Abstract
Under clinical development since the early 90's and with two successfully approved drugs (Fomivirsen and Mipomersen), oligonucleotide-based therapeutics has not yet delivered a clinical drug to the market in the cancer field. Whilst many pre-clinical data has been generated, a lack of understanding still exists on how to efficiently tackle all the different challenges presented for cancer targeting in a clinical setting. Namely, effective drug vectorization, careful choice of target gene or synergistic multi-gene targeting are surely decisive, while caution must be exerted to avoid potential toxic, often misleading off-target-effects. Here a brief overview will be given on the nucleic acid chemistry advances that established oligonucleotide technologies as a promising therapeutic alternative and ongoing cancer related clinical trials. Special attention will be given toward a perspective on the hurdles encountered specifically in the cancer field by this class of therapeutic oligonucleotides and a view on possible avenues for success is presented, with particular focus on the contribution from nanotechnology to the field.
Highlights
OPENING THE THERAPEUTIC LANDSCAPE BY EVOLUTION OF NUCLEIC ACIDS CHEMISTRY Oligonucleotides have been under investigation for over 30 years, whilst achieving only two approved drugs. Those were, Fomivirsen, approved by the FDA in 1998 for the treatment of cytomegalovirus retinitis in patients with AIDS, but discontinued for low demand, and Mipomersen, FDA approved in 2013, targeting ApoB100 for the treatment of homozygous familial hypercholesterolaemia (HoFH), a rare genetic disorder that leads to excessive levels of low-density lipoprotein (LDL) cholesterol
In this paper more emphasis will be put on AONs due to their longer time in development and history of clinical trials
Progress in this field has been proceeding at a steady but somewhat slow pace, driven mostly by the speed at which the different intra and extracellular obstacles encountered by the oligonucleotide drugs are being tackled
Summary
OPENING THE THERAPEUTIC LANDSCAPE BY EVOLUTION OF NUCLEIC ACIDS CHEMISTRY Oligonucleotides have been under investigation for over 30 years, whilst achieving only two approved drugs. In the case of phosphorothioate (PS) modification (one of the first and widely used modifications introduced in therapeutic antisense oligonucleotides) (Eckstein, 1967), it has led to better pharmacokinetics and extended circulation times for AONs systemically applied in a “naked” form (i.e., unprotected by delivery agents).
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