Alnylam and Isis License Intellectual Property for MicroRNA Gene Involved in Hepatitis C Virus Infection; Role of MicroRNA-122 in Hepatitis C Infection Published in Science

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY) and IsisPharmaceuticals, Inc. (Nasdaq: ISIS) announced today a co-exclusivelicense agreement with Stanford University related to the discoveryand development of therapeutic products for hepatitis C virus (HCV)infection by inhibiting a liver-specific microRNA. Data published onSeptember 2, 2005 by Jopling et al. in the journal Science demonstratethat the microRNA known as miR-122 is required for HCV replication inmammalian cells. This study is the first to link endogenous expressionof a specific microRNA with a major infectious disease, and suggeststhat antagonism of miR-122 may comprise a novel therapeutic strategyagainst HCV.

"The recent discoveries that over 250 human genes encode microRNAsand that these microRNAs may control gene expression for as much asone-third of the genome suggests that this part of the RNAi pathwayplays a major role in human health and disease," said John Maraganore,Ph.D., President and Chief Executive Officer of AlnylamPharmaceuticals. "As part of our March 2004 agreement with Isis, weare together actively engaged in consolidating intellectual propertyin the microRNA field, and researchers at both companies are workingto identify novel therapeutic opportunities."

"The identification of miR-122 as a critical host factor for HCVinfection is a remarkable finding that has implications for thediscovery and development of novel anti-HCV therapeutics. Theseexciting results further validate that inhibiting or antagonizingmicroRNAs using antisense oligonucleotides has the potential to leadto exciting new therapeutics for diseases with unmet medical needs,"said C. Frank Bennett, Ph.D., Vice President, Antisense Research ofIsis Pharmaceuticals. "Together with Alnylam, we continue to believethat approaches to antagonize or possibly replace microRNA functionwith traditional antisense oligonucleotides or with siRNA willrepresent an important new therapeutic strategy for the future."

MiR-122 is specifically expressed and is highly abundant in thehuman liver. The study by Jopling et al. from the laboratory of PeterSarnow, Ph.D. at Stanford University demonstrates that miR-122interacts directly with a specific 5' noncoding sequence of the HCVgenome leading to increased abundance of the viral mRNA. Antagonism ofmiR-122 function using an antisense oligonucleotide resulted in adramatic decrease of viral RNA.

About RNA Interference (RNAi)

RNA interference, or RNAi, is a naturally occurring mechanismwithin cells for selectively silencing and regulating specific genes.Since many diseases are caused by the inappropriate activity ofspecific genes, the ability to silence genes selectively through RNAicould provide a new way to treat a wide range of human diseases. RNAiis induced by small, double-stranded RNA molecules. One method toactivate RNAi is with chemically synthesized small interfering RNAs,or siRNAs, which are double-stranded RNAs that are targeted to aspecific disease-associated gene. The siRNA molecules are used by thenatural RNAi machinery in cells to cause highly targeted genesilencing.

About MicroRNA (miRNA)

RNAi can also be induced by microRNAs, or miRNAs, that occurnaturally within all mammalian cells. The miRNA molecules are encodedby the cell's own genes, giving rise to small RNA molecules that aresimilar in structure to siRNAs. There are at least 250 confirmed miRNAgenes in the human genome and there are many other predicted miRNAs.MicroRNA are thought to work through RNAi to regulate the activity ofan estimated one-third of genes in the genome. The inappropriateabsence or presence of specific miRNA molecules in various cells hasbeen shown to be associated with specific human diseases.

About Antisense

An antisense oligonucleotide hybridizes with a complementarytarget RNA to form a duplex. The formation of this duplex prevents thetarget RNA from functioning normally. Antisense drugs are short,chemically-modified RNA-like and DNA-like molecules that scientistsdesign to complement a small, specific segment of messenger RNA, ormRNA. To date, there are at least 12 known antisense mechanisms,including RNase H, RNAi and alternative splicing. Each of thesemechanisms has expanded the opportunities in which antisense drugs maybe successful.

