Lipid-Based DNA Therapeutics: Hallmarks of Non-Viral Gene Delivery

Buck, Jonas; Grossen, Philip; Cullis, Pieter R.; Huwyler, Jörg; Witzigmann, Dominik

doi:10.1021/acsnano.8b07858

Cited by 256 publications

(254 citation statements)

References 290 publications

Supporting

Mentioning

234

Contrasting

Unclassified

Order By: Relevance

“…The licensures of Neovasculgen™ using plasmid in 2011 and ONPATTRO™ with the formulation of lipid‐based nanoparticles (LNPs) in 2018 have opened the door for additional non‐virus vectors. During recent decades, numerous nanoparticulate gene delivery systems have been developed to maximize therapeutic benefits and minimize the toxicity of gene drugs . Promising outcomes dependent on various nanoparticle‐based non‐virus vectors have been achieved in the initiated clinical trials, as summarized in Table .…”

Section: Gene Types and Vectorsmentioning

confidence: 99%

Clinical translation of gene medicine

Wang

Zhou

et al. 2019

The Journal of Gene Medicine

View full text Add to dashboard Cite

Gene therapy has recently witnessed accelerated progress as a new therapeutic strategy with the potential to treat a range of inherited and acquired diseases. Billions of dollars have been invested in basic and clinical research on gene medicine, with ongoing clinical trials focused on cancer, monogenic diseases, cardiovascular diseases and other refractory diseases. Advances addressing the inherent challenges of gene therapy, particularly those related to retaining the delivery efficacy and minimizing unwanted immune responses, provide the basis for the widespread clinical application of gene medicine. Several types of genes delivered by viral or non‐viral delivery vectors have demonstrated encouraging results in both animals and humans. As augmented by clinical indications, gene medicine techniques have rapidly become a promising alternative to conventional therapeutic strategies because of their better clinical benefit and lower toxicities. Their application in the clinic has been extensive as a result of the approval of many gene therapy drugs in recent years. In this review, we provide a comprehensive overview of the clinical translation of gene medicine, focusing on the key events and latest progress made regarding clinical gene therapy products. We also discuss the gene types and non‐viral materials with respect to developing gene therapeutics in clinical trials.

show abstract

Section: Gene Types and Vectorsmentioning

confidence: 99%

Clinical translation of gene medicine

Wang

Zhou

et al. 2019

The Journal of Gene Medicine

View full text Add to dashboard Cite

show abstract

“…[ 1,2 ] In recent years, gene therapy especially oral nucleic acid therapy has emerged as an alternative and promising strategy due to much better patient compliance and that nucleic acids exhibit low immunogenicity and persistent expression of therapeutic protein in local tissues. [ 3–5 ] However, the therapeutic efficacy is significantly limited by low transgene activities as a result from multiple biological barriers including gastrointestinal trafficking, enzymatic degradation, mucosal transport, epithelium transcytosis, clearance by immune cells in circulation, cellular uptake, and intracellular delivery steps. [ 5–9 ] Complexation between genetic materials and cationic lipids or polycations like poly(ethylene imine) and chitosan generate nanocomplex that may overcome some but not all of the biological barriers.…”

Section: Introductionmentioning

confidence: 99%

“…[5][6][7][8][9] Complexation between genetic materials and cationic lipids or polycations like poly(ethylene imine) and chitosan generate nanocomplex that may overcome some but not all of the biological barriers. [5,10,11] Cationic lipids have been a preferred carrier due to its low toxicity, low immunogenicity, and facile modifications. [5,[12][13][14] Examples include nasal administration of plasmid DNA encoding CFTR (cystic fibrosis transmembrane regulator) through polyplex loading onto (2,3dioleoyloxy-propyl)-trimethylammonium (DOTAP) for the treatment of cystic fibrosis, which is now on phase I clinical trial.…”

Section: Introductionmentioning

confidence: 99%

“…[17] Despite the outstanding therapeutic effects, the bioavailability and delivery efficiency are holding back the clinical translation of these nucleic acid delivery therapies as surface-positively charged lipoplexes interact strongly with mucosa in the cases of pulmonary, nasal and oral administration that many of the nanoparticles are trapped, cleared, and lost. [5,[18][19][20][21] Scheme 1. Preparation of plasmid DNA nanoparticles and path of mucus transportation and transfection in vivo.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

