Landmark achievements by Alnylam scientific founders and scientists.

In January 1999, a patent filed by Alnylam scientific founders was the first to describe the use of small interferring RNAs, or siRNAs, for silencing genes in mammalian cells.

In May 2001, Nature published work by Alnylam scientific founders representing the first published scientific report describing the observed mechanism of RNAi in mammalian cells. Additional studies have provided further details of the natural RNAi mechanism and insights into how this can be harnessed for human therapeutics.

In November 2004, Nature published work by Alnylam scientists representing the ability to design and synthesize siRNAs with "drug-like" properties" and to achieve gene silencing in vivo of an endogenous, clinically-relevant gene.

In March 2006, Nature published further research by Alnylam scientist demonstrating, in primates, that a systemically delivered RNAi therapeutic can potently silence an endogenous disease-causing gene in a clinically relevant manner. Alnylam and collaborators showed silencing of the gene for apolipoprotein B (apoB), a protein involved in cholesterol metabolism, with clinically significant efficacy as demonstrated by reductions in levels of cholesterol and low-density lipoproteins (LDL). This peer-reviewed research, published in the world-leading scientific journal Nature, represents a major advance because it suggests that an RNAi therapeutic can be effective when delivered systemically using a dosage appropriate for application in future human clinical studies.

In April 2006, Alnylam presented Phase I clinical data with its lead product candidate, ALN-RSV01. The drug was found to be safe and well tolerated when administered intranasally in two Phase I clinical studies. ALN-RSV01 is being evaluated for the treatment of respiratory syncytial virus (RSV) infection and is the first RNAi therapeutic in human clinical development for an infectious disease.

Recently it has been shown that small interferring RNAs, or siRNAs, associate with cellular proteins to form a protein-based complex called RISC, for RNA-induced silencing complex. Within the RISC complex, the two strands of the siRNA become separated, so that they can target complementary sequences in mRNAs involved in a disease. After pairing with an siRNA strand, the targeted mRNA is cleaved and undergoes degradation thereby interrupting the synthesis of the disease-causing protein. The RISC complex is naturally stable within the cell, enabling siRNAs to cut multiple mRNA molecules consecutively and, therefore, suppressing protein synthesis in a potent and targeted way.

1. Small interfering RNA (siRNA), a 21-25 base pair RNA strand, is targeted to a specific gene.
2. Within cells siRNA unwinds and is incorporated into RISC, a stable protein-RNA complex.
3. siRNA is directed to a targeted messenger RNA (mRNA) that is known to be involved in a disease pathway.
4. The mRNA undergoes degradation, therby interrupting the protein synthesis of the targeted gene.

Alnylam Pharmaceuticals is a leading company in efforts to harness the natural process of RNA to create a whole new class of human therapeutics. If succesfully developed, these RNAi therapeutics could represent breakthroughs in the treatment of human disease.