About Hepatitis C

Hepatitis C is a viral infection of the liver that is a majorcause of acute hepatitis and chronic liver disease, includingcirrhosis and liver cancer. According to the World HealthOrganization, an estimated 170 million persons worldwide arechronically infected with HCV and 3 to 4 million persons are newlyinfected each year. No vaccine is currently available to preventhepatitis C and treatment for chronic hepatitis C is too costly formost persons in developing countries to afford.

About Alnylam

Alnylam is a biopharmaceutical company seeking to develop andcommercialize novel therapeutics based on RNA interference, or RNAi.Growing from its foundation as the world's first company focused onRNAi therapeutics, the company's leadership in the field of RNAi issupported by its preeminent founders and advisors and its strengths infundamental patents, technology, and know-how that underlie thecommercialization of RNAi therapeutics. Alnylam is developing apipeline of RNAi products using Direct RNAi(TM) to treat ocular,central nervous system, and respiratory diseases and Systemic RNAi(TM)to treat a broad range of diseases, including oncology, metabolic, andautoimmune diseases. The company's global headquarters are inCambridge, Massachusetts. For additional information, please visitwww.alnylam.com.

About Isis Pharmaceuticals, Inc.

Isis Pharmaceuticals, Inc. is exploiting its expertise in RNA todiscover and develop novel drugs for its product pipeline and for itspartners. The Company has successfully commercialized the world'sfirst antisense drug and has 12 antisense drugs in development totreat metabolic, cardiovascular and inflammatory diseases, and cancer.In its Ibis division, Isis is developing and commercializing the TIGERbiosensor system, a revolutionary system to identify infectiousorganisms. As an innovator in RNA-based drug discovery anddevelopment, Isis is the owner or exclusive licensee of more than1,500 issued patents worldwide. Additional information about Isis isavailable at www.isispharm.com.

Alnylam Forward-Looking Statements

Various statements in this release concerning our futureexpectations, plans, and prospects constitute forward-lookingstatements for the purposes of the safe harbor provisions under ThePrivate Securities Litigation Reform Act of 1995. Actual results maydiffer materially from those indicated by these forward-lookingstatements as a result of various important factors, including risksrelated to: our approach to discover and develop novel drugs, which isunproven and may never lead to marketable products; our ability toobtain additional funding to support our business activities; ourdependence on third parties for development, manufacture, marketing,sales and distribution of our products; the successful development ofproducts, all of which are in early stages of development; obtainingregulatory approval for products; competition from others usingtechnology similar to ours and others developing products for similaruses; obtaining, maintaining and protecting intellectual propertyutilized by our products; and our short operating history; as well asthose risks more fully discussed in the "Certain Factors That MayAffect Future Results" section of our most recent Form 10-Q filed withthe Securities and Exchange Commission. In addition, anyforward-looking statements represent our views only as of today andshould not be relied upon as representing our views as of anysubsequent date. We do not assume any obligation to update anyforward-looking statements.

Isis Forward-Looking Statements

This press release contains forward-looking statements concerningthe discovery, development and therapeutic potential of RNA-basedtechnology and drugs, the potential success of Isis' agreement withAlnylam and Stanford University and the potential of the Company'sintellectual property position. Any statement describing Isis' goals,expectations, intentions or beliefs is a forward-looking statement andshould be considered an at-risk statement, including those statementsthat are described as Isis' goals. Such statements are subject tocertain risks and uncertainties, particularly those inherent in theprocess of discovering, developing, and commercializing drugs that aresafe and effective for use as human therapeutics, and in the endeavorof building a business around such products. Isis' forward-lookingstatements also involve assumptions that, if they never materialize orprove correct, could cause its results to differ materially from thoseexpressed or implied by such forward-looking statements. AlthoughIsis' forward-looking statements reflect the good faith judgment ofits management, these statements are based only on facts and factorscurrently known by Isis. As a result, you are cautioned not to rely onthese forward-looking statements. These and other risks concerningIsis' programs are described in additional detail in Isis' annualreport on Form 10-K for the year ended December 31, 2004, and itsquarterly report on Form 10-Q for the quarter ended June 30, 2005,which are on file with the SEC. Copies of these and other documentsare available from the Company.