Compacted DNA Nanoparticles Administered to the Nasal Mucosa of Cystic Fibrosis Subjects Are Safe and Demonstrate Partial to Complete Cystic Fibrosis Transmembrane Regulator Reconstitution

Konstan, Michael W.; Davis, Pamela B.; Wagener, Jeffrey S.; Hilliard, Kathleen A.; Stern, Robert C.; Milgram, Laura; Kowalczyk, Tomasz; Hyatt, Susannah L.; Fink, Tamara L.; Gedeon, Christopher R.; Oette, Sharon M.; Payne, Jennifer M.; Muhammad, Osman; Ziady, Assem G.; Moen, Robert C.; Cooper, Mark J.

doi:10.1089/hum.2004.15.ft-2

Cited by 55 publications

(78 citation statements)

References 72 publications

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“…21 Moreover, a phase I clinical trial using PEGylated PLL/pDNA complexes has been conducted in cystic fibrosis (CF) patients with some success in partial correction of the CF chloride transport defect, while no inflammatory response or other toxicity due to the gene vector was observed. 33 Nevertheless, an ideal nonviral gene transfer agent has not been identified up to now. Gene delivery using P(DMAEMA)-based gene vectors is a complex process and PEGylation may largely affect their physiochemical and biological activity but these processes have not been addressed in detail as has previously investigated for PEI-based gene vectors.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Tailor-Made Copolymers of Oligo(ethylene glycol) Methyl Ether Methacrylate and N,N-Dimethylaminoethyl Methacrylate as Nonviral Gene Transfer Agents: Influence of Macromolecular Structure on Gene Vector Particle Properties and Transfection Efficiency

et al. 2009

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Oligo(ethylene glycol) methyl ether methacrylates (OEGMA) of various chain lengths (i.e., 9, 23, or 45 EG units) and N,N-dimethylaminoethyl methacrylate (DMAEMA) were copolymerized by atom transfer radical polymerization (ATRP), yielding well-defined P(DMAEMA-co-OEGMA) copolymers with increasing OEGMA molar fractions (F OEGMA) but a comparable degree of polymerization (DP ∼ 120). Increase of both F OEGMA and OEGMA chain lengths correlated inversely with gene vector size, morphology, and zeta potential. P(DMAEMA-co-OEGMA) copolymers prevented gene vector aggregation at high plasmid DNA (pDNA) concentrations in isotonic solution and did not induce cytotoxicity even at high concentrations. Transfection efficiency of the most efficient P(DMAEMA-co-OEGMA) copolymers was found to be >10-fold lower compared with branched polyethylenimine (PEI) 25 kDa. Although OEGMA copolymerization largely reduced gene vector binding with the cell surface, cellular internalization of the bound complexes was less affected. These observations suggest that inefficient endolysosomal escape limits transfection efficiency of P(DMAEMA-co-OEGMA) copolymer gene vectors. Despite this observation, optimized p(DMAEMA-co-OEGMA) gene vectors remained stable under conditions for in vivo application leading to 7-fold greater gene expression in the lungs compared with PEI. Tailor-made P(DMAEMA-co-OEGMA) copolymers are promising nonviral gene transfer agents that fulfill the requirements for successful in vivo gene delivery.

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Section: Introductionmentioning

confidence: 99%

Characterization of Tailor-Made Copolymers of Oligo(ethylene glycol) Methyl Ether Methacrylate and N,N-Dimethylaminoethyl Methacrylate as Nonviral Gene Transfer Agents: Influence of Macromolecular Structure on Gene Vector Particle Properties and Transfection Efficiency

et al. 2009

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“…10 Attempts to improve the efficiency of nonviral vectors are being made, including the addition of peptide ligands to target the vector to receptors localized on the apical membrane of airway epithelial cells, 11 and the development of nanoparticles to improve nuclear entry. 12 Here we have assessed, if sonoporation, the use of high-frequency ultrasound (US) increases nonviral gene transfer to the lung.…”

