siRNA development

siRNA development

siRNA development is the induction of RNA interference (RNAi) using siRNA (small interfering RNA) toDegrade target mRNA and suppress protein expressionResearch and development of nucleic acid therapeutics. These are expected to be a new therapeutic approach because they can target molecules that were difficult to target with conventional small molecule drugs and antibody drugs. In recent years, advances in delivery technologies such as GalNAc formulations and LNP formulations have made it possible to efficiently deliver drugs to target tissues, and their practical application as pharmaceuticals is steadily progressing.

Representative examples of siRNA development

Onpatro (Pachysilane)

Onpattro (generic name: patisiran) isThe world's first siRNA drugThis is an approved formulation. siRNA is delivered to the liver using LNP (lipid nanoparticle) delivery technology, and by targeting the TTR gene and inducing RNAi, the production of transthyretin (TTR) protein is suppressed.

Gibberellin (Gibberellin)

Gibleril (generic name: Giboseran) is,Targeted siRNA using GalNAcThis is a prime example. It achieves high-efficiency delivery to hepatocytes by selectively targeting receptors on the hepatocyte surface using GalNAc. This technology has become one of the standard delivery strategies in current siRNA drug development.

Amvutra (butagril)

Amvuttra (generic name: butransiran) is,Next-generation GalNAc-siRNA with long-acting effectsThis is a formulation developed as an example. In addition to efficient delivery to hepatocytes using GalNAc, its sustained action has been improved, leading to an extension of the dosing interval. This is a representative example showing the evolution of siRNA drug discovery in both delivery technology and molecular design.

Key challenges in siRNA development

Delivery technologies for efficient delivery to target organizations

siRNA are not easily taken up by cells on their own and are easily degraded in the body, thereforeDelivery technology utilizing DDS is key to drug discovery successGalNAc and LNPs are representative delivery technologies, and by increasing delivery efficiency to target organs, they significantly contribute to improving the effectiveness and safety of siRNA.

Addressing off-target effects and patient variability

In siRNA development,Suppression of off-target genes and response to patient-specific individual differencesis an important challenge. Personalized medicine, which predicts treatment efficacy using target mRNA expression levels, RNA expression analysis, and biomarkers, and selects the optimal treatment for each patient, is expected to be realized.

How to predict drug efficacy and safety in humans

siRNA drugsInternal distribution and safety differ between animals and humans.Therefore, evaluation systems with high human extrapolation are important. To appropriately evaluate the unique safety aspects of nucleic acid drugs, such as immune stimulation and hepatotoxicity, it is necessary to combine efficacy and safety evaluations using disease models to predict clinical efficacy and risks.

Non-clinical evaluation required for siRNA development

Evaluate delivery to the target organization

Regarding siRNA therapeuticsIt cannot exert its medicinal effect if it is not sufficiently delivered to the target organization.Therefore, delivery evaluation is important. By combining in vivo distribution and PK (pharmacokinetics) evaluation of nucleic acid drugs with inter-tissue distribution analysis and intra-tumor distribution analysis, we comprehensively evaluate the relationship between delivery efficiency to target tissues and drug efficacy.

Multifaceted evaluation of RNA interference activity

Regarding siRNA therapeuticsMultifaceted evaluation of RNA interference activityefficacy confirmation is required. A strategy is used to comprehensively evaluate RNAi activity and therapeutic effects by combining target mRNA knockdown, target engagement, biomarker measurement, RNA expression analysis, and pharmacological efficacy testing.

Utilize disease models with high human translatability.

Since animal testing alone cannot fully reproduce human disease states and drug efficacy,Evaluation using disease models with high human translatabilityThis is important. By utilizing organoids, iPS cells, humanized mice, and patient-derived models, the efficacy and safety of siRNA drugs can be evaluated under conditions closer to clinical settings.

Evaluate the specific safety of nucleic acid drugs

For siRNA therapeutics, a multifaceted evaluation of their unique safety profile, common to nucleic acid drugs, is also crucial. This involves confirming immunostimulation, hepatotoxicity, nephrotoxicity, and off-target effects through safety studies.Comprehensive prediction of clinical safety through evaluation strategies for long-term administrationI will do so.

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

For the practical application of siRNA drugs, a non-clinical testing system capable of consistently evaluating delivery, efficacy, and safety is essential. While future expansion to new targets and personalized medicine is expected, challenges such as human translatability and safety assessment remain. To address these, selecting a strategic CRO with extensive technologies and evaluation systems and proceeding with optimal non-clinical evaluation from the early stages of development is a crucial key to success.