Antisense oligonucleotide

Antisense oligonucleotides (ASOs)

Antisense oligonucleotides (ASOs) bind complementarily to target RNA,Nucleic acid drugs that control gene expression and splicingmechanism of action includes several types, such as RNase H-dependent types that degrade target RNA via RNase H, and splicing-regulatory types that produce desired RNA by regulating splicing. In recent years, practical applications have been progressing, mainly for neurological and rare diseases, and they are expected to be a new therapeutic approach for targets that are difficult to address with conventional small molecule drugs and antibody drugs.

Representative examples of antisense oligonucleotides (ASOs)

Spinraza (nusinersen)

Spinraza (nusinersen) is,Splicing-controlled ASO for SMN2 gene splicingThis aims to improve the pathology of spinal muscular atrophy (SMA) by promoting the production of SMN protein. It is known as a representative example of ASO pharmaceuticals and is a therapeutic drug that has significantly advanced the practical application of nucleic acid drugs in the field of neurological diseases.

Tegsedi (inotersen)

Tegsedi (inotersen) isRNase H-inducible ASO that induces degradation via RNase H by targeting TTR mRNAThe therapeutic effect is achieved by degrading the target mRNA and suppressing the production of transthyretin (TTR) protein. It is known as a representative example of an RNase H-type ASO and is a representative therapeutic drug that demonstrates the mechanism of action of ASOs.

Waylivra (mipomersen)

Waylivra (mipomersen) isAntisense oligonucleotide (ASO) that targets ApoB mRNA to suppress its expressionIt improves lipid metabolism by lowering the production of apolipoprotein B and was developed and commercialized for lipid metabolism disorders. It is positioned as one of the representative therapeutic drugs of early ASO drug discovery.

Key challenges in antisense oligonucleotide (ASO) development

Delivery technology for efficient delivery to target RNA

ASO is difficult to be incorporated into cells on its own.The key challenge that affects drug efficacy is whether it can be efficiently delivered to the target organ.In addition to improved stability through chemical modification, optimized in vivo behavior and intracellular migration using DDS technology are expected to enhance the efficiency of targeting RNA and improve therapeutic effects.

Pharmacological evaluation according to the mechanism of action

App Store OptimizationAppropriate drug efficacy evaluation methods differ between RNase H-dependent and splicing-controlled types.Therefore, evaluation according to the mechanism of action is important. In addition to target RNA and protein expression levels, we confirm efficacy by combining them with related biomarkers. Furthermore, variations in drug efficacy due to individual genetic backgrounds and differences in pathological conditions must also be considered.

How to predict safety and long-term administration in humans

In ASO development,Predicting safety in humans, including hepatotoxicity, nephrotoxicity, and immune stimulation, is an important challenge.Because long-term administration has limitations in terms of its effects and human extrapolation, there is a need to build a more reliable evaluation system by combining safety evaluations using disease models with clinical data.

Non-clinical evaluation required for antisense oligonucleotide (ASO) development

Evaluate delivery to the target organization

Delivery assessment to the target organization isTo confirm whether nucleic acid drugs can sufficiently reach target tissues and exert their therapeutic effects.This is important. Pharmacokinetics are understood by analyzing organ distribution and body distribution in combination with PK evaluation. Furthermore, changes in distribution due to chemical modification are also evaluated to clarify the relationship between delivery efficiency and efficacy.

Multidimensional evaluation of RNA expression and efficacy

In the evaluation of RNA expression and drug efficacy,Synthesize multipleIt is important to conduct efficacy and pharmacology studies, in addition to mRNA expression analysis, protein expression analysis, and biomarker analysis, to confirm consistent pharmacological effects from target control to improvement of physiological functions.

Utilize disease models with high human translatability.

To improve human extrapolatedness,Evaluation combining organoids, iPS cells, patient-derived models, and humanized miceare being utilized. Since each disease model can reproduce different pathological conditions and have different evaluation items, combining multiple disease models allows for more accurate prediction of efficacy and safety from the preclinical stage to clinical practice.

Evaluate the specific safety of nucleic acid drugs

In nucleic acid therapeutics,To comprehensively evaluate safety, including hepatotoxicity, nephrotoxicity, immunostimulation, and off-target effects.Furthermore, by confirming the effects of long-term administration and combining various safety tests, we can more appropriately understand the risks anticipated in clinical practice.

Key points when choosing a contract research organization (CRO) for non-clinical studies

Antisense oligonucleotides (ASOs) are nucleic acid therapeutics that realize new treatment methods by controlling target RNA. Their development requires non-clinical studies that can consistently evaluate delivery, efficacy, and safety. To maximize future potential, selecting a CRO that can propose evaluation systems tailored to the development strategy is key to success.