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Gene Therapy Clinical Trials (gene + therapy_clinical_trials)
Selected AbstractsShear-induced degradation of plasmid DNAJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2002C. S. Lengsfeld Abstract The majority of gene therapy clinical trials use plasmid DNA that is susceptible to shear-induced degradation. Many processing steps in the extraction, purification, and preparation of plasmid-based therapeutics can impart significant shear stress that can fracture the phosphodiester backbone of polynucleotides, and reduce biological activity. Much of the mechanistic work on shear degradation of DNA was conducted over 30 years ago, and we rely heavily on this early work in an attempt to explain the empirical observations of more recent investigations concerning the aerosolization of plasmids. Unfortunately, the sporadic reports of shear degradation in the literature use different experimental systems, making it difficult to quantitatively compare results and reach definitive mechanistic conclusions. In this review, we describe the forces imparted to DNA during shear stress, and use published data to quantitatively evaluate their relative effects. In addition, we discuss the effects of molecular weight, strain rate, particle size, flexibility, ionic strength, gas,liquid interfaces, and turbulence on the fluid flow degradation of supercoiled plasmid DNA. Finally, we speculate on computational methods that might allow degradation rates in different experimental systems to be predicted. © 2002 Wiley-Liss Inc. and the American Pharmaceutical Association J Pharm Sci 91:1581,1589, 2002 [source] Inhibition of myostatin with emphasis on follistatin as a therapy for muscle diseaseMUSCLE AND NERVE, Issue 3 2009Louise R. Rodino-Klapac PhD Abstract In most cases, pharmacologic strategies to treat genetic muscle disorders and certain acquired disorders, such as sporadic inclusion body myositis, have produced modest clinical benefits. In these conditions, inhibition of the myostatin pathway represents an alternative strategy to improve functional outcomes. Preclinical data that support this approach clearly demonstrate the potential for blocking the myostatin pathway. Follistatin has emerged as a powerful antagonist of myostatin that can increase muscle mass and strength. Follistatin was first isolated from the ovary and is known to suppress follicle-stimulating hormone. This raises concerns for potential adverse effects on the hypothalamic,pituitary,gonadal axis and possible reproductive capabilities. In this review we demonstrate a strategy to bypass off-target effects using an alternatively spliced cDNA of follistatin (FS344) delivered by adeno-associated virus (AAV) to muscle. The transgene product is a peptide of 315 amino acids that is secreted from the muscle and circulates in the serum, thus avoiding cell-surface binding sites. Using this approach our translational studies show increased muscle size and strength in species ranging from mice to monkeys. Adverse effects are avoided, and no organ system pathology or change in reproductive capabilities has been seen. These findings provide the impetus to move toward gene therapy clinical trials with delivery of AAV-FS344 to increase size and function of muscle in patients with neuromuscular disease. Muscle Nerve 39: 283,296, 2009 [source] Gene therapy clinical trials worldwide to 2007,an updateTHE JOURNAL OF GENE MEDICINE, Issue 10 2007Michael L. Edelstein To date, over 1340 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. In 1997 we set up a database to bring together global information on gene therapy clinical trials as comprehensively as possible. The data are compiled and regularly updated from official agency sources, published literature, conference presentations and posters and from information kindly provided by investigators or trial sponsors themselves. This review updates our descriptive overview of the data in 2004 1, presenting our analysis of the clinical trials that, to the best of our knowledge, have been or are being performed worldwide. As of July 30 2007, we have stored entries on 1309 trials in 28 countries. We have analyzed the geographical distribution of trials, the disease indications (or other reasons) for trials, the proportions to which different vector types are used, and which genes have been transferred. Details of the analyses presented, and our interactive, searchable database can be found on The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at: http://www.wiley.co.uk/genmed/clinical. Copyright © 2007 John Wiley & Sons, Ltd. [source] Viral vectors as tools to model and treat neurodegenerative disordersTHE JOURNAL OF GENE MEDICINE, Issue 5 2005N. Déglon Abstract The identification of disease-causing genes in familial forms of neurodegenerative disorders and the development of genetic models closely replicating human central nervous system (CNS) pathologies have drastically changed our understanding of the molecular events leading to neuronal cell death. If these achievements open new opportunities of therapeutic interventions, including gene-based therapies, the presence of the blood-brain barrier and the post-mitotic and poor regenerative nature of the target cells constitute important challenges. Efficient delivery systems taking into account the specificity of the CNS are required to administer potential therapeutic candidates. In addition, genetic models in large animals that replicate the late stages of the diseases are in most cases not available for pre-clinical studies. The present review summarizes the potential of viral vectors as tools to create new genetic models of CNS disorders in various species including primates and the recent progress toward viral gene therapy clinical trials for the administration of therapeutic candidates into the brain. Copyright © 2005 John Wiley & Sons, Ltd. [source] Tricalcium phosphate nanoparticles enable rapid purification, increase transduction kinetics, and modify the tropism of mammalian virusesBIOTECHNOLOGY & BIOENGINEERING, Issue 4 2009Imke A.J. Dreesen Abstract Adenoviral, adeno-associated viral, and retroviral particles are chosen as gene delivery shuttles in more than 50% of all gene therapy clinical trials. Bulk availability of clinical-grade viral particles and their efficiency to transduce the therapeutic cargo into specific target cells remain the most critical bottlenecks in gene therapy applications to date. Capitalizing on the flame-spray technology for the reproducible economic large-scale production of amorphous tricalcium phosphate nanoparticulate powders (ATCP), we designed a scalable ready-to-use gravity-flow column set-up for the straightforward concentration and purification of transgenic adenoviral, adeno-associated viral, and lentiviral particles. Specific elution buffers enabled rapid release of viral particles from the ATCP matrix of the column and provided high-titer virus preparations in an unsurpassed period of time. The interaction of ATCP with adenoviral, adeno-associated viral, and lentiviral particles in solution increased the transduction kinetics of several mammalian cell lines in culture. The nanoparticles were also able to modify the tropism of murine leukemia virus (MLV) towards transduction of human cells. Based on these findings, we believe that the use of flame-spray tricalcium phosphate nanoparticles will lead to important progress in the development of future gene therapy initiatives. Biotechnol. Bioeng. 2009;102: 1197,1208. © 2008 Wiley Periodicals, Inc. [source] Effect of Protease Inhibitors on Yield of HSV-1-Based Viral VectorsBIOTECHNOLOGY PROGRESS, Issue 3 2000James B. Wechuck The ability to obtain high titer replication-defective herpes simplex virus (HSV) recombinant vectors will dramatically affect their use in gene therapy clinical trials. A variety of techniques and reagents have been employed to increase the overall yield of the vector. The effects of protease inhibitors on the yield of an HSV-1-based viral vector were examined. Experiments were conducted using a commercial protease inhibitor cocktail typically used in mammalian cell culture for protein production. Contrary to our expectation for enhanced vector yield, the results showed a dramatic reduction in vector yield. Moreover, it was found that AEBSF is the only component in the protease cocktail responsible for the low vector yield. On the basis of our hypothesis regarding the mode of action of AEBSF, we suggest that it should not be included in protease inhibitor cocktails designed for use in cultures aimed at production of viral vectors derived from HSV-1 or possibly several other vectors. [source] | ||||||||||