Delivery of Oligonucleotides to the Liver with GalNAc: From Research to Registered Therapeutic Drug

Debacker, Alexandre J.; Voutila, Jon; Catley, Matthew C.; Blakey, David C.; Habib, Nagy

doi:10.1016/j.ymthe.2020.06.015

Cited by 227 publications

(195 citation statements)

References 87 publications

Supporting

Mentioning

192

Contrasting

Unclassified

Order By: Relevance

“…Inclisiran, a siRNA for the treatment of hypercholesterolemia, was developed by Novartis under a license in collaboration with Alnylam Pharmaceuticals. It has been approved in Europe and is expected to receive authorization from the FDA soon [ 13 , 57 , 58 ]. Early members of the oligonucleotide drugs family demonstrated their efficacy in the treatment of some rare hereditary disorders.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, an N-acetyl galactosamine-bearing dendrimer is covalently attached to the 3′ terminus of the sense strand ( Figure 3 ) [ 11 ]. After givosiran, which is used for the treatment of acute hepatic porphyria (AHP) and was approved in November 2019 [ 12 ], lumasiran is the second drug to exploit enhanced stabilization chemistry (ECT)-GalNAc conjugate technology [ 12 , 13 ].…”

Section: Oligonucleotidesmentioning

confidence: 99%

See 1 more Smart Citation

2020 FDA TIDES (Peptides and Oligonucleotides) Harvest

et al. 2021

View full text Add to dashboard Cite

2020 has been an extremely difficult and challenging year as a result of the coronavirus disease 2019 (COVID-19) pandemic and one in which most efforts have been channeled into tackling the global health crisis. The US Food and Drug Administration (FDA) has approved 53 new drug entities, six of which fall in the peptides and oligonucleotides (TIDES) category. The number of authorizations for these kinds of drugs has been similar to that of previous years, thereby reflecting the consolidation of the TIDES market. Here, the TIDES approved in 2020 are analyzed in terms of chemical structure, medical target, mode of action, and adverse effects.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Oligonucleotidesmentioning

confidence: 99%

2020 FDA TIDES (Peptides and Oligonucleotides) Harvest

et al. 2021

View full text Add to dashboard Cite

show abstract

“…It is covalently bound to a ligand containing three N -acetylgalactosamine residues that facilitate uptake into hepatocytes via asialoglycoprotein receptors, which are highly expressed on the cell surface of hepatocytes and are selective for glycoproteins containing N -acetylgalactosamine residues [ 85 ]. It is worth highlighting N -acetylgalactosamine as a very promising molecule for the delivery of siRNA to hepatocytes; in addition to the already approved givosiran, there are another seven conjugates in registrational review or phase 3 trials and at least another 21 conjugates at earlier stages of clinical development [ 86 ]. Additional enhancements, such as hexopyranose chemical modification altriol nucleic acid within siRNA, significantly enhanced the protection of the oligonucleotide against 5 ’ -exonuclease degradation [ 87 ].…”

Section: Conjugatesmentioning

confidence: 99%

Recent Advances in the Development of Exogenous dsRNA for the Induction of RNA Interference in Cancer Therapy

2021

View full text Add to dashboard Cite

Selective regulation of gene expression by means of RNA interference has revolutionized molecular biology. This approach is not only used in fundamental studies on the roles of particular genes in the functioning of various organisms, but also possesses practical applications. A variety of methods are being developed based on gene silencing using dsRNA—for protecting agricultural plants from various pathogens, controlling insect reproduction, and therapeutic techniques related to the oncological disease treatment. One of the main problems in this research area is the successful delivery of exogenous dsRNA into cells, as this can be greatly affected by the localization or origin of tumor. This overview is dedicated to describing the latest advances in the development of various transport agents for the delivery of dsRNA fragments for gene silencing, with an emphasis on cancer treatment.

show abstract

“…Givlaari (Givosiran) targets the aminolevulinate synthase 1 (ALAS1) gene and has received US FDA approval for the treatment of acute hepatic porphyria in 2019 [16]. Givlaari is the first GalNAc-conjugated targeted siRNA drug bearing phosphorothioate (PS) backbone modification, and 2¢-O-Me, 2¢-F sugar modifications [17]. The GalNAcconjugated Givlaari binds to the asialoglycoprotein receptors that are greatly expressed on normal hepatocytes.…”

Section: Introductionmentioning

confidence: 99%

“…The 2¢-position is the most explored position for sugar modification in siRNA therapeutics. Sugar 2¢-modifications include 2¢-O-Me, 2¢-F, 2¢-MOE, locked nucleic acids (LNA), 2¢-O-allyl, 2¢-O-aminoethyl, 2¢-Oguanidinoethyl, and 2¢-O-cyanoethyl, of which 2¢-O-Me and 2¢-F are extensively studied at clinical trials and already being used in recently approved drugs, Patisiran and Givlaari [15][16][17]. Likewise, various 2¢,4¢-dual modifications have also been explored in ribose, including 4¢-AM-2¢-O-Me, 4¢-AMEt-2¢-O-Me, 4¢-AMPr-2¢-O-Me, 4¢-AMEt-2¢-F, 4¢-O-Me-2¢-F, 4¢-F-2¢-O-Me, and 2¢,4¢-di-O-Me [41][42][43][44][45][46].…”

Section: Introductionmentioning

confidence: 99%

Folate Receptor-Mediated siRNA Delivery: Recent Developments and Future Directions for RNAi Therapeutics

Gangopadhyay

Nikam

Gore

2021

Nucleic Acid Therapeutics

View full text Add to dashboard Cite

RNA interference (RNAi), a gene regulatory process mediated by small interfering RNAs (siRNAs), has made remarkable progress as a potential therapeutic agent against various diseases. However, RNAi is associated with fundamental challenges such as poor systemic delivery and susceptibility to the nucleases. Targeting ligand-bound delivery vehicles has improved the accumulation of drug at the target site, which has resulted in high transfection efficiency and enhanced gene silencing. Recently, folate receptor (FR)-mediated targeted delivery of siRNAs has garnered attention due to their enhanced cellular uptake and high transfection efficiency toward tumor cells. Folic acid (FA), due to its small size, low immunogenicity, high in vivo stability, and high binding affinity toward FRs, has attracted much attention for targeted siRNA delivery. FRs are overexpressed in a large number of tumors, including ovarian, breast, kidney, and lung cancer cells. In this review, we discuss recent advances in FA-mediated siRNA delivery to treat cancers and inflammatory diseases. This review summarizes various FA-conjugated nanoparticle systems reported so far in the literature, including liposome, silica, metal, graphene, dendrimers, chitosan, organic copolymers, and RNA nanoparticles. This review will help in the design and development of potential delivery vehicles for siRNA drug targeting to tumor cells using an FR-mediated approach.

show abstract

Delivery of Oligonucleotides to the Liver with GalNAc: From Research to Registered Therapeutic Drug

Cited by 227 publications

References 87 publications

2020 FDA TIDES (Peptides and Oligonucleotides) Harvest

2020 FDA TIDES (Peptides and Oligonucleotides) Harvest

Recent Advances in the Development of Exogenous dsRNA for the Induction of RNA Interference in Cancer Therapy

Folate Receptor-Mediated siRNA Delivery: Recent Developments and Future Directions for RNAi Therapeutics

Contact Info

Product

Resources

About