Highly branched poly(β-amino ester)s for skin gene therapy

Poly(β-amino ester)s (PAEs) have emerged as a promising class of gene delivery vectors with performances that can even be compared to viruses. However, all of the transfection studies (over 2350 PAEs) have been limited to linear poly(β-amino ester)s (LPAEs) despite increasing evidence that polymer s...

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Bibliographic Details
Published in:Journal of controlled release 2016-12, Vol.244 (Pt B), p.336-346
Main Authors: Zhou, Dezhong, Gao, Yongsheng, Aied, Ahmed, Cutlar, Lara, Igoucheva, Olga, Newland, Ben, Alexeeve, Vitali, Greiser, Udo, Uitto, Jouni, Wang, Wenxin
Format: Article
Language:English
Subjects:
Animals
Cell Line
Cells, Cultured
Collagen Type VII - genetics
DNA - administration & dosage
Epidermolysis Bullosa Dystrophica - therapy
Gene transfection
Gene Transfer Techniques
Genetic Therapy
Green Fluorescent Proteins - genetics
HeLa Cells
Highly branched polymers
Humans
Luciferases - genetics
Mesenchymal Stromal Cells
Mice, Knockout
Poly(β-amino ester)
Polymers - administration & dosage
RDEB
Skin
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Summary:Poly(β-amino ester)s (PAEs) have emerged as a promising class of gene delivery vectors with performances that can even be compared to viruses. However, all of the transfection studies (over 2350 PAEs) have been limited to linear poly(β-amino ester)s (LPAEs) despite increasing evidence that polymer structure significantly affects performance. Herein, we describe the development of highly branched poly(β-amino ester)s (HPAEs) via a new “A2+B3+C2” Michael addition approach demonstrating 2 to 126-fold higher in vitro transfection efficiencies of different cell types in comparison to their linear LPAE counterparts as well as greatly out-performing the leading transfection reagents SuperFect and the “gold-standard” polyethyleneimine (PEI) - especially on skin epidermal cells. More importantly, the ability to correct a skin genetic defect is demonstrated in vivo utilizing a recessive dystrophic epidermolysis bullosa (RDEB) knockout mouse model. Our results provide evidence that the “A2+B3+C2” approach can be controlled and offers sufficient flexibility for the synthesis of HPAEs. The branched structures can significantly improve the transfection efficiency and safety of PAEs highlighting the great promise for the successful application of non-viral gene therapy in skin disease. [Display omitted]
ISSN:0168-3659
1873-4995
DOI:10.1016/j.jconrel.2016.06.014