One‐Pot Synthesis of PEGylated Lipoplexes to Facilitate Mucosal Permeation for Oral Insulin Gene Delivery

Nie

Zhu

et al. 2020

Advanced Therapeutics

View full text Add to dashboard Cite

Oral nucleic acid therapy for transgene expressions of insulin in vivo is an emerging strategy in treating type I diabetes (T1D) to address poor patient compliance for daily insulin injections. However, this strategy to achieve high delivery efficiency is impeded by biological barriers including gastrointestinal trafficking, enzymatic degradation, mucosal transport, etc. This article addresses the mucosal transport barrier by adopting a hydrophilic and neutral surface onto cationic lipid/DNA nanoparticles to reduce the obstacle of permeation through the mucus. A facile one‐pot method to coat the PEG layer on a (2,3‐dioleoyloxy‐propyl)‐trimethylammonium (DOTAP)/DNA nanocomplex for expressing insulin is presented. A kinetically controlled mixing technique, namely flash nanocomplexation (FNC), is used to rapidly mix 1,2‐dimyristoyl‐rac‐glycero‐3‐methoxy poly(ethylene glycol)‐2000 (DMG‐PEG) and DOTAP with plasmid DNA. The produced uniform nanoparticles (60 ± 2.1 nm) with a PEG surface demonstrates enhanced transportation in the mucus layer of the GI tract. A systemic transgene expression is confirmed, and the expressed insulin maintains the blood glucose level of streptozotocin (STZ)‐induced T1D mice within the normal range (5–10 mmol L−1) for 24 h following oral gavage and shows repetitive therapeutic effects by multiple doses. This shows the feasibility for fast translation of DMG‐PEG/DOTAP‐DNA nanoparticles in T1D treatment via oral delivery.

show abstract

“…Recently, cationic gemini surfactants have attracted special attention as efficient transfection agents in vitro and promising alternatives to viral vectors in gene therapy [4][5][6]. Successful gene therapy crucially depends on the development of effective vectors, especially for the safe introduction of the selected gene into living cells.…”

Section: Introductionmentioning

confidence: 99%

Lipoaminoacids Enzyme-Based Production and Application as Gene Delivery Vectors

et al. 2019

View full text Add to dashboard Cite

Biosurfactant compounds have been studied in many applications, including biomedical, food, cosmetic, agriculture, and bioremediation areas, mainly due to their low toxicity, high biodegradability, and multifunctionality. Among biosurfactants, the lipoplexes of lipoaminoacids play a key role in medical and pharmaceutical fields. Lipoaminoacids (LAAs) are amino acid-based surfactants that are obtained from the condensation reaction of natural origin amino acids with fatty acids or fatty acid derivatives. LAA can be produced by biocatalysis as an alternative to chemical synthesis and thus become very attractive from both the biomedical and the environmental perspectives. Gemini LAAs, which are made of two hydrophobic chains and two amino acid head groups per molecule and linked by a spacer at the level of the amino acid residues, are promising candidates as both drug and gene delivery and protein disassembly agents. Gemini LAA usually show lower critical micelle concentration, interact more efficiently with proteins, and are better solubilising agents for hydrophobic drugs when compared to their monomeric counterparts due to their dimeric structure. A clinically relevant human gene therapy vector must overcome or avoid detect and silence foreign or misplaced DNA whilst delivering sustained levels of therapeutic gene product. Many non-viral DNA vectors trigger these defence mechanisms, being subsequently destroyed or rendered silent. The development of safe and persistently expressing DNA vectors is a crucial prerequisite for a successful clinical application, and it one of the main strategic tasks of non-viral gene therapy research.

show abstract

Lipid-Based DNA Therapeutics: Hallmarks of Non-Viral Gene Delivery

Cited by 256 publications

References 290 publications

Clinical translation of gene medicine

Clinical translation of gene medicine

One‐Pot Synthesis of PEGylated Lipoplexes to Facilitate Mucosal Permeation for Oral Insulin Gene Delivery

Lipoaminoacids Enzyme-Based Production and Application as Gene Delivery Vectors

Contact Info

Product

Resources

About