Michael Tanowitz
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View article: Single alkyl phosphonate modification of the siRNA backbone in the seed region enhances specificity and therapeutic profile
Single alkyl phosphonate modification of the siRNA backbone in the seed region enhances specificity and therapeutic profile Open
We evaluated the effect of alkyl phosphonate linkages in enhancing the specificity and therapeutic profile of siRNA when incorporated into the seed region. siRNAs modified with a single alkyl phosphonate linkage demonstrated enhanced speci…
View article: Conjugation to a transferrin receptor 1-binding Bicycle peptide enhances ASO and siRNA potency in skeletal and cardiac muscles
Conjugation to a transferrin receptor 1-binding Bicycle peptide enhances ASO and siRNA potency in skeletal and cardiac muscles Open
Improving the delivery of antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) to skeletal and cardiac muscles remains a pivotal task toward the broader application of oligonucleotide therapeutics. The targeting of myofibe…
View article: Conjugation of hydrophobic moieties enhances potency of antisense oligonucleotides in the muscle of rodents and non-human primates
Conjugation of hydrophobic moieties enhances potency of antisense oligonucleotides in the muscle of rodents and non-human primates Open
We determined the effect of attaching palmitate, tocopherol or cholesterol to PS ASOs and their effects on plasma protein binding and on enhancing ASO potency in the muscle of rodents and monkeys. We found that cholesterol ASO conjugates s…
View article: Site-specific replacement of phosphorothioate with alkyl phosphonate linkages enhances the therapeutic profile of gapmer ASOs by modulating interactions with cellular proteins
Site-specific replacement of phosphorothioate with alkyl phosphonate linkages enhances the therapeutic profile of gapmer ASOs by modulating interactions with cellular proteins Open
Phosphorothioate-modified antisense oligonucleotides (PS-ASOs) interact with a host of plasma, cell-surface and intracellular proteins which govern their therapeutic properties. Given the importance of PS backbone for interaction with prot…
View article: Selective tissue targeting of synthetic nucleic acid drugs
Selective tissue targeting of synthetic nucleic acid drugs Open
Antisense oligonucleotides (ASOs) are chemically synthesized nucleic acid analogs designed to bind to RNA by Watson-Crick base pairing. Following binding to the targeted RNA, the ASO perturbs RNA function by promoting selective degradation…
View article: Receptor-Mediated Uptake of Phosphorothioate Antisense Oligonucleotides in Different Cell Types of the Liver
Receptor-Mediated Uptake of Phosphorothioate Antisense Oligonucleotides in Different Cell Types of the Liver Open
Oligonucleotide therapeutics have emerged as a third distinct platform for drug discovery within the pharmaceutical industry. Five oligonucleotide-based drugs have been approved by the US FDA and over 100 oligonucleotides drugs are current…
View article: Asialoglycoprotein receptor 1 mediates productive uptake of N-acetylgalactosamine-conjugated and unconjugated phosphorothioate antisense oligonucleotides into liver hepatocytes
Asialoglycoprotein receptor 1 mediates productive uptake of N-acetylgalactosamine-conjugated and unconjugated phosphorothioate antisense oligonucleotides into liver hepatocytes Open
Antisense oligonucleotide (ASO) therapeutics show tremendous promise for the treatment of previously intractable human diseases but to exert their effects on cellular RNA processing they must first cross the plasma membrane by endocytosis.…
View article: Intra-endosomal trafficking mediated by lysobisphosphatidic acid contributes to intracellular release of phosphorothioate-modified antisense oligonucleotides
Intra-endosomal trafficking mediated by lysobisphosphatidic acid contributes to intracellular release of phosphorothioate-modified antisense oligonucleotides Open
Antisense oligonucleotides (ASOs) with phosphorothioate (PS) linkages are broadly used as research tools and therapeutic agents. Chemically modified PS-ASOs can mediate efficient target reduction by site-specific cleavage of RNA through RN…
View article: Annexin A2 facilitates endocytic trafficking of antisense oligonucleotides
Annexin A2 facilitates endocytic trafficking of antisense oligonucleotides Open
Chemically modified antisense oligonucleotides (ASOs) designed to mediate site-specific cleavage of RNA by RNase H1 are used as research tools and as therapeutics. ASOs modified with phosphorothioate (PS) linkages enter cells via endocytot…