The current landscape of nucleic acid therapeutics.

Published on May 31, 2021in Nature Nanotechnology31.538
· DOI :10.1038/S41565-021-00898-0
Jayesh A. Kulkarni14
Estimated H-index: 14
(UBC: University of British Columbia),
Dominik Witzigmann16
Estimated H-index: 16
+ 4 AuthorsRoy van der Meel21
Estimated H-index: 21
(TU/e: Eindhoven University of Technology)
Sources
Abstract
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.
Download
📖 Papers frequently viewed together
2020
4 Authors (Wenjie Chen)
3 Citations
54 Citations
13 Citations
References156
Newest
#1Amy Henrickson (U of L: University of Lethbridge)H-Index: 4
#2Jayesh A. KulkarniH-Index: 14
Last. Borries Demeler (UM: University of Montana)H-Index: 57
view all 6 authors...
Previous work suggested that lipid nanoparticle (LNP) formulations, encapsulating nucleic acids, display electron-dense morphology when examined by cryogenic-transmission electron microscopy (cryo-TEM). Critically, the employed cryo-TEM method cannot differentiate between loaded and empty LNP formulations. Clinically relevant formulations contain high lipid-to-nucleic acid ratios (10-25 (w/w)), and for systems that contain mRNA or DNA, it is anticipated that a substantial fraction of the LNP pop...
3 CitationsSource
#1Lindsey R. BadenH-Index: 74
#2Hana M. El SahlyH-Index: 19
Last. Tal ZaksH-Index: 2
view all 37 authors...
Abstract Background Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle–e...
2,170 CitationsSource
#1Lukas Villiger (ETH Zurich)H-Index: 4
#2Tanja Rothgangl (ETH Zurich)H-Index: 1
Last. Gerald Schwank (ETH Zurich)H-Index: 18
view all 17 authors...
Base editors are RNA-programmable deaminases that enable precise single-base conversions in genomic DNA. However, off-target activity is a concern in the potential use of base editors to treat genetic diseases. Here, we report unbiased analyses of transcriptome-wide and genome-wide off-target modifications effected by cytidine base editors in the liver of mice with phenylketonuria. The intravenous delivery of intein-split cytidine base editors by dual adeno-associated viruses led to the repair o...
7 CitationsSource
#1Fernando P. PolackH-Index: 40
#2Stephen J. Thomas (State University of New York Upstate Medical University)H-Index: 42
Last. Kathrin U. JansenH-Index: 71
view all 3 authors...
Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a world...
3,363 CitationsSource
#1Christopher R. Brown (Alnylam Pharmaceuticals)H-Index: 18
#2Swati Gupta (Alnylam Pharmaceuticals)H-Index: 3
Last. Vasant Jadhav (Alnylam Pharmaceuticals)H-Index: 16
view all 24 authors...
One hallmark of trivalent N-acetylgalactosamine (GalNAc)-conjugated siRNAs is the remarkable durability of silencing that can persist for months in preclinical species and humans. Here, we investigated the underlying biology supporting this extended duration of pharmacological activity. We found that siRNA accumulation and stability in acidic intracellular compartments is critical for long-term activity. We show that functional siRNA can be liberated from these compartments and loaded into newly...
21 CitationsSource
#1Ugur Sahin (University of Mainz)H-Index: 69
#2Alexander MuikH-Index: 10
Last. Özlem TüreciH-Index: 59
view all 42 authors...
An effective vaccine is needed to halt the spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic Recently, we reported safety, tolerability and antibody response data from an ongoing placebo-controlled, observer-blinded phase I/II coronavirus disease 2019 (COVID-19) vaccine trial with BNT162b1, a lipid nanoparticle-formulated nucleoside-modified mRNA that encodes the receptor binding domain (RBD) of the SARS-CoV-2 spike protein1 Here we present antibody and T cell r...
540 CitationsSource
#1Mark J. Mulligan (NYU: New York University)H-Index: 62
#2Kirsten E. Lyke (UMB: University of Maryland, Baltimore)H-Index: 33
Last. Kathrin U. Jansen (Pfizer)H-Index: 71
view all 25 authors...
In March 2020, the World Health Organization (WHO) declared a pandemic of coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. With rapidly accumulating cases and deaths reported globally2, a vaccine is urgently needed. We report the available safety, tolerability, and immunogenicity data from an ongoing placebo-controlled, observer-blinded dose escalation study among 45 healthy adults, 18 to 55 years of age, randomized to receive 2 doses, se...
566 CitationsSource
#1Atsushi Mikami (Alnylam Pharmaceuticals)H-Index: 1
#2Namrata Erande (Alnylam Pharmaceuticals)H-Index: 5
Last. Muthiah Manoharan (Alnylam Pharmaceuticals)H-Index: 82
view all 11 authors...
