Highly branched  poly(β-amino ester) delivery of minicircle DNA for transfection of neurodegenerative disease related cells

Abstract

Current therapies for most neurodegenerative disorders are only symptomatic in nature and do not change the course of the disease. Gene therapy plays an important role in disease modifying therapeutic strategies. Herein, we have designed and optimized a series of highly branched poly(β-amino ester)s (HPAEs) containing biodegradable disulfide units in the HPAE backbone (HPAESS) and guanidine moieties (HPAESG) at the extremities. The optimized polymers are used to deliver minicircle DNA to multipotent adipose derived stem cells (ADSCs) and astrocytes, and high transfection efficiency is achieved (77% in human ADSCs and 52% in primary astrocytes) whilst preserving over 90% cell viability. Furthermore, the top-performing candidate mediates high levels of nerve growth factor (NGF) secretion from astrocytes, causing neurite outgrowth from a model neuron cell line. This synergistic gene delivery system provides a viable method for highly efficient non-viral transfection of ADSCs and astrocytes.

Gene therapy for neurodegenerative disorders: advances, insights and prospects

“…Nanoparticles functionalized with bradykinin B2 receptor antibodies, transferrin receptor or apolipoprotein E have also been indicated to successfully deliver siRNA and mRNA to astrocytes 152 , 153 . For example, optimized branched poly ( β -amino ester)s are applied to deliver NGF expression DNA to astrocytes, and high transfection efficiency is achieved, which provides a viable gene therapy approach for neurodegenerative disorders 154 . Collectively, these studies indicate that targeting microglia or astrocyte may be a promising therapeutic strategy for neurodegenerative diseases.…”

Physicochemical Properties and Biological Performance of Polymethacrylate Based Gene Delivery Vector Systems: Influence of Amino Functionalities

“…[ 1–3 ] DNA delivery is preferably carried out by vectors that are able to condense and protect the nucleic acid, facilitate cellular uptake and endosomal escape, and enable gene expression. [ 4,5 ] A large number of viral [ 6–8 ] and non‐viral [ 9–17 ] vectors have been developed. Despite the positive results, viral vectors are often associated with a number of potential risks for the patient (high cytotoxicity, severe immune response, insertional mutagenesis, restoration of virulence resulting in additional diseases, etc.).…”

“…[ 6–8 ] The non‐viral vectors can be considerably safer and more biocompatible, but generally less efficient. [ 9–17 ]…”

“…Polyplexes are promising non‐viral gene delivery systems. [ 4,5,9–18 ] These are nanosized polyelectrolyte particles formed from natural or synthetic polymers and DNA. The complexation is based on electrostatic interactions; therefore, a necessary prerequisite is the presence of positively charged groups, such as amino groups, into the polymer chain.…”

Cationic dynamic covalent polymers for gene transfection

“…This method provides a safe and efficient gene delivery in the intracellular compartment where the concentration of glutathione reaches the mM range. 138 As further discussed below, disulphide exchange reactions have also been shown to take place in situ with constituents of cell membranes.…”