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8.4 Application of Riboswitches in Gene Therapy 215
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control the expression of genes in patients using synthetic riboswitches. Self-cleaving
ribozymes are a common expression platform employed by researchers when engineering a riboswitch intended for human applications [112, 125–130]. These
ribozymes function naturally as cis-acting RNAs that improve the rate constant of
RNA strand scission by internal phosphoester transfer (often by 6 orders of magnitude or greater) [131–139]. Self-cleaving ribozymes can be fused with aptamers to
generate allosteric ribozymes in which self-cleaving activity is conditional on the
presence or absence of the target ligand [122–124, 140].
Allostery can occur in two distinct ways: (i) an inactive ribozyme is turned on
by the presence of the target ligand or (ii) an active ribozyme is inhibited by the
presence of the target ligand. The latter model is well suited for gene therapy applications and could be used to control gene expression by inserting such a switch in the
3′UTR of an mRNA [141]. When the drug is absent, the ribozyme rapidly cleaves
o the 3′poly-A tail from the precursor mRNA. The cleaved precursor mRNA is
degraded by the exosome [142, 143], keeping background gene expression levels very
low.When the drug is administered, the ribozyme is disabled, and gene expression is
turned on. These features were showcased in a recent report describing the regulation of a rapid self-cleaving ribozyme with antisense morpholino oligonucleotides
[112]. One drawback of this approach is that it would require injections of morpholino oligonucleotides. The ability to externally control the switch with an oral
inducer that is less invasive would be a preferred treatment option.
Curiously, allosteric self-cleaving ribozymes have not been found to control gene
expression in nature [144]. Though it could simply be the case that these examples
are yet to be discovered, it merits exploring other possible expression platforms that
more directly interface with mammalian gene regulatory machinery. For example,
a recent report describes an engineered riboswitch that uses the initial or “P1”
stem of a guanine aptamer to hide or reveal a polyadenylation sequence [145]. This
approach is attractive because of the simplicity of the design. However, a second
engineered riboswitch that incorporated a self-cleaving ribozyme was required
in tandem to suciently improve the dynamic range. Similarly, researchers have
developed riboswitches that control alternative splicing by hiding or revealing a
5′splice site within the P1 stem of a tetracycline aptamer [113, 146]. Another report
describes an engineered riboswitch that regulates an internal ribosome entry site
(IRES) in response to theophylline [147]. One drawback of this approach is that the
IRES itself is quite large and would consume valuable vector space. Additionally,
it is unlikely to be a generalizable approach to engineering riboswitches without
much trial-and-error experimentation during the design process.
In another example, researchers used tetracycline to hide or reveal a microRNA
(miRNA) binding site [148]. A disadvantage noted by the authors is that this
approach might disrupt the natural miRNA system within the cell and produce unwanted o-target eects. Recently, an aptamer that binds a tetracycline
repressor (TetR) protein was exploited to regulate alternative splicing [149].
This involves expressing a foreign protein, which could present issues with
both immunogenicity and vector space limitations. Another example involved a
theophylline aptamer that regulated a -1 ribosomal frameshifting element [150].
216 8 Prospects for Riboswitches in Drug Development
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This approach produces nonsense protein products which could also pose issues
with immunogenicity.
8.4.3 Barriers and Future Developments
Many proof-of-principle studies have been published using ribozyme-based expression platforms, among other mechanisms for gene control. There are various
aspects to consider when selecting an expression platform, including the length
of the construct (including aptamer and expression platform) in nucleotides, the
relative ease with which allostery is expected to be achieved with an aptamer
domain (design diculty), whether the design is reasonably expected to modular,
expected o-target eects from the nature of the expression platform itself, and the
expected dynamic range. We have evaluated these features for several eukaryotic
expression platforms (Figure 8.7). Some devices, such as allosteric ribozymes, could
be implemented with various placements within an mRNA, whereas others must
be positioned precisely to exhibit gene control.
