New pre-clinical data for RNAi therapeutics for the treatment of hemoglobinopathies, presented at the54th American Society of Hematology (ASH) Annual Meeting being held December 8-11, 2012 in Atlanta, shows that ALN-TMP, an RNAi therapeutic targeting therapeutic targeting transmembrane protease serine 6 or Tmprss6, leads to disease modifying effects, including a correction in globin gene expression, in a model of ?-thalassemia.

These studies were conducted in collaboration between Alnylam Pharmaceuticals, Inc., a leading RNAi therapeutics company, and Boston Children?s Hospital.

RNA Interference (RNAi)
RNAi (RNA interference) represents a breakthrough in understanding how genes are turned on and off in cells. It offers a completely new approach to drug discovery and development. Its discovery has been heralded as a major scientific breakthrough that happens once every decade or so, and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded The 2006 Nobel Prize for Physiology or Medicine.

RNAi is a natural processof gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.

ALN-TMP comprises a systemically delivered RNAi Tmprss6 for the treatment of hemoglobinopathies, including ?-thalassemia and sickle cell anemia. Hemoglobinopathies are associated with chronic anemia, extra-medullary hematopoiesis, and iron overload. Tmprss6, a genetically validated target expressed on hepatocytes, functions by cleaving hemojuvelin, resulting in reduced hepcidin levels and increased iron mobilization. Pre-clinical animal model studies with ALN-TMP have demonstrated corrective effects on iron overload in addition to broader disease modifying effects including improvements in hemoglobin levels, spleen histopathology, and globin gene expression.

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Unmet needs
The joint program in hemoglobinopathies is aimed at bringing innovative medicines to patients with a focus on RNAi therapeutics toward genetically defined targets for diseases with very high unmet medical need. ALN-TMP exemplifies one area where we are advancing RNAi therapeutics for the treatment of hemoglobinopathies,? explained Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. ?We are very excited by these new data with ALN-TMP where we have demonstrated disease modifying effects in models of ?-thalassemia, including amelioration of anemia, iron overload, extra-medullary hematopoiesis, and ineffective erythropoiesis, in addition to correction of globin gene expression.?

Worldwide burden
?Mouse genetic studies have shown that knockdown of Tmprss6 and up-regulation of the hepcidin pathway can result in disease modifying effects in models of ?-thalassemia, a disease of enormous worldwide burden with limited treatment options for certain groups of patients. Our studies with ALN-TMP, an RNAi therapeutic targeting Tmprss6, recapitulate these genetic findings with an innovative pharmacologic strategy. This work is an example of how rare disease research that brings in RNA silencing technologies to target the untargetablecould rapidly lead to therapies for more common disorders,? said Mark Fleming, M.D., D.Phil., Pathologist-in-Chief at Boston Children?s Hospital and S. Burt Wolbach Professor of Pathology at Harvard Medical School, who collaborated on the work. ?Specifically, we have demonstrated that ALN-TMP administration results in disease modifying effects in a model of ?-thalassemia. Indeed, our studies show that ALN-TMP administration results in reduced iron overload, decreased extra-medullary hematopoiesis, increased hemoglobin levels, and a reduction in ineffective erythropoiesis. Further, we have found that these effects are accompanied by a decrease in membrane-associated hemoglobin, one of the primary causes of the decreased red blood cell survival in ?-thalassemia. Clearly, these results could be of significance for the treatment of patients with ?-thalassemia and possibly other hemoglobinopathies.?

In a poster titled RNAi-Mediated Inhibition of Tmprss6 Ameliorates Anemia and Secondary Iron Overload in a Mouse Model of ?-Thalassemia Intermedia and Decreases Iron Overload in Hfe-/- Mice, (#1018)scientists presented data showing that systemic administration of ALN-TMP resulted in disease modifying effects in a model of ?-thalassemia. Furthermore, ALN-TMP demonstrated pre-clinical efficacy in a model of hereditary hemochromatosis. In the pre-clinical studies, ALN-TMP administration resulted in a greater than 80% silencing of Tmprss6 mRNA levels and a greater than two-fold elevation of Hamp1, the gene that encodes for hepcidin, a liver hormone that negatively regulates iron transport and absorption. ALN-TMP administration resulted in an approximately 30% decrease in serum iron and non-heme liver iron, as well as a similar reduction in transferrin saturation. In a mouse model of ?-thalassemia, ALN-TMP reduced the severity of anemia as evidenced by an approximately 1 g/dL increase in total hemoglobin. Moreover, treatment with ALN-TMP was found to significantly attenuate extra-medullary hematopoiesis, including a two-to-three fold reduction in spleen size. Treatment with ALN-TMP also decreased ineffective erythropoiesis, with a three-to-four fold decrease in reticulocyte count, an approximate 30% increase in red blood cell count (RBC), and a normalization of RBC morphology and lifespan. Finally, ALN-TMP administration was found to restore the ratio of alpha globin to beta globin, thereby correcting the genetic defect associated with ?-thalassemia with possible implications for the treatment of other hemoglobinopathies such as sickle cell anemia.

For more information:
– Nai A, Pagani A, Mandelli G, Lidonnici MR, Silvestri L, Ferrari G, Camaschella C. Deletion of TMPRSS6 attenuates the phenotype in a mouse model of ?-thalassemia. Blood May 24, 2012 vol. 119 no. 21 5021-5029
– Meynard D, Vaja V, Sun CC, Corradini E, Chen S, L?pez-Ot?n C, Grgurevic L, Hong CC, et al. Regulation of TMPRSS6 by BMP6 and iron in human cells and mice Blood July 21, 2011 vol. 118 no. 3 747-756.

Illustrations: Courtesy of Alnylam Pharmaceuticals, Inc

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