The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Fred D Ledley - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetic considerations in Somatic Gene Therapy
    Advanced Drug Delivery Reviews, 1998
    Co-Authors: Fred D Ledley, T S Ledley
    Abstract:

    It is anticipated that Gene therapies will be useful for achieving long durations of action with little temporal fluctuation in the level of the therapeutic Gene product, localized effects in specific tissues or cell types, and levels of biological products that can be regulated over time by drugs or physiological events. The effective clinical application of Gene therapies will require detailed consideration of the pharmacokinetics of the Gene and its Gene product. This requires understanding not only the apparent kinetics of the bioactive Gene product, but the intrinsic kinetics of each step involved in Gene delivery, Gene expression and the bioavailability of the Gene product. Numerical models are described for three different approaches to Gene Therapy: (i) those that involve permanent integration of a transGene into the target cell, (ii) those that involve transient residence of the transGene within the cell, and (iii) those that allow control over Gene expression by regulatory factors or administered drugs. Experimental studies describing the dynamics and kinetics of DNA in vivo and early pharmacokinetic studies of viral and non-viral systems are reviewed.

  • pharmaceutical approach to Somatic Gene Therapy
    Pharmaceutical Research, 1996
    Co-Authors: Fred D Ledley
    Abstract:

    The pharmaceutical approach to Somatic Gene Therapy is based on consideration of a Gene as a chemical entity with specific physical, chemical and colloidal properties. The Genes that are required for Gene Therapy are large molecules (>1 × 106 Daltons, >100 nm diameter) with a net negative charge that prevents diffusion through biological barriers such as an intact endothelium, the plasma membrane or the nuclear membrane. New methods for Gene Therapy are based on increasing knowledge of the pathways by which DNA may be internalized into cells and traffic to the nucleus, pharmaceutical experience with particulate drug delivery systems, and the ability to control Gene expression with recombined Genetic elements. This article reviews two themes in the development of Gene therapies: first, the current approaches involving the administration of cells, viruses and plasmid DNA; second, the emerging pharmaceutical approach to Gene Therapy based on the pharmaceutical characteristics of DNA itself and methods for advanced drug delivery.

  • overexpression of human methylmalonyl coa mutase in mice after in vivo Gene transfer with asialoglycoprotein polylysine dna complexes
    Human Gene Therapy, 1994
    Co-Authors: Jozsef Stankovics, Ana Crane, Elizabeth Andrews, Fred D Ledley
    Abstract:

    ABSTRACT Methylmalonic acidemia resulting from Genetic deficiency of methylmalonyl CoA mutase (MCM) is an often fatal metabolic disease. Somatic Gene Therapy for this disorder may require Gene replacement in the liver. We describe overexpression of MCM in the liver of mice after in vivo Gene delivery using asialoglycoprotein/polylysine/DNA (ASO/PL/DNA) targeted delivery to the liver of plasmids expressing recombinant MCM. After intravenous administration of the ASO/PL/DNA complex, the vector sequences are cleared from the blood with t1/2 = 2.5 min and >95% of the vector is taken up by the liver. Vector sequences are cleared from the liver with t1/2 = 1.0–1.3 hr. MCM enzyme activity in the liver increases to levels 30–40% over baseline 6–24 hr after injection. No acute or chronic toxicity was observed. This net level of expression is likely to be therapeutic for MCM if the complex could be administered repetitively to treat acute episodes of life-threatening acidosis or establish a steady-state level of MC...

  • Development in Somatic Gene Therapy
    Expert Opinion on Investigational Drugs, 1994
    Co-Authors: Fred D Ledley
    Abstract:

    Clinical trials of Gene transfer have begun to validate the clinical potential of Gene Therapy. With this progress, attention has turned increasingly to analysing the ability of various methods of Gene Therapy to satisfy clinical and commercial needs. There are fundamental differences between cell-based therapies, which employ Genetically modified cells as a therapeutic product, virus-based therapies, which employ recombinant viral vectors as a therapeutic product and Gene-based therapies in which DNA itself is formulated as a pharmaceutical product, in terms of the technologies required to develop and produce the product, the mode of clinical application, the clinical risks and the economics of commercialisation. This report reviews the potential indications for Gene Therapy and the status of various approaches to Gene Therapy in development in the context of a field which is moving rapidly from basic research to product development.

