Efficient Synthesis and Biological Evaluation of 5′-GalNAc Conjugated Antisense Oligonucleotides

Østergaard, Michael E.; Yu, Jinghua; Kinberger, Garth A.; Wan, Wei; Migawa, Michael T.; Vasquez, Guillermo; Schmidt, Karsten; Gaus, Hans; Murray, Heather; Low, Audrey; Swayze, Eric E.; Prakash, Thazha P.; Seth, Punit P.

doi:10.1021/acs.bioconjchem.5b00265

Cited by 70 publications

(67 citation statements)

References 22 publications

(28 reference statements)

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“…It could be also attached to 5′-hexylamino (5′-HA)-modified ASOs via a solution-phase conjugation strategy by involving pentafluorophenolic ester intermediates, which avoided loading of GalNAc clusters onto a solid support 105 . Meanwhile, 5′ conjugation of the GalNAc cluster could be easily achieved based on a nitromethanetrispropionic acid core 106 .…”

Section: Introductionmentioning

confidence: 99%

“…Meanwhile, 5′ conjugation of the GalNAc cluster could be easily achieved based on a nitromethanetrispropionic acid core 106 . Data manifested that 5′-conjugated ASOs are more potent in primary hepatocytes as well as in animals than 3′-conjugated ASOs, 105 and the GalNAc ASOs showed 5- to 10-fold improvement in activity compared with the parent ASOs without GalNAc moiety 104, 106…”

Section: Introductionmentioning

confidence: 99%

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Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics

Huang

2017

Molecular Therapy - Nucleic Acids

234

203

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A main challenge in realizing the full potential of nucleic acid therapeutics is efficient delivery of them into targeted tissues and cells. N-acetylgalactosamine (GalNAc) is a well-defined liver-targeted moiety benefiting from its high affinity with asialoglycoprotein receptor (ASGPR). By conjugating it directly to the oligonucleotides or decorating it to a certain delivery system as a targeting moiety, GalNAc has achieved compelling successes in the development of nucleic acid therapeutics in recent years. Several oligonucleotide modalities are undergoing pivotal clinical studies, followed by a blooming pipeline in the preclinical stage. This review covers the progress of GalNAc-decorated oligonucleotide drugs, including siRNAs, anti-miRs, and ASOs, which provides a panorama for this field.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics

Huang

2017

Molecular Therapy - Nucleic Acids

234

203

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show abstract

“…Additionally, their preferential uptake by clearance organs such as the liver and spleen hinders delivery to target tissues (4,8). siRNA conjugates have emerged as an alternative to nanocarrier-mediated delivery (9)(10)(11)(12)(13)(14), offering the possibility of improving siRNA pharmacokinetics without requiring a more complex delivery vehicle. Alnylam Pharmaceuticals has demonstrated high gene silencing potency of a trivalent N-Acetylgalactosamine (GalNAc) siRNA conjugate, which binds with high specificity and affinity to the asialoglycoprotein receptor on hepatocytes (15,16).…”

mentioning

confidence: 99%

Lipophilic siRNA targets albumin in situ and promotes bioavailability, tumor penetration, and carrier-free gene silencing

Sarett

Werfel

Lee

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

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Clinical translation of therapies based on small interfering RNA (siRNA) is hampered by siRNA's comprehensively poor pharmacokinetic properties, which necessitate molecule modifications and complex delivery strategies. We sought an alternative approach to commonly used nanoparticle carriers by leveraging the long-lived endogenous serum protein albumin as an siRNA carrier. We synthesized siRNA conjugated to a diacyl lipid moiety (siRNA-L2), which rapidly binds albumin in situ. siRNA-L2, in comparison with unmodified siRNA, exhibited a 5.7-fold increase in circulation half-life, an 8.6-fold increase in bioavailability, and reduced renal accumulation. Benchmarked against leading commercial siRNA nanocarrier in vivo jetPEI, siRNA-L2 achieved 19-fold greater tumor accumulation and 46-fold increase in per-tumor-cell uptake in a mouse orthotopic model of human triple-negative breast cancer. siRNA-L2 penetrated tumor tissue rapidly and homogeneously; 30 min after i.v. injection, siRNA-L2 achieved uptake in 99% of tumor cells, compared with 60% for jetPEI. Remarkably, siRNA-L2 achieved a tumor:liver accumulation ratio >40:1 vs. <3:1 for jetPEI. The improved pharmacokinetic properties of siRNA-L2 facilitated significant tumor gene silencing for 7 d after two i.v. doses. Proof-of-concept was extended to a patient-derived xenograft model, in which jetPEI tumor accumulation was reduced fourfold relative to the same formulation in the orthotopic model. The siRNA-L2 tumor accumulation diminished only twofold, suggesting that the superior tumor distribution of the conjugate over nanoparticles will be accentuated in clinical situations. These data reveal the immense promise of in situ albumin targeting for development of translational, carrier-free RNAi-based cancer therapies.

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“…A highly important strategy in dyslipidemia therapy is to use trivalent N-acetylgalactosamine (GalNAc)-tethered AONs 123–125) . GalNAc is a carbohydrate ligand for asialoglycoprotein receptors (ASGPR), which are abundant on the surface of hepatocytes.…”

Section: Understanding Mechanisms Of Cellular Uptake and Intracellulamentioning

confidence: 99%

Development of Antisense Drugs for Dyslipidemia

Yamamoto

Wada

Harada‐Shiba

2016

JAT

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Abnormal elevation of low-density lipoprotein (LDL) and triglyceride-rich lipoproteins in plasma as well as dysfunction of anti-atherogenic high-density lipoprotein (HDL) have both been recognized as essential components of the pathogenesis of atherosclerosis and are classified as dyslipidemia. This review describes the arc of development of antisense oligonucleotides for the treatment of dyslipidemia. Chemically-armed antisense candidates can act on various kinds of transcripts, including mRNA and miRNA, via several different endogenous antisense mechanisms, and have exhibited potent systemic anti-dyslipidemic effects. Here, we present specific cutting-edge technologies have recently been brought into antisense strategies, and describe how they have improved the potency of antisense drugs in regard to pharmacokinetics and pharmacodynamics. In addition, we discuss perspectives for the use of armed antisense oligonucleotides as new clinical options for dyslipidemia, in the light of outcomes of recent clinical trials and safety concerns indicated by several clinical and preclinical studies.

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Efficient Synthesis and Biological Evaluation of 5′-GalNAc Conjugated Antisense Oligonucleotides

Cited by 70 publications

References 22 publications

Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics

Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics

Lipophilic siRNA targets albumin in situ and promotes bioavailability, tumor penetration, and carrier-free gene silencing

Development of Antisense Drugs for Dyslipidemia

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