Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today the publication of new research findings in the journal Nature describing the discovery and validation of the role of the gene Sort1 in the development of cardiovascular disease, including myocardial infarction (MI). This work was done with collaborators at University of Pennsylvania (UPenn) School of Medicine, Massachusetts General Hospital (MGH), and the Broad Institute. The collaborative effort combined genome-wide association studies (GWAS) and RNAi technology to identify and validate novel genes as targets for new therapies for heart disease.
“I am encouraged by the results of our disease association studies to date and am pleased with the combined efforts of my team at MGH, and collaborators at UPenn, the Broad Institute, and Alnylam to extend the association data to mechanism and function.”
"We are excited by the important advances we are making in the discovery and validation of novel genes in cardiovascular disease and metabolic syndrome," said Kevin Fitzgerald, Ph.D., Senior Director, Research at Alnylam. "This work illustrates the power of our RNAi platform to significantly enhance the value of genome-wide association studies, and to functionally link phenotypes at complex genetic loci to specific pathways, mechanisms and ultimately individual gene targets. We look forward to continuing our efforts in the discovery of novel pathways and targets that may allow for therapeutic intervention in the reduction of cholesterol and prevention of heart attacks."
"Worldwide, heart disease is the leading cause of mortality, and it is our goal with this effort to identify new gene targets for potential disease intervention in this area of profound medical need," said Sekar Kathiresan, M.D. of the Center for Human Genetic Research and Cardiovascular Research Center and Director, Preventive Cardiology at MGH. "I am encouraged by the results of our disease association studies to date and am pleased with the combined efforts of my team at MGH, and collaborators at UPenn, the Broad Institute, and Alnylam to extend the association data to mechanism and function."
Coronary heart disease (CHD) is the leading cause of mortality in both men and women worldwide and its incidence is highly correlated with levels of cholesterol and triglycerides in the blood. Plasma concentrations of low-density lipoprotein cholesterol (LDL-C, or "bad" cholesterol) and high-density lipoprotein cholesterol (HDL-C, or "good" cholesterol), as well as triglycerides, have a strong inherited basis and recent genetic association studies have linked previously unsuspected genes to these complex traits. Despite aggressive use of LDL-C-lowering medications such as statins, many individuals do not achieve LDL-C levels recommended by clinical guidelines. There remains a need for new medicines for reducing LDL-C.
The work described in Nature (Musunuru et al., Nature 466: 714-721, 2010) is part of a collaborative effort focused on validating novel genes as targets for new therapies for lipid disorders and heart disease, and provides early proof of concept on how GWAS combined with RNAi technology can yield important new insights into disease biology. Recent GWAS - including a report published in the same issue of Nature - have identified a locus on chromosome 1p13 as strongly associated with both high LDL-C levels and incidence of MI and CHD. The findings published in Nature today show through a series of studies in patient cohorts and human-derived hepatocytes that a common non-coding polymorphism at the 1p13 locus creates a novel transcription factor binding site which in turn increases the expression of several liver genes. Using a combination of over-expression and RNAi silencing techniques, the gene Sort1 was identified as a candidate gene responsible for the associated CHD effects. Knockdown in mouse liver using RNAi demonstrated that Sort1 alters plasma LDL-C and very low-density lipoprotein (VLDL) particle levels by modulating hepatic VLDL secretion. Specifically, results showed the following for animals treated with an siRNA targeting Sort1:
- a 70%-80% reduction in Sort1 mRNA expression in liver, confirmed to be due to RNAi-mediated cleavage;
- a greater than 90% knockdown of Sort1 protein expression;
- in Apobec1-/-; APOB Tg mice, a 46% increase in total cholesterol compared to control mice at two weeks, with a more than two-fold increase in LDL-C; and,
- a significant increase in plasma VLDL levels.
"Our expertise in translational medicine as applied to human lipid disorders and their association with human disease, combined with our collaborators' expertise in development of RNAi therapeutics, represents a powerful and rare opportunity to advance new innovative medicines in this area," said Daniel Rader, M.D., the Cooper-McClure Professor of Medicine at the UPenn School of Medicine.