  • Somatic Gene Therapy in otolaryngology head and neck surgery
    Archives of Otolaryngology-head & Neck Surgery, 1993
    Co-Authors: Bert W Omalley, Fred D Ledley
    Abstract:

    The initial clinical trials of Somatic Gene Therapy have demonstrated that Gene transfer can be performed safely in a clinical setting and with public acceptance. These trials have focused attention on the broad applications of this technology in routine medical and surgical practice. This article reviews the reasons why Somatic Gene Therapy could lead to significant improvements in clinical practice as well as specific therapies in otolaryngology—head and neck surgery. Early applications include the treatment of inherited diseases such as cystic fibrosis, new approaches for treating malignancies, new methods for enhancing tissue repair, and reGeneration after plastic and reconstructive surgery, and the potential for using the thyroid as a target for Somatic Gene Therapy. The following review will illustrate how Somatic Gene Therapy may have a significant impact not only on the treatment of rare Genetic diseases but on managing the common problems encountered by physicians and patients in daily practice. (Arch Otolaryngol Head Neck Surg. 1993;119:1191-1197)

Brunhilde Wirth - One of the best experts on this subject based on the ideXlab platform.

  • quantitative analyses of smn1 and smn2 based on real time lightcycler pcr fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy
    American Journal of Human Genetics, 2002
    Co-Authors: Markus Feldkotter, Verena Schwarzer, Radu Wirth, Thomas F Wienker, Brunhilde Wirth
    Abstract:

    Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans, caused by homozygous absence of the survival motor neuron Gene 1 (SMN1). SMN2, a copy Gene, influences the severity of SMA and may be used in Somatic Gene Therapy of patients with SMA in the future. We present a new, fast, and highly reliable quantitative test, based on real-time LightCycler PCR that amplifies either SMN1 or SMN2. The SMN1 copies were determined and validated in 329 carriers and controls. The specificity of the test is 100%, whereas the sensitivity is 96.2%. The quantitative analysis of SMN2 copies in 375 patients with type I, type II, or type III SMA showed a significant correlation between SMN2 copy number and type of SMA as well as duration of survival. Thus, 80% of patients with type I SMA carry one or two SMN2 copies, and 82% of patients with type II SMA carry three SMN2 copies, whereas 96% of patients with type III SMA carry three or four SMN2 copies. Among 113 patients with type I SMA, 9 with one SMN2 copy lived

  • quantitative analyses of smn1 and smn2 based on real time lightcycler pcr fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy
    American Journal of Human Genetics, 2002
    Co-Authors: Markus Feldkotter, Verena Schwarzer, Radu Wirth, Thomas F Wienker, Brunhilde Wirth
    Abstract:

    Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans, caused by homozygous absence of the survival motor neuron Gene 1 (SMN1). SMN2, a copy Gene, influences the severity of SMA and may be used in Somatic Gene Therapy of patients with SMA in the future. We present a new, fast, and highly reliable quantitative test, based on real-time LightCycler PCR that amplifies either SMN1 or SMN2. The SMN1 copies were determined and validated in 329 carriers and controls. The specificity of the test is 100%, whereas the sensitivity is 96.2%. The quantitative analysis of SMN2 copies in 375 patients with type I, type II, or type III SMA showed a significant correlation between SMN2 copy number and type of SMA as well as duration of survival. Thus, 80% of patients with type I SMA carry one or two SMN2 copies, and 82% of patients with type II SMA carry three SMN2 copies, whereas 96% of patients with type III SMA carry three or four SMN2 copies. Among 113 patients with type I SMA, 9 with one SMN2 copy lived <11 mo, 88/94 with two SMN2 copies lived <21 mo, and 8/10 with three SMN2 copies lived 33-66 mo. On the basis of SMN2 copy number, we calculated the posterior probability that a child with homozygous absence of SMN1 will develop type I, type II, or type III SMA.

Markus Feldkotter - One of the best experts on this subject based on the ideXlab platform.

