The business of RNAi therapeutics.

BUSINESS FOR RNA INTERFERENCE (RNAi) therapeutics has never been better. The confluence of the genome revolution, a pharmaceutical industry greatly challenged by generic competition and starved for innovation, and preexisting nucleic acid drug development know-how that can now be directly applied to RNAi therapeutics means that RNAi, less than 10 years after its discovery in worms, has every chance of becoming the next major drug development platform for improving healthcare and generating profits at multiple levels. From the perspective of a molecular biologist interested in both basic and applied aspects of RNAi and related investments, I would like first to put RNAi into the context of the drug development enterprise and then discuss various strategies for translating the science of RNAi into commercially viable drugs as well as some of the risks the industry faces. Although the discussion will focus on RNAi therapeutics and the major U.S. and European markets, it should be kept in mind that RNAi is a global effort and holds further commercial promise in agriculture, the research reagent and services markets, and the related area of microRNA-based therapeutics and diagnostics.

[1]  H. Paulson,et al.  RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia , 2004, Nature Medicine.

[2]  A. Reynolds,et al.  A protocol for designing siRNAs with high functionality and specificity , 2007, Nature Protocols.

[3]  Michael S. Goldberg,et al.  Effective RNAi-mediated gene silencing without interruption of the endogenous microRNA pathway , 2007, Nature.

[4]  Keith Bowman,et al.  Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs , 2005, Nature Biotechnology.

[5]  Anton P. McCaffrey,et al.  Inhibition of hepatitis B virus in mice by RNA interference , 2003, Nature Biotechnology.

[6]  L. Lim,et al.  Position-specific chemical modification of siRNAs reduces "off-target" transcript silencing. , 2006, RNA.

[7]  Jonathan C. Cohen,et al.  Molecular biology of PCSK9: its role in LDL metabolism. , 2007, Trends in biochemical sciences.

[8]  V. Hornung,et al.  siRNA and isRNA: two edges of one sword. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[9]  B. Li,et al.  Expression profiling reveals off-target gene regulation by RNAi , 2003, Nature Biotechnology.

[10]  Arthur M. Krieg,et al.  Toll-like receptor 9 (TLR9) agonists in the treatment of cancer , 2008, Oncogene.

[11]  S. Barik,et al.  Inhibition of respiratory viruses by nasally administered siRNA , 2005, Nature Medicine.

[12]  Judy Lieberman,et al.  Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors , 2005, Nature Biotechnology.

[13]  B. Wiedenmann,et al.  Effects of interferon alpha on vascular endothelial growth factor gene transcription and tumor angiogenesis. , 2003, Journal of the National Cancer Institute.

[14]  S. Akira,et al.  Sequence-specific potent induction of IFN-α by short interfering RNA in plasmacytoid dendritic cells through TLR7 , 2005, Nature Medicine.

[15]  Theresa A. Storm,et al.  Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways , 2006, Nature.

[16]  A. Lee,et al.  Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[17]  F. Natt,et al.  Independent combinatorial effect of antisense oligonucleotides and RNAi-mediated specific inhibition of the recombinant rat P2X3 receptor. , 2003, Nucleic acids research.

[18]  T. Tuschl,et al.  Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells , 2001, Nature.

[19]  R. W. Hansen,et al.  The price of innovation: new estimates of drug development costs. , 2003, Journal of health economics.

[20]  Judy Lieberman,et al.  Interfering with disease: a progress report on siRNA-based therapeutics , 2007, Nature Reviews Drug Discovery.

[21]  A. Fire,et al.  Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans , 1998, Nature.

[22]  Charles Schmidt.  Negotiating the RNAi patent thicket , 2007, Nature Biotechnology.

[23]  Matthias John,et al.  RNAi-mediated gene silencing in non-human primates , 2006, Nature.

[24]  Yong Wang,et al.  Cell type–specific delivery of siRNAs with aptamer-siRNA chimeras , 2006, Nature Biotechnology.

[25]  Matthias John,et al.  Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs , 2004, Nature.

[26]  Reuven Agami,et al.  A large-scale RNAi screen in human cells identifies new components of the p53 pathway , 2004, Nature.

[27]  B. Davidson,et al.  Transvascular delivery of small interfering RNA to the central nervous system , 2007, Nature.