Alnylam Pharmaceuticals, Inc. has announced the publication of new pre-clinical results in the journal Blood (doi: 10.1182/blood-2012-04-423715) that describe targeting the egg-laying nine homolog (EglN) pathway for the treatment of anemia using RNAi therapeutics.
The new findings show that activation of hepatic erythropoietin production using systemically delivered siRNA targeting EglN prolyl hydroxylases leads to improved red blood cell production in pre-clinical models of anemia.
New approaches that induce endogenous mechanisms for erythropoiesis could address unmet medical needs in the management of anemia in patients who are refractive to current therapies.
“Anemia of chronic disease remains a major cause of morbidity in patients with chronic kidney disease, inflammatory disorders, and cancer. While administration of exogenous recombinant erythropoietin has transformed the management of anemia, significant unmet need exists in a subset of patients who become refractory to therapy due to underlying inflammatory disease and increased production of factors such as hepcidin,” said Rachel Meyers, Ph.D., Vice President, Research and RLD at Alnylam.
Meyers continued, “These new results described in Blood demonstrate the ability of an RNAi therapeutic targeting the EglN pathway to reactivate a natural developmental pathway of hepatic erythropoietin production. This approach would allow the body to produce endogenous erythropoietin, thereby obviating the need for exogenous administration of recombinant or mimetic versions of this hormone.”
Specifically, data showed that a systemically administrated RNAi therapeutic targeting the EglN family of proteins achieved dose-dependent silencing of EglN genes in vivo in animal models.
The research showed that EglN silencing resulted in sustained increase in circulating erythropoietin that was generated specifically by the liver.
The induction of endogenous liver erythropoietin expression recapitulates a developmental pathway for red blood cell production known to exist in the fetus.
This increase in erythropoietin was detectable out to two weeks after administration of a single dose of the RNAi therapeutic and was associated with a sustained increased in red blood cell parameters including reticulocyte count, hemoglobin and hematocrit.
Further, RNAi therapeutics targeting the EglN pathway were found to significantly correct anemia in models of both renal failure and chronic inflammation.
Other changes observed with RNAi therapeutic targeting EglNs, such as decreased production of hepcidin, were also demonstrated and could enhance the effectiveness of endogenous erythropoiesis by improving iron mobilization, thereby lowering the circulating erythropoietin levels needed to promote red blood cell production.
This research was conducted in collaboration with researchers at the Dana-Farber Cancer Institute and the David Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology (MIT).