Cell-Specific Aptamer-Functionalized RNAi: A New Prospect for Targeted siRNA Delivery - Nanotechnology for the Delivery of Therapeutic Nucleic Acids - page 108

specific aptamers in cell recognition and targeted delivery, with a
particular focus on the development of the aptamer-functionalized
siRNA or nanocarrier for targeted gene silencing.

5.1 Introduction

Although the concept of nucleic acid based therapeutics is not a
new one, it has captured the wide attention of scientists for a long
time [1, 2]. Over the past few decades, a wide variety of nucleic
acids such as siRNAs [1, 2], microRNAs [3, 4], aptamers [5, 6],
antisense DNA and RNA [7, 8], mRNAs [9, 10], plasmid DNAs [11],
DNAzymes, and ribozymes [12] have been proposed as possible
drugs. Some of these nucleic acid candidates have been put on the
back burner or are still in development because of current technical
challenges; however, some nucleic acids have entered clinic trails,
and a few have even successfully made it to market; e.g., Vitravene
[13], the antisense oligonucleotide inhibiting cytomegalovirus
(CMV)-induced retinitis, and Pegaptanib (or Macugen) [14], the first
therapeutic aptamer approved for the treatment of neovascular age-
related macular degeneration (AMD).
Since the discovery of RNAi in 1998 [15], the use of RNAi-based
therapeutics (for example, siRNAs [16]) to silence target genes
associated with human diseases has progressed tremendously due
to their high specificity and potency. The research on RNAi has
fuelled excitement for their potential clinical application [1]. So far,
there are over 20 RNAi-based drugs in early- or mid-stage clinical
trials, several of which are indicating strong promise for further
drug development [3]. For example, in 2004 Acuity Pharmaceuticals
(now Opko Health) announced the first siRNA-related clinical trial,
in which Bevasiranib, an unmodified siRNA targeting vascular
endothelial growth factor (VEGF), was given in patients with wet
AMD [17]. Additionally, the first in-human Phase I clinical trial using
a targeted nanoparticle system to deliver siRNA to patients was
conducted and showed the direct evidence for siRNA-mediated gene
silencing the RNAi pathway [18]. However, like any other drugs

in development, some impediments have caused failures in the
clinical translation of RNAi-based therapeutics. In March 2009, Opko
decided to terminate the Phase III clinical trial of bevasiranib, since
it was unlikely to achieve its primary endpoint of reducing vision

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