The number
and diversity of new nucleic acid based therapeutics in clinical trial
illustrates the remarkable flexibility of this approach to therapy. The use of
synthetic oligomers has the advantage of control of dose and duration of action
over gene therapy and Cas9/CRISPR approaches that are developed in parallel.
Further, synthetic compounds may contain a variety of modifications to fine
tune their therapeutic purpose and define their mechanism of action. The
expansion in diversity of nucleic acid therapeutics may also reflect the
approaches to barriers observed in previous clinical trials. The objective of
this review is to provide new insight into the clinical adverse event data
reported for nucleic acid based therapeutics in advanced development, with the
goal of establishing a comprehensive framework for evaluating the current
implications, and future direction, of therapeutic antisense technologies. A
pattern of adverse events, some sufficiently severe to require discontinuation
of treatment, include Flu-Like Symptoms (FLS), Injection Site Reactions (ISR),
kidney abnormalities, elevated liver enzymes, and thrombocytopenia are
frequently observed with oligomer chemistries that have negatively charged
phosphate linkages and naturally occurring sugars. Anti-Drug Antibodies (ADA)
have been reported in high percentages following chronic treatment with
oligomer chemistries designed to enhance duration of tissue residence time.
However, these common adverse events are not observed with Phosphorodiamidate
Morpholino Oliogmers (PMO) containing morpholino sugars and no negative charge
in the phosphate linkage.
Oligonucleotide drug development must be viewed through a lens,
which recognizes that humans are well equipped to recognize both foreign and
endogenous DNA/RNA in the circulation. This protective recognition arises
either as part of an innate, microbial DNA immune response or in response to
cellular danger signaled by DNA Damage-Associated Molecular Patterns (DAMPs)
[1,2]. Now that synthetic analogues of DNA and RNA are being developed as
therapeutics for both acute and chronic treatment regimens, it is critical that
we clarify the extent to which these emerging therapeutics result in chronic or
inappropriate activation of these nucleic-acid sensors.
Information available to guide optimal therapeutic oligomer
chemistry has transitioned from what chemical structures can be made to
properties in biological systems and then on to efficacy in animal models.
Recently, advanced therapeutic development of oligonucleotides has provided a
wealth of information from well controlled clinical trials. Human data are the
most pertinent information as, in some cases, the preclinical efficacy reports
are discordant with human efficacy observations such as the case with
TKM-100802 which was highly effective in nonhuman primates but its use in patients from the recent Ebola
outbreak were not effective and
off-target effects including activation of inflammatory cytokines were notable
outcomes. In addition, detailed summaries are only recently publicly available
for Ampligen, mipomersen, drisapersen, and eteplirsen which provide
comprehensive evaluation of efficacy and safety from multiple human studies.
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