- Review Article
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Aptamers as targeted therapeutics: current potential and challenges
Nature Reviews Drug Discoveryvolume 16, pages181–202 (2017)Cite this article
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ACorrigendum to this article was published on 28 April 2017
This article has beenupdated
Key Points
Nucleic acid aptamers, often termed chemical antibodies, are short, single-stranded DNA or RNA molecules (20–100 nucleotides in length) with defined structures that can specifically bind to a molecular target via three-dimensional structures.
Similarly to the way antibodies bind to antigens, aptamers specifically recognize and bind to their cognate targets through unique three-dimensional structures.
SELEX (systematic evolution of ligands by exponential enrichment) is a gold-standard methodology for generating aptamers, in which an iterative selection procedure — including binding, partitioning, recovery and re-amplification steps — is conducted. Specific sequences (that is, aptamers) can be enriched and dominate the population of library species.
Aptamer-based therapeutics typically exploit one of three strategies: an aptamer can serve as an antagonist for blocking the interaction of disease-associated targets (for example, receptor–ligand interactions); an aptamer can serve as an agonist for activating the function of target receptors; or a cell-type-specific aptamer can serve as a carrier for delivering other therapeutic agents to the target cells or tissue.
There are three aptamers designated for use in ophthalmology, including one drug approved by the US Food and Drug Administration (FDA) (pegaptanib (Macugen)), and two in late-stage development (ACR-1905 and E-10030).
Six RNA and four DNA aptamers have undergone clinical trials for the treatment of various conditions, including macular degeneration, coagulation, oncology and inflammation. All aptamers that have entered clinical trials so far act as antagonists.
Abstract
Nucleic acid aptamers, often termed 'chemical antibodies', are functionally comparable to traditional antibodies, but offer several advantages, including their relatively small physical size, flexible structure, quick chemical production, versatile chemical modification, high stability and lack of immunogenicity. In addition, many aptamers are internalized upon binding to cellular receptors, making them useful targeted delivery agents for small interfering RNAs (siRNAs), microRNAs and conventional drugs. However, several crucial factors have delayed the clinical translation of therapeutic aptamers, such as their inherent physicochemical characteristics and lack of safety data. This Review discusses these challenges, highlighting recent clinical developments and technological advances that have revived the impetus for this promising class of therapeutics.
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Change history
28 April 2017
Base Pair Biotechnologies and Apterna were omitted from Table 3 in this article. These have now been included.
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Acknowledgements
This work was supported by the US National Institutes of Health (grant numbers R01AI29329, R01AI42552 and R01HL07470 to J.J.R.). Funding for open access charge was provided by the US National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health. The authors thank S. T. Wilkinson (City of Hope) for helpful advice in scientific writing.
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Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, 91010, California, USA
Jiehua Zhou & John Rossi
Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, 91010, California, USA
John Rossi
- Jiehua Zhou
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Competing interests
J.J.R. and J.Z. have an issued patent entitled “Cell-type specific aptamer-siRNA delivery system for HIV-1 therapy” [USPTO, No. US 8, 222, 226 B2, July 17, 2012]. J.J.R., J.Z., Marco S. Weinberg and Kevin V. Morris have a patent pending on “Cell-specific internalizing RNA aptamers against human CCR5 and used therefore” [United States Patent, application number: 62/025, 368, filed on July 16, 2014].
Glossary
- Nucleic acid aptamers
Short, single-stranded DNA or RNA molecules (20–100 nucleotides in length) with defined structures that can specifically bind to a molecular target via three-dimensional structures.
- Systematic evolution of ligands by exponential enrichment
(SELEX). An iterative selection procedure for aptamer generation. Each cycle consists of binding, partitioning, recovery and re-amplification steps. Specific sequences (that is, aptamers) can be enriched and dominate the population of library species.
- G-quadruplex
A G-quadruplex structure can be formed in a guanine-rich sequence when four guanine bases are associated through hydrogen bonding.
- Kissing hairpin
If two RNA stem-loops have complementary sequences in the loop regions, the two loops will base pair to form a kissing complex.
- Macugen
Trade name of pegaptanib, a modified RNA aptamer that targets vascular endothelial growth factor (VEGF), and the first federally approved aptamer drug for the treatment of wet age-related macular degeneration.
- Vascular endothelial growth factor
(VEGF). A secreted protein that is capable of inducing angiogenesis and increasing vascular permeability and inflammation.
- Bevacizumab
Trade name Avastin; a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF), and an approved antibody drug for the treatment of certain metastatic cancers and eye diseases.
