Nucleic acid-based drug delivery strategies.
Journal of controlled release : official journal of the Controlled Release Society
Nucleic acids have not been widely considered as an optimal material for drug delivery. Indeed, unmodified nucleic acids are enzymatically unstable, too hydrophilic for cell uptake and payload encapsulation, and may cause unintended biological responses such as immune system activation and prolongation of the blood coagulation pathway. Recently, however, three major areas of development surrounding nucleic acids have made it worthwhile to reconsider their role for drug delivery. These areas include DNA/RNA nanotechnology, multivalent nucleic acid nanostructures, and nucleic acid aptamers, which, respectively, provide the ability to engineer nanostructures with unparalleled levels of structural control, completely reverse certain biological properties of linear/cyclic nucleic acids, and enable antibody-level targeting using an all-nucleic acid construct. These advances, together with nucleic acids' ability to respond to various stimuli (engineered or natural), have led to a rapidly increasing number of drug delivery systems with potential for spatiotemporally controlled drug release. In this review, we discuss recent progress in nucleic acid-based drug delivery strategies, their potential, unique use cases, and risks that must be overcome or avoided.
10.1016/j.jconrel.2020.03.040
Targeting transcription factors in cancer - from undruggable to reality.
Nature reviews. Cancer
Mutated or dysregulated transcription factors represent a unique class of drug targets that mediate aberrant gene expression, including blockade of differentiation and cell death gene expression programmes, hallmark properties of cancers. Transcription factor activity is altered in numerous cancer types via various direct mechanisms including chromosomal translocations, gene amplification or deletion, point mutations and alteration of expression, as well as indirectly through non-coding DNA mutations that affect transcription factor binding. Multiple approaches to target transcription factor activity have been demonstrated, preclinically and, in some cases, clinically, including inhibition of transcription factor-cofactor protein-protein interactions, inhibition of transcription factor-DNA binding and modulation of levels of transcription factor activity by altering levels of ubiquitylation and subsequent proteasome degradation or by inhibition of regulators of transcription factor expression. In addition, several new approaches to targeting transcription factors have recently emerged including modulation of auto-inhibition, proteolysis targeting chimaeras (PROTACs), use of cysteine reactive inhibitors, targeting intrinsically disordered regions of transcription factors and combinations of transcription factor inhibitors with kinase inhibitors to block the development of resistance. These innovations in drug development hold great promise to yield agents with unique properties that are likely to impact future cancer treatment.
10.1038/s41568-019-0196-7
Reexamining assumptions about miRNA-guided gene silencing.
Nucleic acids research
MicroRNAs (miRNAs) are short endogenously expressed RNAs that have the potential to regulate the expression of any RNA. This potential has led to the publication of several thousand papers each year connecting miRNAs to many different genes and human diseases. By contrast, relatively few papers appear that investigate the molecular mechanism used by miRNAs. There is a disconnect between rigorous understanding of mechanism and the extraordinary diversity of reported roles for miRNAs. Consequences of this disconnect include confusion about the assumptions underlying the basic science of human miRNAs and slow development of therapeutics that target miRNAs. Here, we present an overview of investigations into miRNAs and their impact on gene expression. Progress in our understanding of miRNAs would be aided by a greater focus on the mechanism of miRNAs and a higher burden of evidence on researchers who seek to link expression of a particular miRNA to a biological phenotype.
10.1093/nar/gkab1256
The current landscape of nucleic acid therapeutics.
Nature nanotechnology
The increasing number of approved nucleic acid therapeutics demonstrates the potential to treat diseases by targeting their genetic blueprints in vivo. Conventional treatments generally induce therapeutic effects that are transient because they target proteins rather than underlying causes. In contrast, nucleic acid therapeutics can achieve long-lasting or even curative effects via gene inhibition, addition, replacement or editing. Their clinical translation, however, depends on delivery technologies that improve stability, facilitate internalization and increase target affinity. Here, we review four platform technologies that have enabled the clinical translation of nucleic acid therapeutics: antisense oligonucleotides, ligand-modified small interfering RNA conjugates, lipid nanoparticles and adeno-associated virus vectors. For each platform, we discuss the current state-of-the-art clinical approaches, explain the rationale behind its development, highlight technological aspects that facilitated clinical translation and provide an example of a clinically relevant genetic drug. In addition, we discuss how these technologies enable the development of cutting-edge genetic drugs, such as tissue-specific nucleic acid bioconjugates, messenger RNA and gene-editing therapeutics.
10.1038/s41565-021-00898-0
RNA-Targeted Therapeutics.
Crooke Stanley T,Witztum Joseph L,Bennett C Frank,Baker Brenda F
Cell metabolism
RNA-targeted therapies represent a platform for drug discovery involving chemically modified oligonucleotides, a wide range of cellular RNAs, and a novel target-binding motif, Watson-Crick base pairing. Numerous hurdles considered by many to be impassable have been overcome. Today, four RNA-targeted therapies are approved for commercial use for indications as diverse as Spinal Muscular Atrophy (SMA) and reduction of low-density lipoprotein cholesterol (LDL-C) and by routes of administration including subcutaneous, intravitreal, and intrathecal delivery. The technology is efficient and supports approaching "undruggable" targets. Three additional agents are progressing through registration, and more are in clinical development, representing several chemical and structural classes. Moreover, progress in understanding the molecular mechanisms by which these drugs work has led to steadily better clinical performance and a wide range of mechanisms that may be exploited for therapeutic purposes. Here we summarize the progress, future challenges, and opportunities for this drug discovery platform.
10.1016/j.cmet.2018.03.004
Nucleic acid delivery for therapeutic applications.
Gupta Akash,Andresen Jason L,Manan Rajith S,Langer Robert
Advanced drug delivery reviews
Recent medical advances have exploited the ability to address a given disease at the underlying level of transcription and translation. These treatment paradigms utilize nucleic acids - including short interfering RNA (siRNA), microRNA (miRNA), antisense oligonucleotides (ASO), and messenger RNA (mRNA) - to achieve a desired outcome ranging from gene knockdown to induced expression of a selected target protein. Towards this end, numerous strategies for encapsulation or stabilization of various nucleic acid structures have been developed in order to achieve intracellular delivery. In this review, we discuss several therapeutic applications of nucleic acids directed towards specific diseases and tissues of interest, in particular highlighting recent technologies which have reached late-stage clinical trials and received FDA approval.
10.1016/j.addr.2021.113834