Antisense Oligonucleotides and RNA Interference - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 324

This chapter anticipates the accomplishment of the therapeutic use of oligonucle-
otides and siRNA. One AS ODN, Fomivirsen, is marketed under the trade name
Vitravene ® by ISIS pharmaceuticals as a local injection to treat retinitis [10] . Another
similar approach to inhibit proteins is via specific three-dimensional complex-structured
molecules called aptamers. Pigatinib (Macugen TM ) is an FDA-approved aptamer for
the treatment of wet macular degeneration [10] . Currently, many antisense agents are
under clinical trials and many others at preclinical stage are in a queue to enter clinics
for various applications such as cancer, HIV, age-related macular degeneration (AMD),
and respiratory syncytial virus, as well as rare diseases like pachyonychia congenita.
Conversely, some antisense agents, like Bevasiranib of Acuity Pharmaceuticals and
Sirna-027 of Sirna Therapeutics, have recently been terminated at phase III and phase
II, respectively, of clinical trials (Tables 7.1-7.3).
The major obstacle in navigating these molecules for regulatory approval is effi-
cient delivery to the desired site. However, this challenge can be met by better under-
standing of the various formidable barriers encountered, from the site of delivery
to the site of action of antisense drugs. Two major limitations, insufficient delivery
to target cells and off-target side effects, can be addressed by designing a suitable
delivery system, by chemical modifications such as using structural modifications or
nanocarriers, or by conjugation with receptor-specific targeting ligands, or combina-
tions thereof [11,12] . Thus, the purpose of this chapter is to highlight the limitations
of antisense agents in therapeutics, the progress made to meet delivery challenges,
and the clinical applications of antisense technology. This chapter surveys the agents
employed in antisense technologies and discusses the various mechanisms of gene
silencing. The emphasis will be on those techniques that employ oligonucleotides
composed of both modified and unmodified DNA and/or RNA nucleotides, and
another major antisense technology called RNA interference, or RNAi.
7.2 The Evolution of Antisense Drug Technology
Since its discovery, antisense technology has continued to progress rapidly. In this sec-
tion, we review our knowledge of antisense drug delivery, from discovery to application.
7.2.1 History
It was discovered in the late 1970s that the expression of a specific gene product
could be inhibited using a short complementary DNA sequence [1] . This led to inten-
sive research on the antisense approach. In 1978, the concept of antisense technique
came into view after the discovery of single-stranded DNA molecules, known as
antisense oligodeoxynucleotide (AS ODNs), by Zamecnik and Stephenson [1] . Since
then, new applications of antisense technology have continued to develop rapidly. In
early developmental stages, blockage of target protein expression was achieved by
administering whole DNA or RNA locally as therapeutics [13] . Then, single-stranded
DNA molecules (AS ODNs) were first locally administered for the treatment of