Sequence-Specific DNA Binders for the Therapy of Mitochondrial Diseases

This book describes the author's work on the development of sequence-specific DNA binders for the therapy of mitochondrial diseases. In the first chapter, the author provides a detailed background of pyrroleimidazole polyamides (PIPs) and mitochondrial disease research followed by chapters presenting the author's own research and discoveries. Firstly, the developed compounds called MITO-PIPs, which recognize specific sequences in mitochondrial DNA, are presented. The following chapter demonstrates how, by introducing a DNA alkylating reagent into a MITO-PIP that recognizes the adjacent sequence to a target mutation, the copy number of mutated mitochondrial DNA was successfully reduced in live cells. Furthermore, because nuclear DNA is another important target for treating mitochondrial diseases, the author demonstrated that tri-arginine vectors can enhance nuclear uptake of PIPs and improve their biological activity in cells.
This work willattract readers' interest because it paves the way for a transgene-free chemical gene therapy for mitochondrial diseases. The book includes a detailed description of experimental procedures, especially compound synthesis. This description helps readers to have a clear image of the author's studies and to perform similar and extended studies themselves.

Is nominated as an outstanding Ph.D. thesis by Kyoto University Provides a study for a transgene-free gene therapy for mitochondrial diseases Describes DNA-binding molecules to control nuclear or mitochondrial DNA

Auteur

Takuya Hidaka received his Ph.D. in 2021 under the supervision of Professor Hiroshi Sugiyama at Kyoto University for his chemical biology research on artificial control of DNA transcription and replication using DNA-binding molecules. He has been a research fellow of the Japan Society for the Promotion of Science (JSPS) from 2021 and is working on the development of proteome analysis techniques based on single-molecule imaging.

Texte du rabat

This book describes the author s work on the development of sequence-specific DNA binders for the therapy of mitochondrial diseases. In the first chapter, the author provides a detailed background of pyrrole imidazole polyamides (PIPs) and mitochondrial disease research followed by chapters presenting the author's own research and discoveries. Firstly, the developed compounds called MITO-PIPs, which recognize specific sequences in mitochondrial DNA, are presented. The following chapter demonstrates how, by introducing a DNA alkylating reagent into a MITO-PIP that recognizes the adjacent sequence to a target mutation, the copy number of mutated mitochondrial DNA was successfully reduced in live cells. Furthermore, because nuclear DNA is another important target for treating mitochondrial diseases, the author demonstrated that tri-arginine vectors can enhance nuclear uptake of PIPs and improve their biological activity in cells. This work willattract readers interest because it paves the way for a transgene-free chemical gene therapy for mitochondrial diseases. The book includes a detailed description of experimental procedures, especially compound synthesis. This description helps readers to have a clear image of the author s studies and to perform similar and extended studies themselves.

Contenu
General Introduction.- Creation of Synthetic Ligand for Mitochondrial DNA sequence Recognition and Promoter-Specific Transcription Suppression.- Allele-Specific Replication Inhibition of Mitochondrial DNA by MITO-PIP Conjugated with Alkylation Reagent.- Enhanced Nuclear Accumulation of PyrroleImidazole Polyamides by Incorporation of the Tri-arginine Vector.