Polyaminoglycoside-mediated cell reprogramming system for the treatment of diabetes mellitus

Yunqi Pan; Meiyu Shao; Pan Li; Chen Xu; Jingjun Nie; Kai Zhang; Sen Wu; Dandan Sui; Fu-Jian Xu

doi:10.1016/j.jconrel.2022.01.041

Polyaminoglycoside-mediated cell reprogramming system for the treatment of diabetes mellitus

J Control Release. 2022 Mar:343:420-433. doi: 10.1016/j.jconrel.2022.01.041. Epub 2022 Jan 29.

Authors

Yunqi Pan¹, Meiyu Shao¹, Pan Li², Chen Xu¹, Jingjun Nie¹, Kai Zhang¹, Sen Wu², Dandan Sui³, Fu-Jian Xu⁴

Affiliations

¹ State Key Laboratory of Chemical Resource Engineering, Key Laboratory of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education, Beijing Laboratory of Biomedical Materials, College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing, China.
² Beijing Advanced Innovation Center for Food Nutrition and Human Health, State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
³ State Key Laboratory of Chemical Resource Engineering, Key Laboratory of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education, Beijing Laboratory of Biomedical Materials, College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing, China. Electronic address: suidd@mail.buct.edu.cn.
⁴ State Key Laboratory of Chemical Resource Engineering, Key Laboratory of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education, Beijing Laboratory of Biomedical Materials, College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing, China. Electronic address: xufj@mail.buct.edu.cn.

PMID: 35101476
DOI: 10.1016/j.jconrel.2022.01.041

Abstract

Diabetes mellitus is a disease of metabolism, featuring persistent hyperglycaemia due to insufficient insulin secretion or insulin resistance. At present, the generation of new beta cells from autologous cells by ectopic expression of specific transcription factors is a promising treatment for diabetes. The application of this strategy urgently needs safe and effective gene delivery vectors. In this work, a therapeutic plasmid (pNPMN-PBase), combined multiple specific transcription factors Ngn3, Pdx1, Mafa and Neruod1 (NPMN), was firstly constructed. Then, phenylboronic acid (PBA)-functionalized branched polymers (SS-HPT-P) have been proposed to deliver pNPMN-PBasefor the promising treatment of diabetes. SS-HPT-P had good biocompatibility and low cytotoxicity, and could achieve liver-targeted delivery. SS-HPT-P/pNPMN-PBase system can effectively realize the liver delivery of exogenous therapeutic genes, induce the reprogramming of hepatocytes into beta-like cells, reestablish the endogenous insulin-expression system, and alleviate diabetes and its complications. The present study thus provides an effective strategy for the cell replacement therapy of diabetes.

Keywords: Diabetes; Gene therapy; Liver-targeted; Phenylboronic acid; Reprogramming; Vector.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / metabolism
Cellular Reprogramming
Diabetes Mellitus* / therapy
Genetic Vectors
Humans
Insulin / metabolism
Insulin-Secreting Cells* / metabolism
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Transcription Factors / metabolism

Substances

Basic Helix-Loop-Helix Transcription Factors
Insulin
Nerve Tissue Proteins
Transcription Factors