Advantages
- Transferred into the brain by peripheral intravenous administration, High cell permeability, nuclear translocation, and low cytotoxicity; no need for DDS
- Suppresses transcription selectively to abnormally extended repeats, no off-target effects.
- Effective against abnormally expanded repeats in both translated and untranslated regions.
Background and Technology
Abnormal expansion of CAG/CTG (CWG) sequence repeats in genomic DNA causes serious genetic neurological diseases, triplet repeat diseases. e.g. CAG repeat expansion in the translated region: Huntington’s disease/HD, CTG repeat expansion in the UTR: myotonic dystrophy type 1/DM1.
| Polyamides with amide bonds of N-methyl-pyrrole and N-methyl-imidazole (PIPs) are designed to match the target DNA sequence based on simple DNA recognition rules, and bind specifically by acting on the minor groove of the target DNA. We have synthesized various PIPs as new therapeutic modalities and have conducted research for the purpose of anticancer drugs, DNA probes, and gene regulation. Furthermore, we found that cyclic PIPs exhibit higher binding properties and developed CWG-cPIP, which selectively suppresses transcription of abnormally expanded repeats in CWG triplet repeat neurological diseases. |  |
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Reference
Principal Investigator
Norifumi SHIODA, Prof. （Institute of Molecular Embryology and Genetics, Kumamoto University）
Current Stage and Next Step
- Confirmed a decrease in RNA aggregates/abnormal proteins in the DM1/HD mouse neuron model and patient-derived fibroblasts (in vitro).
- In DM1/HD brain-specific CWG repeat-expressing mice, a decrease in RNA aggregate-positive cells/polyQ aggregate-positive cells, electrophysiological improvement, and cognitive function improvement (upper figure) by i.c.v. administration of cPIP were confirmed (in vivo).
- Confirmed that cPIP moves into the brain after peripheral intravenous administration, and long-term efficacy evaluation is currently underway.
- We are looking for collaborative partner companies for preclinical and clinical development.
Project No. BK-04516