Section: Introductionmentioning

confidence: 99%

Use of ultrasound to enhance nonviral lung gene transfer in vivo

et al. 2007

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We have assessed if high-frequency ultrasound (US) can enhance nonviral gene transfer to the mouse lung. Cationic lipid GL67/pDNA, polyethylenimine (PEI)/pDNA and naked plasmid DNA (pDNA) were delivered via intranasal instillation, mixed with Optison microbubbles, and the animals were then exposed to 1 MHz US. Addition of Optison alone significantly reduced the transfection efficiency of all three gene transfer agents. US exposure did not increase GL67/ pDNA or PEI/pDNA gene transfer compared to Optisontreated animals. However, it increased naked pDNA transfection efficiency by approximately 15-fold compared to Optison-treated animals, suggesting that despite ultrasound being attenuated by air in the lung, sufficient energy penetrates the tissue to increase gene transfer. US-induced lung haemorrhage, assessed histologically, increased with prolonged US exposure. The left lung was more affected than the right and this was mirrored by a lesser increase in naked pDNA gene transfer, in the left lung. The positive effect of US was dependent on Optison, as in its absence US did not increase naked pDNA transfection efficiency. We have thus established proof of principle that US can increase nonviral gene transfer, in the air-filled murine lung.

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“…[104] In fact, polyplexes are being investigated in phase I and phase II clinical trials for the treatment of cystic fibrosis and ocular degenerative diseases. [105] Hybrids of lipids with polymers have been explored to improve gene delivery. [106] In this system, DNA is pre-condensed with either poly-L-lysine, [107] protamine, [108] histone or several synthetic polypeptides, [109] followed by lipid wrapping using either cationic liposomes, anionic liposomes or amphiphilic polymers.…”

Section: Polymer-based Nonviral Vectorsmentioning

confidence: 99%

Advances in Gene Delivery Systems

et al. 2011

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The transfer of genes into cells, both in vitro and in vivo, is critical for studying gene function and conducting gene therapy. Methods that utilize viral and nonviral vectors, as well as physical approaches, have been explored. Viral vector-mediated gene transfer employs replication-deficient viruses such as retro-virus, adenovirus, adeno-associated virus and herpes simplex virus. A major advantage of viral vectors is their high gene delivery efficiency. The nonviral vectors developed so far include cationic liposomes, cationic polymers, synthetic peptides and naturally occurring compounds. These nonviral vectors appear to be highly effective in gene delivery to cultured cells in vitro but are significantly less effective in vivo. Physical methods utilize mechanical pressure, electric shock or hydrodynamic force to transiently permeate the cell membrane to transfer DNA into target cells. They are simpler than viral-and nonviral-based systems and highly effective for localized gene delivery. The past decade has seen significant efforts to establish the most desirable method for safe, effective and target-specific gene delivery, and good progress has been made. The objectives of this review are to (i) explain the rationale for the design of viral, nonviral and physical methods for gene delivery; (ii) provide a summary on recent advances in gene transfer technology; (iii) discuss advantages and disadvantages of each of the most commonly used gene delivery methods; and (iv) provide future perspectives.

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Compacted DNA Nanoparticles Administered to the Nasal Mucosa of Cystic Fibrosis Subjects Are Safe and Demonstrate Partial to Complete Cystic Fibrosis Transmembrane Regulator Reconstitution

Cited by 55 publications

References 72 publications

Characterization of Tailor-Made Copolymers of Oligo(ethylene glycol) Methyl Ether Methacrylate and N,N-Dimethylaminoethyl Methacrylate as Nonviral Gene Transfer Agents: Influence of Macromolecular Structure on Gene Vector Particle Properties and Transfection Efficiency

Characterization of Tailor-Made Copolymers of Oligo(ethylene glycol) Methyl Ether Methacrylate and N,N-Dimethylaminoethyl Methacrylate as Nonviral Gene Transfer Agents: Influence of Macromolecular Structure on Gene Vector Particle Properties and Transfection Efficiency

Use of ultrasound to enhance nonviral lung gene transfer in vivo

Advances in Gene Delivery Systems

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