Gene therapy clinical trials worldwide to 2012 – an update

Ginn, Samantha L.; Alexander, Ian E.; Edelstein, Michael; Abedi, Mohammad Reza; Wixon, Jo

doi:10.1002/jgm.2698

Cited by 1,129 publications

(536 citation statements)

References 71 publications

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“…N onviral gene therapy vectors are of great importance, and they are used in 18% of the total number of clinical trials (Edelstein et al, 2007;Schleef et al, 2010;Ginn, 2013). This is because of their intrinsic biosafety characteristics and many technological improvements, which made nonviral vectors a promising alternative over viral vectors in gene therapy.…”

Section: Introductionmentioning

confidence: 99%

A Seven-Year Storage Report of Good Manufacturing Practice–Grade Naked Plasmid DNA: Stability, Topology, andIn Vitro/In VivoFunctional Analysis

Walther

Schmeer²,

Kobelt³

et al. 2013

Human Gene Therapy Clinical Development

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The great interest for naked plasmid DNA in gene therapy studies is reflected by the fact that it is currently used in 18% of all gene therapy trials. Therefore, validation of topology and functionality of DNA resulting from its long-term stability is an essential requirement for safe and effective gene transfer. To this aim, we analyzed the stability of good manufacturing practice-grade pCMVb reporter plasmid DNA by capillary gel electrophoresis, agarose gel electrophoresis, and atomic force microscopy. The plasmid DNA was produced for a clinical gene transfer study started in 2005 and was stored for meanwhile 7 years under continuously monitored conditions at -20°C. The stability of plasmid DNA was monitored by LacZ transgene expression functional assays performed in vitro and in vivo on the 7-year-old plasmid DNA samples compared with plasmid batches newly produced in similar experimental conditions and quality standards. The analyses revealed that during the overall storage time and conditions, the proportion of open circular and supercoiled or covalently closed circular forms is conserved without linearization or degradation of the plasmid. The in vitro transfection and the in vivo jetinjection of DNA showed unaltered functionality of the long-stored plasmid. In summary, the 7-year-old and the newly produced plasmid samples showed similar topology and expression performance. Therefore, our stable storage conditions are effective to preserve the integrity of the DNA to be used in clinical studies. This is an important prerequisite for the long-term performance of gene transfer materials used in trials of long duration as well as of the reference material used in standardization procedures and assays.

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Section: Introductionmentioning

confidence: 99%

A Seven-Year Storage Report of Good Manufacturing Practice–Grade Naked Plasmid DNA: Stability, Topology, andIn Vitro/In VivoFunctional Analysis

Walther

Schmeer²,

Kobelt³

et al. 2013

Human Gene Therapy Clinical Development

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“…Studies have demonstrated that rAAV1 vectors transduce skeletal muscle more efficiently than rAAV2 vectors, and do not elicit a humoral immune response to the transgene protein (Chao et al, 2001;Mah et al, 2007). Currently, more than 90 clinical trials have begun using rAAV vectors (Ginn et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Toxicology and Biodistribution Studies of Recombinant Adeno-Associated Virus 1 Human Acid α-Glucosidase