  • quantitative analyses of smn1 and smn2 based on real time lightcycler pcr fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy
    American Journal of Human Genetics, 2002
    Co-Authors: Markus Feldkotter, Verena Schwarzer, Radu Wirth, Thomas F Wienker, Brunhilde Wirth
    Abstract:

    Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans, caused by homozygous absence of the survival motor neuron Gene 1 (SMN1). SMN2, a copy Gene, influences the severity of SMA and may be used in Somatic Gene Therapy of patients with SMA in the future. We present a new, fast, and highly reliable quantitative test, based on real-time LightCycler PCR that amplifies either SMN1 or SMN2. The SMN1 copies were determined and validated in 329 carriers and controls. The specificity of the test is 100%, whereas the sensitivity is 96.2%. The quantitative analysis of SMN2 copies in 375 patients with type I, type II, or type III SMA showed a significant correlation between SMN2 copy number and type of SMA as well as duration of survival. Thus, 80% of patients with type I SMA carry one or two SMN2 copies, and 82% of patients with type II SMA carry three SMN2 copies, whereas 96% of patients with type III SMA carry three or four SMN2 copies. Among 113 patients with type I SMA, 9 with one SMN2 copy lived

  • quantitative analyses of smn1 and smn2 based on real time lightcycler pcr fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy
    American Journal of Human Genetics, 2002
    Co-Authors: Markus Feldkotter, Verena Schwarzer, Radu Wirth, Thomas F Wienker, Brunhilde Wirth
    Abstract:

    Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans, caused by homozygous absence of the survival motor neuron Gene 1 (SMN1). SMN2, a copy Gene, influences the severity of SMA and may be used in Somatic Gene Therapy of patients with SMA in the future. We present a new, fast, and highly reliable quantitative test, based on real-time LightCycler PCR that amplifies either SMN1 or SMN2. The SMN1 copies were determined and validated in 329 carriers and controls. The specificity of the test is 100%, whereas the sensitivity is 96.2%. The quantitative analysis of SMN2 copies in 375 patients with type I, type II, or type III SMA showed a significant correlation between SMN2 copy number and type of SMA as well as duration of survival. Thus, 80% of patients with type I SMA carry one or two SMN2 copies, and 82% of patients with type II SMA carry three SMN2 copies, whereas 96% of patients with type III SMA carry three or four SMN2 copies. Among 113 patients with type I SMA, 9 with one SMN2 copy lived <11 mo, 88/94 with two SMN2 copies lived <21 mo, and 8/10 with three SMN2 copies lived 33-66 mo. On the basis of SMN2 copy number, we calculated the posterior probability that a child with homozygous absence of SMN1 will develop type I, type II, or type III SMA.

Radu Wirth - One of the best experts on this subject based on the ideXlab platform.

  • quantitative analyses of smn1 and smn2 based on real time lightcycler pcr fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy
    American Journal of Human Genetics, 2002
    Co-Authors: Markus Feldkotter, Verena Schwarzer, Radu Wirth, Thomas F Wienker, Brunhilde Wirth
    Abstract:

    Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans, caused by homozygous absence of the survival motor neuron Gene 1 (SMN1). SMN2, a copy Gene, influences the severity of SMA and may be used in Somatic Gene Therapy of patients with SMA in the future. We present a new, fast, and highly reliable quantitative test, based on real-time LightCycler PCR that amplifies either SMN1 or SMN2. The SMN1 copies were determined and validated in 329 carriers and controls. The specificity of the test is 100%, whereas the sensitivity is 96.2%. The quantitative analysis of SMN2 copies in 375 patients with type I, type II, or type III SMA showed a significant correlation between SMN2 copy number and type of SMA as well as duration of survival. Thus, 80% of patients with type I SMA carry one or two SMN2 copies, and 82% of patients with type II SMA carry three SMN2 copies, whereas 96% of patients with type III SMA carry three or four SMN2 copies. Among 113 patients with type I SMA, 9 with one SMN2 copy lived