Various chemical modifications have been identified that enhance potency of small interfering RNAs (siRNAs) and that reduce off-target effects, immune stimulation, and toxicities of metabolites of these therapeutic agents. We previously described 5'-C-methyl pyrimidine nucleotides also modified at the 2' position of the sugar. Here, we describe the synthesis of 2'-position unmodified 5'-(R)- and 5'-(S)-C-methyl guanosine and evaluation of these nucleotides in the context of siRNA. The (R) isomer...
3 CitationsSource
#1Evan J. Anderson (Emory University)H-Index: 34
#2Nadine Rouphael (Emory University)H-Index: 30
Last. John H. BeigelH-Index: 28
view all 37 authors...
Abstract Background Testing of vaccine candidates to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in an older population is important, since increased inciden...
518 CitationsSource
#1Thomas C. Roberts (University of Oxford)H-Index: 24
#2Robert Langer (MIT: Massachusetts Institute of Technology)H-Index: 296
Last. Wood Mja. (University of Oxford)H-Index: 15
view all 3 authors...
Oligonucleotides can be used to modulate gene expression via a range of processes including RNAi, target degradation by RNase H-mediated cleavage, splicing modulation, non-coding RNA inhibition, gene activation and programmed gene editing. As such, these molecules have potential therapeutic applications for myriad indications, with several oligonucleotide drugs recently gaining approval. However, despite recent technological advances, achieving efficient oligonucleotide delivery, particularly to...
219 CitationsSource
Cited By7
Newest
#5Kai Wang (PKU: Peking University)
Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality worldwide. Conventional therapies involving surgery or pharmacological strategies have shown limited therapeutic effects due to a lack of cardiac tissue repair. Gene therapy has opened an avenue for the treatment of cardiac diseases through manipulating the underlying gene mechanics. Several gene therapies for cardiac diseases have been assessed in clinical trials, while the clinical translation greatly depends on the...
Source
Long non-coding RNAs (lncRNAs) are an emerging group of RNAs with a crucial role in cancer pathogenesis. In gastrointestinal cancers, TP53 target 1 (TP53TG1) is an epigenetically regulated lncRNA that represents a promising therapeutic target due to its tumor suppressor properties regulating the p53-mediated DNA damage and the intracellular localization of the oncogenic YBX1 protein. However, to translate this finding into the clinic as a gene therapy, it is important to develop effective carrie...
Source
#1Yangmeihui Song (HUST: Huazhong University of Science and Technology)H-Index: 1
#2Wenyu Song (HUST: Huazhong University of Science and Technology)H-Index: 1
Last. Dawei Jiang (HUST: Huazhong University of Science and Technology)H-Index: 24
view all 5 authors...
Source
#1Jeremy P Bost (KI: Karolinska Institutet)H-Index: 1
#2Hanna M. G. Barriga (KI: Karolinska Institutet)H-Index: 6
Last. Molly M. Stevens (KI: Karolinska Institutet)H-Index: 95
view all 11 authors...
Oligonucleotides (ONs) comprise a rapidly growing class of therapeutics. In recent years, the list of FDA-approved ON therapies has rapidly expanded. ONs are small (15-30 bp) nucleotide-based therapeutics which are capable of targeting DNA and RNA as well as other biomolecules. ONs can be subdivided into several classes based on their chemical modifications and on the mechanisms of their target interactions. Historically, the largest hindrance to the widespread usage of ON therapeutics has been ...
Source
#1Julius Ramakers (HHU: University of Düsseldorf)
#2Christopher Blum (HHU: University of Düsseldorf)H-Index: 1
Last. Markus Kollmann (HHU: University of Düsseldorf)H-Index: 19
view all 5 authors...
We present a Deep Learning approach to predict 3D folding structures of RNAs from their nucleic acid sequence. Our approach combines an autoregressive Deep Generative Model, Monte Carlo Tree Search, and a Score Model to find and rank the most likely folding structures for a given RNA sequence. We confirm the predictive power of our approach by setting new benchmarks for some longer sequences in a simulated blind test of the RNA Puzzles prediction challenge.
Source
#1Kai K. EwertH-Index: 29
#2Pablo ScodellerH-Index: 15
Last. Cyrus R. SafinyaH-Index: 69
view all 7 authors...
Cationic liposomes (CLs) are effective carriers of a variety of therapeutics. Their applications as vectors of nucleic acids (NAs), from long DNA and mRNA to short interfering RNA (siRNA), have been pursued for decades to realize the promise of gene therapy, with approvals of the siRNA therapeutic patisiran and two mRNA vaccines against COVID-19 as recent milestones. The long-term goal of developing optimized CL-based NA carriers for a broad range of medical applications requires a comprehensive...
Source