We considered expression platforms that can simply be contained within the
P1 stem of an aptamer (such as hiding or revealing a polyadenylation signal,
miRNA-binding site, or Kozak sequence) as favorable. Constructs that involve
another relatively small domain (such as a self-cleaving ribozyme or a short intron
sequence) were considered intermediate and those that involved a large domain
(IRES, frameshifting element) were considered unfavorable.
For design diculty, some constructs are relatively straightforward to design
(those that involve hiding or revealing a sequence via ligand-mediated formation
Key
Favorable Unfavorable
Size (nucleotides)
Design difficulty
Modular
Off-target effects
Dynamic range
Regulate polyadenylation
Allosteric ribozyme – 3ctail
Regulate alternative splicing
Allosteric ribozyme – intron
Regulate access to miRNA-binding site
Allosteric ribozyme – 5c cap
IRES-based regulation
Regulate ribosomal frameshifting
Regulate access to Kozak sequence
Figure 8.7 Evaluation of mammalian expression platforms that could be applied to
regulate gene expression in eukaryotes.
Natural examples
Proof-of-principle
8.5 Concluding Remarks 217
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of a P1 stem). Development of constructs considered intermediate in this category
might involve screening many constructs, but numerous literature precedents
exist to guide researchers (e.g. allosteric ribozymes). Constructs considered
unfavorably might require substantial trial and error to develop (e.g. regulating
a large domain such as an IRES or frameshifting element). Devices inserted
in the 5′UTR (e.g. for regulating access to a Kozak sequence) are likely to be
incredibly challenging to implement as ON switches. This is likely true because
highly structured RNAs such as aptamers that occur between the 5′cap and start
codon have been shown to reduce translation of the associated ORF [151], thereby
potentially reducing overall gene expression even when the riboswitch would be in
the ON state.
Some engineered RNA switches are expected to be (or have been reported to
be) modular in architecture, wherein the aptamer domain can be swapped out for
another with dierent ligand specicity and the device still functions reasonably
well. This characteristic is desirable because it reduces the time required to develop
a device that responds to a dierent compound and still maintains robust switch
function. Lastly, we considered the expected or reported ranges for potential
ON-switch devices that could be (or have been) developed. For devices such as
allosteric ribozymes, which are expected to have extremely low expression in the
OFF state, a large dynamic range may not be required as even low gene expression
levels might be sucient to provide the therapeutic eect.
A common theme among reported examples is that the compounds used to
control the riboswitch are often repeated from the same group of classic aptamers
(guanine, tetracycline, and theophylline). There is a pressing need for aptamers that
respond to drug-like compounds like those described earlier (see Section 8.4.1).
8.5 Concluding Remarks
Numerous bacterial discoveries have led to fundamental molecular biology tools,
such as polymerase chain reaction (PCR) [152], restriction enzyme technology
[153], and novel therapeutic technologies (e.g. clustered regularly interspaced
short palindromic repeats [CRISPR] [154]). Since the rst experimentally validated
bacterial riboswitch was reported just over 20 years ago [33], riboswitch-based
technologies have seen substantial progress in preclinical drug development.
Despite this, many exciting challenges remain. Known bacterial riboswitches
present a valuable and still largely untapped collection of targets for the development of new antibacterial agents. Furthermore, the discovery and validation
of new riboswitch classes is a driving force for identifying new biological targets
for antibiotic development. In addition to presenting novel riboswitch classes
themselves, new proteins have been discovered by pathways that are elucidated
by riboswitch discovery – such as guanidine hydrolases [155, 156]. The prospect
of discovering hypothesized riboswitches that naturally occur in humans would
present tantalizing opportunities for drug development researchers, especially with
the increase in interest in RNA drug development resulting from the advent of
218 8 Prospects for Riboswitches in Drug Development
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mRNA vaccines [157]. Meanwhile, synthetic biologists seek to advance riboswitch
technology ever closer to human gene therapy applications.
Acknowledgment
We thank members of the Breaker laboratory for helpful comments and discussions. RNA research in the Breaker laboratory is supported by the Howard Hughes
Medical Institute and grants from the NIH. M.G.M. is a Howard Hughes Medical
Institute Awardee of the Life Sciences Research Foundation.
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