoietin (EPO) and increased levels of hepcidin.
- However, current systemic administration of small molecule inhibitors to regulate these hormones has significant toxicities due to systemic inhibition of HIF and off-target profiles inherent in small molecule inhibitors. Hence, there is an unmet need for an EGLN/PHD inhibitor that increases EPO levels and decreases hepcidin levels with reduced toxicity
- Dr. William Kaelin’s team at Dana-Farber has demonstrated that targeted inhibition of hepatic EGLN using systemically delivered small interfering RNAs (siRNAs) results in increased circulating EPO leading to a sustained increase in RBC production.
- This technology is available for licensing for further development into new therapeutics or vaccines.
Technology
A central regulator of EPO is the transcription factor hypoxia-inducible factor 1 (HIF1), which upregulates EPO expression in response to hypoxic stimuli. EPO production is also controlled by a family of prolyl hydroxylases (PHD), which regulate the stability of HIF transcription factors. These PHD proteins are members of the 2-oxoglutarate-dependent dioxygenase superfamily and are encoded by the genes EGLN1, EGLN2, and EGLN3. Inhibition of EGLN enzymes leads to stabilization of HIF, increased EPO expression, and correction of anemia.
Small-molecule EGLN inhibitors have demonstrated the ability to stimulate RBC production in both preclinical models and in patients with anemia, including those with CKD-associated anemia. Inhibition of the EGLN/PHD axis is a clinically validated approach that modulates both EPO and hepcidin levels, thereby reducing anemia in CKD patients. However, the systemic administration of small-molecule inhibitors is associated with significant toxicities due to widespread HIF activation and off-target effects inherent to these compounds. This highlights the need for a safer approach to selectively modulate EPO and hepcidin without the systemic side effects of small molecules.
Dr. William Kaelin’s team demonstrated that targeted inhibition of hepatic EGLN using systemically delivered small interfering RNAs (siRNAs) results in increased circulating EPO and reduced hepcidin levels, leading to a sustained increase in RBC production. EGLN siRNAs were effective against anemia in the setting of chronic renal failure in the murine 5/6 nephrectomy model, a widely used and physiologically relevant model for anemia linked to renal failure. siRNA-mediated knockdown of EGLN was also effective in alleviating anemia in a rat model. This technology represents a significant advancement over existing methods. By enabling the body to produce its own EPO, it eliminates the need for recombinant hormone therapies, which are costly and can trigger adverse immune responses. Furthermore, reduced hepcidin levels may lower the amount of circulating EPO levels needed, which can lessen the risk of a refractory response and adverse cardiovascular events.
Team Members: William G. Kaelin, Jr., MD
Applications
- Chronic Kidney Disease (CKD) Management: Providing a safer alternative to recombinant erythropoietin for anemia treatment.
- Inflammation-Related Anemia: Addressing anemia in conditions with elevated hepcidin levels, such as chronic inflammatory diseases.
- Pharmaceutical Development: Using siRNAs as tools for in vivo modeling of drug effects, paving the way for new therapeutic discoveries.
- Cardiovascular Risk Reduction: Offering a treatment option that potentially reduces cardiovascular risks associated with high erythropoietin levels.
Opportunities
Dana-Farber Cancer Institute is looking for the right partner with an interest in licensing these assets for further development into new therapeutics or vaccines.
Team Members