Recent preclinical and clinical advances in oligonucleotide conjugates

Abstract

Oligonucleotide therapeutics have the potential to change the way disease is treated due to their ability to modulate gene expression of any therapeutic target in a highly specific and potent manner. Unfortunately, this drug class is plagued with inherently poor pharmacological characteristics, which need to be overcome. The development of a chemical modification library for oligonucleotides has addressed many of the initial challenges, but delivery of these payloads across plasma membranes remains difficult. The latest technological advances in oligonucleotide therapeutics utilizes direct conjugation to targeting ligands, which has improved bioavailability and target tissue exposure many-fold. The success of this approach has resulted in numerous clinical programs over the past 5 years. Areas Covered: We review the literature on oligonucleotide conjugate strategies which have proven effective preclinically and clinically. We summarize the chemical modifications which allow parenteral administration as well as evaluate the efficacy of a multitude of conjugate approaches including lipids, peptides, carbohydrates, and antibodies. Expert Opinion: The success of future conjugate strategies will likely rely on the effective combination of characteristics from earlier technologies. High-affinity ligand-receptor interactions can be critical to achieving meaningful accumulation in target tissues, but pharmacokinetic modulators which increase the circulating half-life may also be necessary. Synthesis of these approaches has the potential to bring the next breakthrough in oligonucleotide therapeutics.

Amphiphilic “Like-A-Brush” Oligonucleotide Conjugates with Three Dodecyl Chains: Self-Assembly Features of Novel Scaffold Compounds for Nucleic Acids Delivery

“…Synthetic oligonucleotide conjugates with lipophilic groups are in the focus of considerable attention as nucleic acid (NA)-based biological tools in a wide range of fields of biotechnology and biomedicine [ 1 , 2 ]. Lipid-oligonucleotide conjugates (LOCs) are particularly interesting as delivery vehicles, which bring therapeutic oligonucleotides (e.g., antisense oligomers or siRNA) to their intracellular targets [ 3 , 4 , 5 , 6 ]. Negatively charged native oligonucleotides show poor cell penetration [ 5 , 6 ].…”

“…The association of the LOCs with one or more serum proteins (albumin, etc.) is also believed to participate in their cellular uptake mechanisms [ 4 ]. Albumin is the major blood protein that binds and transports numerous endogenous and exogenous substances, including fatty acids and other poor water-soluble compounds [ 34 ].…”

Clinical advances of siRNA therapeutics

“…In addition, other oligo pharmaceutical companies (e.g. Arrowhead, Dicerna, Silence, Ionis, Wave Life, Regulus and Suzhou Ribo Life Science) are also devoted to establishing their own GalNAc‐oligo conjugate platform . As a result, a series of promising nucleic acid drug development pipelines have been established for the treatment of genetic and/or orphan diseases, cardio‐metabolic diseases and hepatic infectious diseases, etc.…”

“…[56][57][58] Silence, 66 Ionis, 36 Wave Life, Regulus and Suzhou Ribo Life Science) are also devoted to establishing their own GalNAc-oligo conjugate platform. 65 As a result, a series of promising nucleic acid drug development pipelines have been established for the treatment of genetic and/or orphan diseases, cardio-metabolic diseases and hepatic infectious diseases, etc. Five of them (Givosiran, Fitusiran, Inclisiran, Lumasiran and Vutrisiran) are undergoing phase III clinical trials, exhibiting a promising prospect in the field of RNAi pharmaceuticals.…”

Distribution of Antisense Oligonucleotides in Rat Eyeballs Using MALDI Imaging Mass Spectrometry

“…Oligonucleotide-based therapeutics such as antisense oligonucleotides, 1 – 3 ) small interfering RNAs (siRNAs), 4 – 6 ) decoy 7 ) and aptamer 8 ) have been developed extensively. Oligonucleotide have a low stability against nuclease in vivo , but owing to the remarkable progress of chemically modified nucleic acids 2 , 9 – 11 ) and drug delivery system technology, 12 , 13 ) many stable and highly effective candidate products have been developed. Although only six oligonucleotide therapeutics have been approved to date, there are about 20 candidate products in Phase III or higher stages.…”