Small molecule conjugated oligonucleotide for enhancing delivery to the spleen

This technology utilizes small-molecule ligands that enhance the efficacy of oligonucleotide therapeutics in reducing gene expression within the spleen.

Advantages

  • Enhances knockdown efficiency in the spleen by more than twofold.
  • Ligand effects are independent of nucleic acid sequence and linker structure.

Technology Overview & Background

Oligonucleotide therapeutics have garnered significant attention as a novel therapeutic modality for treating difficult-to-address diseases. Despite this, systemically administered oligonucleotide therapeutics primarily accumulate in the liver, making it challenging to effectively target other organs and tissues. There is an urgent need to develop drug delivery systems (DDS) that expand the therapeutic reach of these drugs. One promising DDS approach involves tissue-selective delivery of oligonucleotide therapeutics by conjugating drug-delivery-capable ligands.

In this study, researchers synthesized antisense oligonucleotides (ASOs) conjugated with over 100 small-molecule ligands, identifying those that demonstrate efficacy beyond the liver through both in vitro screening and in vivo testing. This research led to the discovery of a ligand that exhibits heightened activity within the spleen. The spleen, the body’s largest lymphatic organ, is critical for erythrocyte degradation and hematopoiesis, but until now, no ligands have been identified for ASOs targeting this organ. The identified ligand significantly improves knockdown efficiency in vivo, and this effect has been confirmed to be independent of both ASO sequence and linker structure. This technology may enable the use of ASO-based therapy for spleen-related diseases, a therapeutic target that has been challenging for oligonucleotide therapeutics.

Development stage & Future Research Plans

  • In this experiment, we prepared ASO targeting mouse MALAT1 (a type of long noncoding RNA) and conjugated with small molecular ligand. Administration(i.v.) of ligand conjugated ASO into the mice, the knockdown activity in the spleen was observed to be approximately twofold higher than that of ASO alone. This activity also demonstrated a dose-dependent enhancement.
  • Similar experiments with different ASO sequences showed comparable spleen knockdown efficiency, assuming that the ligand-ASO conjugate is sequence-independent. Modifications to the linker structure between ASO and the ligand yielded consistent results, indicating possible independence from linker structure as well.
  • Future research will focus on elucidating the mechanism underlying the spleen-specific knockdown and further enhancing the knockdown efficiency.

Patent

Applied (Unpublished)

Principal Investigator & Academic Institution

Assistant Prof. Takashi OSAWA (Graduate School of Pharmaceutical Sciences, Osaka University)

Collaboration Opportunities

TECH MANAGE CORP. is looking for a pharmaceutical company/start-up interested in drug development based on this research project. Direct meetings with the research team are available upon request. Under a non-disclosure agreement with Osaka University, we can also consider collaborative research, technology evaluations, and potential MTA agreements or preferential negotiation rights.

 

 

Project No.TT-04974

 

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