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A status report on RNAi therapeutics.

Vaishnaw AK, Gollob J, Gamba-Vitalo C, Hutabarat R, Sah D, Meyers R, de Fougerolles T, Maraganore J - Silence (2010)

Bottom Line: More importantly, two key properties of the RNAi pathway - sequence-mediated specificity and potency - suggested that RNAi might be the most important pharmacological advance since the advent of protein therapeutics.The implications were profound.One could now envisage selecting disease-associated targets at will and expect to suppress proteins that had remained intractable to inhibition by conventional methods, such as small molecules.

View Article: PubMed Central - HTML - PubMed

Affiliation: Alnylam Pharmaceuticals Inc,, 300 Third Street, Cambridge, MA 02142, USA. avaishnaw@alnylam.com.

ABSTRACT
Fire and Mello initiated the current explosion of interest in RNA interference (RNAi) biology with their seminal work in Caenorhabditis elegans. These observations were closely followed by the demonstration of RNAi in Drosophila melanogaster. However, the full potential of these new discoveries only became clear when Tuschl and colleagues showed that 21-22 bp RNA duplexes with 3" overhangs, termed small interfering (si)RNAs, could reliably execute RNAi in a range of mammalian cells. Soon afterwards, it became clear that many different human cell types had endogenous machinery, the RNA-induced silencing complex (RISC), which could be harnessed to silence any gene in the genome. Beyond the availability of a novel way to dissect biology, an important target validation tool was now available. More importantly, two key properties of the RNAi pathway - sequence-mediated specificity and potency - suggested that RNAi might be the most important pharmacological advance since the advent of protein therapeutics. The implications were profound. One could now envisage selecting disease-associated targets at will and expect to suppress proteins that had remained intractable to inhibition by conventional methods, such as small molecules. This review attempts to summarize the current understanding on siRNA lead discovery, the delivery of RNAi therapeutics, typical in vivo pharmacological profiles, preclinical safety evaluation and an overview of the 14 programs that have already entered clinical practice.

No MeSH data available.


Related in: MedlinePlus

In vivo pharmacokinetic profile of a cholesterol-conjugated (squares) and unconjugated (circles) radio-labeled small interfering (si)RNA against ApoB in the mouse [16]. The half-life and clearance were calculated to be 95 minutes and 0.5 mL/minute and 6 minutes and 17.6 mL/minute, for the conjugated and unconjugated molecules, respectively.
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Figure 2: In vivo pharmacokinetic profile of a cholesterol-conjugated (squares) and unconjugated (circles) radio-labeled small interfering (si)RNA against ApoB in the mouse [16]. The half-life and clearance were calculated to be 95 minutes and 0.5 mL/minute and 6 minutes and 17.6 mL/minute, for the conjugated and unconjugated molecules, respectively.

Mentions: Soutschek et al. [16] were the first to report a delivery strategy with significant translational potential. In a mouse system, they demonstrated that cholesterol conjugation to the sense or 'passenger' strand of an ApoB-specific siRNA administered intravenously resulted in a significant reduction in clearance and an associated 16-fold increase in t1/2, relative to the unconjugated control (Figure 2). Subsequent work elucidated that the change in pharmacokinetic (PK) characteristics was secondary to loading of the conjugated siRNA into circulating lipoprotein particles via the appended cholesterol moiety [17]. This also facilitated receptor-mediated uptake of the siRNA into hepatocytes, and resulted in ~60% knockdown of ApoB mRNA in the mouse liver [16]. Notably, intravenous administration of cholesterol-conjugated siRNAs targeting ApoB also resulted in efficient knockdown of ApoB mRNA in the jejunum. More recently, conjugation-based approaches with other ligands have been used, such as prostate-specific membrane antigen aptamer-siRNA conjugates to deliver drug to tumor cells in vivo [18].


A status report on RNAi therapeutics.

Vaishnaw AK, Gollob J, Gamba-Vitalo C, Hutabarat R, Sah D, Meyers R, de Fougerolles T, Maraganore J - Silence (2010)

In vivo pharmacokinetic profile of a cholesterol-conjugated (squares) and unconjugated (circles) radio-labeled small interfering (si)RNA against ApoB in the mouse [16]. The half-life and clearance were calculated to be 95 minutes and 0.5 mL/minute and 6 minutes and 17.6 mL/minute, for the conjugated and unconjugated molecules, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2908561&req=5

Figure 2: In vivo pharmacokinetic profile of a cholesterol-conjugated (squares) and unconjugated (circles) radio-labeled small interfering (si)RNA against ApoB in the mouse [16]. The half-life and clearance were calculated to be 95 minutes and 0.5 mL/minute and 6 minutes and 17.6 mL/minute, for the conjugated and unconjugated molecules, respectively.
Mentions: Soutschek et al. [16] were the first to report a delivery strategy with significant translational potential. In a mouse system, they demonstrated that cholesterol conjugation to the sense or 'passenger' strand of an ApoB-specific siRNA administered intravenously resulted in a significant reduction in clearance and an associated 16-fold increase in t1/2, relative to the unconjugated control (Figure 2). Subsequent work elucidated that the change in pharmacokinetic (PK) characteristics was secondary to loading of the conjugated siRNA into circulating lipoprotein particles via the appended cholesterol moiety [17]. This also facilitated receptor-mediated uptake of the siRNA into hepatocytes, and resulted in ~60% knockdown of ApoB mRNA in the mouse liver [16]. Notably, intravenous administration of cholesterol-conjugated siRNAs targeting ApoB also resulted in efficient knockdown of ApoB mRNA in the jejunum. More recently, conjugation-based approaches with other ligands have been used, such as prostate-specific membrane antigen aptamer-siRNA conjugates to deliver drug to tumor cells in vivo [18].

Bottom Line: More importantly, two key properties of the RNAi pathway - sequence-mediated specificity and potency - suggested that RNAi might be the most important pharmacological advance since the advent of protein therapeutics.The implications were profound.One could now envisage selecting disease-associated targets at will and expect to suppress proteins that had remained intractable to inhibition by conventional methods, such as small molecules.

View Article: PubMed Central - HTML - PubMed

Affiliation: Alnylam Pharmaceuticals Inc,, 300 Third Street, Cambridge, MA 02142, USA. avaishnaw@alnylam.com.

ABSTRACT
Fire and Mello initiated the current explosion of interest in RNA interference (RNAi) biology with their seminal work in Caenorhabditis elegans. These observations were closely followed by the demonstration of RNAi in Drosophila melanogaster. However, the full potential of these new discoveries only became clear when Tuschl and colleagues showed that 21-22 bp RNA duplexes with 3" overhangs, termed small interfering (si)RNAs, could reliably execute RNAi in a range of mammalian cells. Soon afterwards, it became clear that many different human cell types had endogenous machinery, the RNA-induced silencing complex (RISC), which could be harnessed to silence any gene in the genome. Beyond the availability of a novel way to dissect biology, an important target validation tool was now available. More importantly, two key properties of the RNAi pathway - sequence-mediated specificity and potency - suggested that RNAi might be the most important pharmacological advance since the advent of protein therapeutics. The implications were profound. One could now envisage selecting disease-associated targets at will and expect to suppress proteins that had remained intractable to inhibition by conventional methods, such as small molecules. This review attempts to summarize the current understanding on siRNA lead discovery, the delivery of RNAi therapeutics, typical in vivo pharmacological profiles, preclinical safety evaluation and an overview of the 14 programs that have already entered clinical practice.

No MeSH data available.


Related in: MedlinePlus