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Alnylam Pharmaceuticals, Inc. Message Board

  • ysh072001 ysh072001 Nov 15, 2004 9:15 AM Flag

    am soc of cell bio meeting abstract

    Identification and characterization of potent stable siRNA to human VEGF for the treatment of ocular neovascular disease

    Small inhibitory RNA (siRNA) molecules targeting VEGF specifically degrade VEGF mRNA leading to inhibition of VEGF protein production and are therefore promising therapeutics for the treatment of ocular neovascular diseases, such as age-related macular degeneration and diabetic retinopathy. A comprehensive screen of unmodified and chemically modified siRNAs targeted to human VEGF was conducted. siRNAs were tested for the ability to inhibit endogenous constitutive and hypoxia-induced expression of VEGF. Numerous siRNAs were identified which demonstrated significantly improved in vitro efficacy and potency (>90% inhibition VEGF protein; IC 50 <1 nM,) OVER ANY previously published VEGF siRNA. In vitro duration of inhibition with these potent siRNA was significantly longer (>80% inhibition over 7 days) THAN WITH OTHER published siRNA. Chemical modifications to the siRNA were made on several lead compounds which enhanced nuclease stability while maintaining full silencing activity. The increased in vitro stability in different ocular extracts was confirmed by the distinct in vivo pharmacokinetic benefit conferred on nuclease stable siRNA in the ocular environment. These stable, long-lasting VEGF siRNAs represent a promising therapeutic for the treatment of ocular neovascular diseases, such as age-related macular degeneration and diabetic retinopathy.

 
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