A perspective on oligonucleotide therapy: Approaches to patient customization

Thakur, Shikha; Sinhari, Apurba; Jain, Parul; Jadhav, Hemant R.

doi:10.3389/fphar.2022.1006304

Cited by 67 publications

(54 citation statements)

References 134 publications

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“…The development of oligonucleotide-based therapeutics has shown considerable progress in the recent years [ 1 ]. Permanent interest in oligonucleotides as therapeutic agents has arisen from multiple factors that include a wide range of druggable targets, well-established and relatively inexpensive methods of oligonucleotide preparation and modification, a range of molecular mechanisms of their therapeutic action available for selection, new emerging methods of delivery, and a high specificity of targeting [ 2 , 3 , 4 , 5 ]. Currently, the most frequently used types of therapeutic oligonucleotides are antisense oligonucleotides, small interfering RNAs, gene-editing guide RNAs, and aptamers.…”

Section: Introductionmentioning

confidence: 99%

The Regioselective Conjugation of the 15-nt Thrombin Aptamer with an Optimized Tripeptide Sequence Greatly Increases the Anticoagulant Activity of the Aptamer

et al. 2023

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Currently, oligonucleotide therapy has emerged as a new paradigm in the treatment of human diseases. In many cases, however, therapeutic oligonucleotides cannot be used directly without modification. Chemical modification or the conjugation of therapeutic oligonucleotides is required to increase their stability or specificity, improve their affinity or inhibitory characteristics, and address delivery issues. Recently, we proposed a conjugation strategy for a 15-nt G-quadruplex thrombin aptamer aimed at extending the recognition interface of the aptamer. In particular, we have prepared a series of designer peptide conjugates of the thrombin aptamer, showing improved anticoagulant activity. Herein, we report a new series of aptamer–peptide conjugates with optimized peptide sequences. The anti-thrombotic activity of aptamer conjugates was notably improved. The lead conjugate, TBA–GLE, was able to inhibit thrombin-induced coagulation approximately six-fold more efficiently than the unmodified aptamer. In terms of its anticoagulant activity, the TBA–GLE conjugate approaches NU172, one of the most potent G-quadruplex thrombin aptamers. Molecular dynamics studies have confirmed that the principles applied to the design of the peptide side chain are efficient instruments for improving aptamer characteristics for the proposed TBA conjugate model.

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Section: Introductionmentioning

confidence: 99%

The Regioselective Conjugation of the 15-nt Thrombin Aptamer with an Optimized Tripeptide Sequence Greatly Increases the Anticoagulant Activity of the Aptamer

et al. 2023

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“…Antisense oligonucleotides (ASOs) are short synthetic nucleic acid molecules that, when designed to be complementary to an intracellular mRNA target, can influence RNA processing and/or impact protein expression levels. In the four decades since their initial application in the laboratory, more than a dozen different antisense therapies have been approved in the United States for the treatment of a variety of diseases 1 . The inherent flexibility of a sequence-based targeting modality, in combination with well-established pharmacokinetic and pharmacodynamic properties, make ASOs a particularly attractive strategy for the treatment of genetic disorders.…”

Section: Mainmentioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

Rapid and scalable preclinical evaluation of personalized antisense oligonucleotide therapeutics using organoids derived from rare disease patients

Means

Louiselle

Farrow

et al. 2023

Preprint

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Personalized antisense oligonucleotides (ASOs) have achieved positive results in the treatment of rare genetic disease. As clinical sequencing technologies continue to advance, the ability to identify rare disease patients harboring pathogenic genetic variants amenable to this therapeutic strategy will likely improve. Here, we describe a scalable platform for generating patient-derived cellular models and demonstrate that these personalized models can be used for preclinical evaluation of patient-specific ASOs. We establish robust protocols for delivery of ASOs to patient-derived organoid models and confirm reversal of disease-associated phenotypes in cardiac organoids derived from a Duchenne muscular dystrophy (DMD) patient harboring a structural deletion in the dystrophin gene amenable to treatment with existing ASO therapeutics. Furthermore, we design novel patient-specific ASOs for two additional DMD patients (siblings) harboring a deep intronic variant in the dystrophin gene that gives rise to a novel splice acceptor site, incorporation of a cryptic exon, and premature transcript termination. We show that treatment of patient-derived cardiac organoids with patient-specific ASOs results in restoration of DMD expression and reversal of disease-associated phenotypes. The approach outlined here provides the foundation for an expedited path towards the design and preclinical evaluation of personalized ASO therapeutics for a broad range of rare diseases.

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“…Oligonucleotide therapeutics are a class of drug based on the structure of DNA and/or RNA that act at the interface between genes and proteins. , In recent years, there has been significant advancement in next-generation therapeutics for a multitude of diseases through the development of natural and modified oligonucleotides (oligos). Many of these therapeutics are effective for the treatment of a cornucopia of rare diseases as augmented by the increasing number of oligos receiving approval from the FDA . Due to the successes within the rare disease area, the development of oligo based therapeutics for larger disease populations is well underway and highlighted with the recent approval of Leqvio (inclisiran) for the treatment of adults with primary hypercholesterolaemia or mixed dyslipidaemia .…”

mentioning

confidence: 99%

Convergent Biocatalytic Mediated Synthesis of siRNA

et al. 2023

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New technologies are required to combat the challenges faced with manufacturing commercial quantities of oligonucleotide drug substances which are required for treating large patient populations. Herein we report a convergent biocatalytic synthesis strategy for an Alnylam model siRNA. The siRNA chemical structure includes several of the unnatural modifications and conjugations typical of siRNA drug substances. Using Almac’s 3–2–3–2 hybrid RNA ligase enzyme strategy that sequentially ligates short oligonucleotide fragments (blockmers), the target siRNA was produced to high purity at 1 mM concentration. Additional strategies were investigated including the use of polynucleotide kinase phosphorylation and the use of crude blockmer starting materials without chromatographic purification. These findings highlight a path toward a convergent synthesis of siRNAs for large-scale manufacture marrying both enzymatic liquid and classical solid-phase synthesis.

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A perspective on oligonucleotide therapy: Approaches to patient customization

Cited by 67 publications

References 134 publications

The Regioselective Conjugation of the 15-nt Thrombin Aptamer with an Optimized Tripeptide Sequence Greatly Increases the Anticoagulant Activity of the Aptamer

The Regioselective Conjugation of the 15-nt Thrombin Aptamer with an Optimized Tripeptide Sequence Greatly Increases the Anticoagulant Activity of the Aptamer

Rapid and scalable preclinical evaluation of personalized antisense oligonucleotide therapeutics using organoids derived from rare disease patients

Convergent Biocatalytic Mediated Synthesis of siRNA

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