Dale C. Guenther

Antisense Oligonucleotides Targeting an LDLR Regulatory RNA Increase LDLR Expression and Reduce LDL-cholesterol in Vivo

Keerthana Gnanapradeepan, Salomé Manska, Brian Schwartz, Gabriel Golczer et autres

Abstract Regulatory RNAs (regRNAs) are non-coding RNAs expressed from promoters and enhancers that modulate gene transcription. Targeting regRNAs with antisense oligonucleotides (ASOs) can increase transcription and presents a potential therapeutic strategy to restore expression in haploinsufficient diseases. This approach requires high-quality regRNA …

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Modified unlocked nucleic acid (MUNA) mitigates off-target effects of small interfering RNAs

S. Mori, Dhrubajyoti Datta, Lydia A. Perkins, Michelle M. Jung et autres

Unlocked nucleic acid (UNA) is a nucleic acid analog that has an acyclic ribose ring lacking the bond between C2' and C3' atoms. The base-pairing properties of UNA have been studied, and it has been used as a scaffold for conjugation, but …

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Single-Stranded Hairpin Loop RNAs (loopmeRNAs) Potently Induce Gene Silencing through the RNA Interference Pathway

Krishna Chaitanya Aluri, Dhrubajyoti Datta, Scott Waldron, Nate Taneja et autres

-acetylgalactosamine (GalNAc) are clinically validated drugs for treatment of liver diseases. Incorporation of phosphorothioate linkages and ribose modifications are necessary for stability, potency, and duration of pharmacology. Although multiple alternative siRNA designs such as Dicer-substrate RNA, shRNA, and circular RNA have been …

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Evaluating the oral delivery of GalNAc-conjugated siRNAs in rodents and non-human primates

Mikyung Yu, June Qin, Xiumin Liu, Diane Ramsden et autres

Oral delivery is the most widely used and convenient route of administration of medicine. However, oral administration of hydrophilic macromolecules is commonly limited by low intestinal permeability and pre-systemic degradation in the gastrointestinal (GI) tract. Overcoming some of these challenges allowed emergence …

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Shorter Is Better: The α-( l )-Threofuranosyl Nucleic Acid Modification Improves Stability, Potency, Safety, and Ago2 Binding and Mitigates Off-Target Effects of Small Interfering RNAs

Shigeo Matsuda, Saikat Bala, Jen-Yu Liao, Dhrubajyoti Datta et autres

Chemical modifications are necessary to ensure the metabolic stability and efficacy of oligonucleotide-based therapeutics. Here, we describe analyses of the α-( l )-threofuranosyl nucleic acid (TNA) modification, which has a shorter 3′–2′ internucleotide linkage than the natural DNA and RNA, in the …

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Role of a “Magic” Methyl: 2′-Deoxy-2′-α-F-2′-β-C-methyl Pyrimidine Nucleotides Modulate RNA Interference Activity through Synergy with 5′-Phosphate Mimics and Mitigation of Off-Target Effects

Dale C. Guenther, S. Mori, Shigeo Matsuda, Jason A. Gilbert et autres

-methyl-containing sugar ring. These data indicate that 2'-F/Me nucleotides are promising tools for nucleic acid-based therapeutic applications to increase potency, duration, and safety.

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Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates

Kirk M. Brown, Jayaprakash K. Nair, Maja M. Janas, Yesseinia I. Angleró-Rodriguez et autres

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Small circular interfering RNAs (sciRNAs) as a potent therapeutic platform for gene-silencing

Hartmut Jahns, Rohan Degaonkar, Peter Podbevšek, Swati Gupta et autres

In order to achieve efficient therapeutic post-transcriptional gene-silencing mediated by the RNA interference (RNAi) pathway, small interfering RNAs (siRNAs) must be chemically modified. Several supra-RNA structures, with the potential to stabilize siRNAs metabolically have been evaluated for their ability to induce gene …

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The Nonclinical Disposition and Pharmacokinetic/Pharmacodynamic Properties of N-Acetylgalactosamine–Conjugated Small Interfering RNA Are Highly Predictable and Build Confidence in Translation to Human

Robin McDougall, Diane Ramsden, Sagar Agarwal, Saket Agarwal et autres

-acetylgalactosamine (GalNAc) ligands has become the primary strategy for hepatocyte-targeted delivery, and with the recent approvals of GIVLAARI (givosiran) for the treatment of acute hepatic porphyria, OXLUMO (lumasiran) for the treatment of primary hyperoxaluria, and Leqvio (inclisiran) for the treatment of hypercholesterolemia, …

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Recognition of double-stranded DNA using LNA-modified toehold Invader probes

Shiva P. Adhikari, Philip Vukelich, Dale C. Guenther, Saswata Karmakar et autres

, Invader probes with 5'-single-stranded overhangs. This design provides access to probes with shortened double-stranded segments, which facilitates probe denaturation. The single-stranded overhangs can, furthermore, be modified with affinity-enhancing modifications like LNA (locked nucleic acid) monomers to additionally increase target affinity. Herein, …

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Chimeric siRNAs with chemically modified pentofuranose and hexopyranose nucleotides: altritol-nucleotide (ANA) containing GalNAc–siRNA conjugates: in vitro and in vivo RNAi activity and resistance to 5′-exonuclease

Pawan Kumar, Rohan Degaonkar, Dale C. Guenther, Mikhail Abramov et autres

In this report, we investigated the hexopyranose chemical modification Altriol Nucleic Acid (ANA) within small interfering RNA (siRNA) duplexes that were otherwise fully modified with the 2'-deoxy-2'-fluoro and 2'-O-methyl pentofuranose chemical modifications. The siRNAs were designed to silence the transthyretin (Ttr) gene …

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Impact of non-nucleotidic bulges on recognition of mixed-sequence dsDNA by pyrene-functionalized Invader probes

Dale C. Guenther, Raymond G. Emehiser, Allison Inskeep, Saswata Karmakar et autres

Invader probes, i.e., DNA duplexes modified with +1 interstrand zippers of intercalator-functionalized nucleotides like 2'-O-(pyren-1-yl)methyl-RNA monomers, are energetically activated for sequence-unrestricted recognition of double-stranded DNA (dsDNA) as they are engineered to violate the neighbor exclusion principle, while displaying high affinity towards complementary …

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