Axcelead offers strong support in oligonucleotide drug discovery research, from selection and creation of oligonucleotide drug candidates to preclinical development

Challenges in Oligonucleotide Drug Discovery Research

There are three main challenges in oligonucleotide drug discovery research: (1) safety concerns, (2) insufficient delivery to target tissues and cells, and (3) lack of specific ICH guidelines. Axcelead offers solutions to address each of these challenges, taking advantage of our technology and know-how, developed through our drug discovery research to date. 

1. Solutions to address challenges in safety

Two types of toxicity are observed in oligonucleotide drugs: A) hybridization-dependent toxicity and B) hybridization-independent toxicity. Among cases of hybridization-dependent toxicity, hybridization to the non-target sequences is specific to oligonucleotide drugs and selecting oligonucleotide drug candidates that have a low risk of toxicity to humans is important.

On the other hand, hybridization-independent toxicity can usually be detected by conventional toxicity tests, but special attention should be given to toxicity to the immune system, blood system, liver, and kidneys, which are often problematic areas with oligonucleotide drugs.

— Axcelead Solutions —

1. Assessment of off-target toxicity (hybridization-dependent) using transcriptome analysis
2. Assessment of off-target toxicity (hybridization- independent) using various toxicity assay systems (immune system, blood system, liver, and kidney toxicity)
3. LNP formation and analysis of immunostimulatory activity

2. Solutions to challenges in delivery to target tissues and cells

Oligonucleotide drugs have a pharmacokinetic tendency to accumulate in specific organs such as the liver or kidneys. This makes it difficult to deliver them to tissues other than these specific organs. In addition, even if a oligonucleotide drug is delivered to the target tissue, efficacy may not be achieved at the cellular level due to factors such as low intracellular migration.

Intracellular behavior of oligonucleotides

— Axcelead Solutions —

1. Assessment of delivery to cells in target tissues (PK/PD analysis)
2. Design and synthesis of peptide-oligonucleotide conjugates
3. LNP formation and in vivo biodistribution analysis

3. Solutions to address challenges due to a lack of specific ICH guidelines

ICH guidelines for GLP study on oligonucleotide drugs are still in the developmental stages, and certain studies can be simplified or omitted on a case-by-case basis.
On the other hand, for matters that are of concern to the regulatory authorities, implementation of additional studies, in advance, and assessment may be required.
The overall speed and total cost of studies vary greatly depending on their design.

— Axcelead Solutions —

Proposal of an optimal GLP study package

4. Solutions to address challenges in the assessment of drug efficacy

In order to select and create a superior oligonucleotide drug candidate, drug efficacy is assessed in a system with high clinical extrapolation capability. For in vitro studies, various phenotypic analyses using human cells (disease models) are conducted. For in vivo studies, drug efficacy is assessed using animal disease models with high clinical extrapolation capability.

— Axcelead Solutions —

1. Various phenotypic analytical methods using human cells (disease models)
2. Assessment of drug efficacy using animal disease models
3. Creation of genetically-modified mice and rats

For those involved in oligonucleotide drug discovery

Take advantage of Axcelead’s assessment system and know-how!
Please feel free to contact us.