- Ranibizumab
Trade name Lucentis; a monoclonal antibody fragment created from bevacizumab, and an approved antibody drug for the treatment of age-related macular degeneration.
- Hairpin
A complementary region of nucleic acid that can form Watson–Crick base pairs and generally results in a stem–loop structure that resembles a hairpin.
- Emulsion PCR (ePCR) or droplet digital PCR (ddPCR)
Systems that compartmentalize and miniaturize PCR by generating a water-in-oil emulsion containing numerous droplets, which creates a local homogeneous amplification microenvironment.
- High-throughput sequencing
(HTS). A next-generation sequencing technology that is capable of parallelizing the sequencing process and producing thousands or millions of sequences at once.
- SOMAmer
(Slow off-rate modified aptamer). A chemically modified DNA aptamer that is highly specific for its respective cognate protein target; selected through anin vitro SELEX procedure, in which modified deoxyuracil carrying hydrophobic functional groups is incorporated. More than 1,300 different SOMAmer agents have been developed by SomaLogic.
- Spiegelmers
Trade name of theL-ribonucleic acid aptamers developed by NOXXON Pharma; mirror-image RNAs built from naturalL-ribose units.
- REG1 system
A modified RNA aptamer RB006 (pegnivacogin) and an antidote oligonucleotide RB007 (anivamersen); the first aptamer-based anticoagulation system in clinical trials.
- Co-stimulatory receptors
A class of molecules expressed by T lymphocytes that regulate the activation of T cells and the generation of effector T cell responses, including OX40, 4-1BB, CD40, CD28 and programmed cell death protein 1 (PD1). OX40, 4-1BB and CD40 belong to the tumour necrosis factor (TNF) family and are involved in the later phase of T cell activation, whereas CD28 is a member of the larger immunoglobulin superfamily and involved in triggering of the cell-mediated immune response.
- Short hairpin RNA
(shRNA). An artificial RNA molecule with a short hairpin turn; like small interfering RNAs (siRNAs), this is another class of an RNA interference (RNAi) trigger.
- Nonsense-mediated mRNA decay
(NMD). A translation-coupled mechanism that degrades mRNA containing premature translation-termination codons (PTCs).
- Small interfering RNAs
(siRNAs). A class of double-stranded RNA molecules 20–25 base pairs in length that are capable of triggering sequence-specific, post-transcriptional gene silencing.
- MicroRNAs
(miRNAs). A class of small non-coding RNA molecules∼22 nucleotides in length. The mechanism of miRNA-mediated silencing is repression of target mRNA translation accompanied by deadenylation and subsequent degradation of the mRNA targets.
- AntimiRs
Synthetic oligonucleotides designed to neutralize microRNA function.
- RNA interference
(RNAi). A highly conserved endogenous process for post-transcriptional regulation of gene silencing that is triggered by small regulatory RNAs, including small interfering RNAs.
- gp120
An HIV-1 envelope glycoprotein. gp120 is exposed on the surface of virus particles and the plasma membrane of HIV-1-infected cells. The interaction of HIV-1 gp120 with the cellular CD4 receptor is a crucial step in the entry of HIV into T cells.
- Gelonin
A small 28 kDaN-glycosidase protein capable of inducing cell death.
- Plekho1
(Pleckstrin homology domain-containing family O member 1). Has a role in the regulation of the actin cytoskeleton through its interactions with actin capping protein.
- ARC-1905
A modified RNA aptamer targeting complement 5 (C5) protein that has undergone clinical trials for the treatment of dry age-related macular degeneration.
- E-10030
A modified DNA aptamer targeting platelet-derived growth factor (PDGF) that has undergone clinical trials for wet age-related macular degeneration therapy.
- Aflibercept
Trade name Eylea; a recombinant fusion protein inhibitor of vascular endothelial growth factor (VEGF), and an approved biopharmaceutical drug for the treatment of wet age-related macular degeneration.
- von Willebrand factor
(vWF). A key factor in the coagulation cascade associated with platelet recruitment. A deficiency or impairment of vWF causes von Willebrand disease.
- von Willebrand disease
A condition that can cause extended or excessive bleeding.
- Stromal cell-derived factor 1
(SDF1; also known as CXCL12). A small cytokine protein that has an important role in tumour proliferation, new blood vessel formation and metastasis.
- Hepcidin
A small 2.8 kDa peptide thought to be the central mediator of iron homeostasis.
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Zhou, J., Rossi, J. Aptamers as targeted therapeutics: current potential and challenges.Nat Rev Drug Discov16, 181–202 (2017). https://doi.org/10.1038/nrd.2016.199
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