Conlon

Erger²,

Porvasnik³

et al. 2013

Human Gene Therapy Clinical Development

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A biodistribution and toxicology study was performed to test the acute toxicities of intradiaphragmatic injection of a recombinant adeno-associated virus (rAAV) 2/1-human acid alpha-Glucosidase (hGAA) driven by a cytomegalovirus (CMV) promoter (rAAV1-CMV-hGAA) in New Zealand white rabbits and in the rodent Pompe disease model by injecting at the right quadriceps. Studies performed using fluoroscopy and AAV2-GFP demonstrated spread upon intradiaphragmatic injection, and the ability of AAV to infect and express acid a-glucosidase (GAA) throughout the diaphragm. For the preclinical study, 10 rabbits (5 male, 5 female) were divided into two groups, vehicle control (Lactated Ringer's) and test article (1.5 · 10 12 vector genomes [vg] rAAV1-CMV-hGAA), and euthanized on day 21. After direct visualization, the left hemidiaphragm was injected at three locations. There was up to a 2,500-fold increase in circulating anti-AAV1 antibodies directed to the vector capsids. In addition, up to an 18-fold increase in antibodies against the GAA protein was generated. Injection sites maintained up to 1.0 · 10 5 vg/lg genomic DNA (gDNA), while uninjected sites had up to 1.0 · 10 4 vg/lg gDNA. Vector DNA was present in blood at 24 hr postinjection at up to 1.0 · 10 6 vg/lg gDNA, followed by a decrease to 1.0 · 10 3 vg/lg gDNA at euthanization on day 21. Nominal amounts of vector DNA were present in peripheral organs, including the brain, spinal cord, gonads, and skeletal muscle. Upon histopathological examination, fibroplasias of the serosal surface were noted at diaphragm injections sites of both groups. In addition, an increase in mononuclear cell infiltration in the diaphragm and esophagus in vector-dosed animals was found. Elevated creatine phosphokinase levels, an indicator of muscle repair, was observed in all animals postprocedure but persisted in vector-injected rabbits until euthanization. A follow-up study suggested that this was directed against the human transgene expression in a foreign species. Overall, this study demonstrates diffusion of vector throughout the diaphragm after localized injections.

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“…Nonetheless, viral vectors such as adenovirus, retrovirus, vaccinia virus and adeno-associated viruses have accounted for more than 65 % of the clinical trials, mainly because transfection activities using such viral vectors are typically higher than that of non-viral ones [77]. To understand the crucial rate-limiting step in the transfection efficacy in non-viral vectors, we previously compared intracellular trafficking between adenovirus and Lipofectamine Plus ® (lipoplex), as typical viral and non-viral gene carriers [78,79].…”

Section: Lipid Nanoparticles Prepared With Ph-activated and Ss-cleavamentioning

confidence: 99%

“Programmed packaging” for gene delivery

Hyodo

Sakurai

Akita

et al. 2014

Journal of Controlled Release

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We report on the development of a Multifunctional Envelope-type Nano Device (MEND) based on our packaging concept "Programmed Packaging" to control not only intracellular trafficking but also the biodistribution of encapsulated compounds such as nucleic acids/proteins/peptides. Our strategy for achieving this is based on molecular mechanisms of cell biology such as endocytosis, vesicular trafficking, etc. In this review, we summarize the concept of programmed packaging and discuss some of our recent successful examples of using MENDs. Systematic evolution of ligands by exponential enrichment (SELEX) was applied as a new methodology for identifying a new ligand toward cell or mitochondria. The delivery of siRNA to tumors and the tumor vasculature was achieved using pH sensitive lipid (YSK05), which was newly designed and optimized under in vivo conditions. The efficient delivery of pDNA to immune cells such as dendritic cells has also been developed using the KALA ligand, which can be a breakthrough technology for DNA vaccine. Finally, ss-cleavable and pH-activated lipid-like surfactant (ssPalm) which is a lipid like material with pH-activatable and SS-cleavable properties is also introduced as a proof of our concept.

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Gene therapy clinical trials worldwide to 2012 – an update

Cited by 1,129 publications

References 71 publications

A Seven-Year Storage Report of Good Manufacturing Practice–Grade Naked Plasmid DNA: Stability, Topology, andIn Vitro/In VivoFunctional Analysis

A Seven-Year Storage Report of Good Manufacturing Practice–Grade Naked Plasmid DNA: Stability, Topology, andIn Vitro/In VivoFunctional Analysis

Preclinical Toxicology and Biodistribution Studies of Recombinant Adeno-Associated Virus 1 Human Acid α-Glucosidase

“Programmed packaging” for gene delivery

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