  • quantitative analyses of smn1 and smn2 based on real time lightcycler pcr fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy
    American Journal of Human Genetics, 2002
    Co-Authors: Markus Feldkotter, Verena Schwarzer, Radu Wirth, Thomas F Wienker, Brunhilde Wirth
    Abstract:

    Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans, caused by homozygous absence of the survival motor neuron Gene 1 (SMN1). SMN2, a copy Gene, influences the severity of SMA and may be used in Somatic Gene Therapy of patients with SMA in the future. We present a new, fast, and highly reliable quantitative test, based on real-time LightCycler PCR that amplifies either SMN1 or SMN2. The SMN1 copies were determined and validated in 329 carriers and controls. The specificity of the test is 100%, whereas the sensitivity is 96.2%. The quantitative analysis of SMN2 copies in 375 patients with type I, type II, or type III SMA showed a significant correlation between SMN2 copy number and type of SMA as well as duration of survival. Thus, 80% of patients with type I SMA carry one or two SMN2 copies, and 82% of patients with type II SMA carry three SMN2 copies, whereas 96% of patients with type III SMA carry three or four SMN2 copies. Among 113 patients with type I SMA, 9 with one SMN2 copy lived <11 mo, 88/94 with two SMN2 copies lived <21 mo, and 8/10 with three SMN2 copies lived 33-66 mo. On the basis of SMN2 copy number, we calculated the posterior probability that a child with homozygous absence of SMN1 will develop type I, type II, or type III SMA.

Verena Schwarzer - One of the best experts on this subject based on the ideXlab platform.

  • quantitative analyses of smn1 and smn2 based on real time lightcycler pcr fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy
    American Journal of Human Genetics, 2002
    Co-Authors: Markus Feldkotter, Verena Schwarzer, Radu Wirth, Thomas F Wienker, Brunhilde Wirth
    Abstract:

    Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans, caused by homozygous absence of the survival motor neuron Gene 1 (SMN1). SMN2, a copy Gene, influences the severity of SMA and may be used in Somatic Gene Therapy of patients with SMA in the future. We present a new, fast, and highly reliable quantitative test, based on real-time LightCycler PCR that amplifies either SMN1 or SMN2. The SMN1 copies were determined and validated in 329 carriers and controls. The specificity of the test is 100%, whereas the sensitivity is 96.2%. The quantitative analysis of SMN2 copies in 375 patients with type I, type II, or type III SMA showed a significant correlation between SMN2 copy number and type of SMA as well as duration of survival. Thus, 80% of patients with type I SMA carry one or two SMN2 copies, and 82% of patients with type II SMA carry three SMN2 copies, whereas 96% of patients with type III SMA carry three or four SMN2 copies. Among 113 patients with type I SMA, 9 with one SMN2 copy lived

  • quantitative analyses of smn1 and smn2 based on real time lightcycler pcr fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy
    American Journal of Human Genetics, 2002
    Co-Authors: Markus Feldkotter, Verena Schwarzer, Radu Wirth, Thomas F Wienker, Brunhilde Wirth
    Abstract:

    Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans, caused by homozygous absence of the survival motor neuron Gene 1 (SMN1). SMN2, a copy Gene, influences the severity of SMA and may be used in Somatic Gene Therapy of patients with SMA in the future. We present a new, fast, and highly reliable quantitative test, based on real-time LightCycler PCR that amplifies either SMN1 or SMN2. The SMN1 copies were determined and validated in 329 carriers and controls. The specificity of the test is 100%, whereas the sensitivity is 96.2%. The quantitative analysis of SMN2 copies in 375 patients with type I, type II, or type III SMA showed a significant correlation between SMN2 copy number and type of SMA as well as duration of survival. Thus, 80% of patients with type I SMA carry one or two SMN2 copies, and 82% of patients with type II SMA carry three SMN2 copies, whereas 96% of patients with type III SMA carry three or four SMN2 copies. Among 113 patients with type I SMA, 9 with one SMN2 copy lived <11 mo, 88/94 with two SMN2 copies lived <21 mo, and 8/10 with three SMN2 copies lived 33-66 mo. On the basis of SMN2 copy number, we calculated the posterior probability that a child with homozygous absence of SMN1 will develop type I, type II, or type III SMA.