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Biomedicines, Volume 2, Issue 1 (March 2014), Pages 1-131

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Research

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Open AccessArticle Gulonolactone Addition to Human Hepatocellular Carcinoma Cells with Gene Transfer of Gulonolactone Oxidase Restores Ascorbate Biosynthesis and Reduces Hypoxia Inducible Factor 1
Biomedicines 2014, 2(1), 98-109; doi:10.3390/biomedicines2010098
Received: 20 December 2013 / Revised: 26 February 2014 / Accepted: 26 February 2014 / Published: 5 March 2014
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Abstract
Humans are unable to synthesise ascorbate (Vitamin C) due to the lack of a functional gulonolactone oxidase (Gulo), the enzyme that catalyses the final step in the biosynthesis pathway. Ascorbate is a vital micronutrient required for many biological functions, including as a cofactor
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Humans are unable to synthesise ascorbate (Vitamin C) due to the lack of a functional gulonolactone oxidase (Gulo), the enzyme that catalyses the final step in the biosynthesis pathway. Ascorbate is a vital micronutrient required for many biological functions, including as a cofactor for metalloenzymes that regulate the transcription factor hypoxia-inducible factor-1 (HIF-1), which governs cell survival under hypoxia. In most animals, ascorbate is made in liver cells. This study aimed to restore ascorbate synthesis to human hepatocellular carcinoma HepG2 cells and determine the effect of internally produced ascorbate on HIF-1 activation. HepG2 cells were gene-modified with a plasmid encoding the mouse Gulo cDNA, tested for genomic incorporation by PCR and ascorbate synthesis by high performance liquid chromatography. Levels of HIF-1 protein were measured using Western blotting. Gulo-modified HepG2 cells showed increased adherence compared to control HepG2 cells. A PCR-positive clone synthesised ascorbate when the Gulo substrate, l-gulono-1,4-lactone, was supplied. Intracellular ascorbate concentrations reached 5% of saturation levels (6 nmol/106 cells). Addition of ascorbate or gulonolactone reduced HIF-1 accumulation in the Gulo clone, but also in parental HepG2 cells. Our data confirm the requirement for a number of factors in addition to Gulo in the ascorbate biosynthesis pathway in human cells. Full article
(This article belongs to the Special Issue Gene Therapy Used in Cancer Treatment)
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Review

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Open AccessReview Conjugates of Small Molecule Drugs with Antibodies and Other Proteins
Biomedicines 2014, 2(1), 1-13; doi:10.3390/biomedicines2010001
Received: 19 November 2013 / Revised: 17 January 2014 / Accepted: 17 January 2014 / Published: 24 January 2014
Cited by 5 | PDF Full-text (319 KB) | HTML Full-text | XML Full-text
Abstract
Conjugates of small molecule drugs with antibodies (ADCs) and with other proteins (protein-drug conjugates, PDC) are used as a new class of targeted therapeutics combining the specificity of monoclonal antibodies (mAbs) and other proteins with potent cytotoxic activity of small molecule drugs for
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Conjugates of small molecule drugs with antibodies (ADCs) and with other proteins (protein-drug conjugates, PDC) are used as a new class of targeted therapeutics combining the specificity of monoclonal antibodies (mAbs) and other proteins with potent cytotoxic activity of small molecule drugs for the treatment of cancer and other diseases. A(P)DCs have three major components, antibody (targeting protein), linker and payload, the cytotoxic drug. Recently, advances in identifying targets, selecting highly specific mAbs of preferred isotypes, optimizing linker technology and improving chemical methods for conjugation have led to the approval of two ADCs by Food and Drug Administration (FDA) and more than 30 ADCs in advanced clinical development. However, the complex and heterogeneous nature of A(P)DCs often cause poor solubility, instability, aggregation and eventually unwanted toxicity. This article reviews the main components of A(P)DCs, and discusses the choices for drugs, linkers and conjugation methods currently used. Future work will need to focus on developments and strategies for overcoming such major problems associated with the A(P)DCs. Full article
(This article belongs to the Special Issue Feature Papers)
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Open AccessReview Design and Potential of Non-Integrating Lentiviral Vectors
Biomedicines 2014, 2(1), 14-35; doi:10.3390/biomedicines2010014
Received: 7 November 2013 / Revised: 22 January 2014 / Accepted: 23 January 2014 / Published: 27 January 2014
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Abstract
Lentiviral vectors have demonstrated promising results in clinical trials that target cells of the hematopoietic system. For these applications, they are the vectors of choice since they provide stable integration into cells that will undergo extensive expansion in vivo. Unfortunately, integration can
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Lentiviral vectors have demonstrated promising results in clinical trials that target cells of the hematopoietic system. For these applications, they are the vectors of choice since they provide stable integration into cells that will undergo extensive expansion in vivo. Unfortunately, integration can have unintended consequences including dysregulated cell growth. Therefore, lentiviral vectors that do not integrate are predicted to have a safer profile compared to integrating vectors and should be considered for applications where transient expression is required or for sustained episomal expression such as in quiescent cells. In this review, the system for generating lentiviral vectors will be described and used to illustrate how alterations in the viral integrase or vector Long Terminal Repeats have been used to generate vectors that lack the ability to integrate. In addition to their safety advantages, these non-integrating lentiviral vectors can be used when persistent expression would have adverse consequences. Vectors are currently in development for use in vaccinations, cancer therapy, site-directed gene insertions, gene disruption strategies, and cell reprogramming. Preclinical work will be described that illustrates the potential of this unique vector system in human gene therapy. Full article
(This article belongs to the Special Issue Feature Papers)
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Open AccessReview Oncolytic Adenoviruses in Cancer Treatment
Biomedicines 2014, 2(1), 36-49; doi:10.3390/biomedicines2010036
Received: 15 January 2014 / Revised: 13 February 2014 / Accepted: 14 February 2014 / Published: 21 February 2014
Cited by 4 | PDF Full-text (310 KB) | HTML Full-text | XML Full-text
Abstract
The therapeutic use of viruses against cancer has been revived during the last two decades. Oncolytic viruses replicate and spread inside tumors, amplifying their cytotoxicity and simultaneously reversing the tumor immune suppression. Among different viruses, recombinant adenoviruses designed to replicate selectively in tumor
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The therapeutic use of viruses against cancer has been revived during the last two decades. Oncolytic viruses replicate and spread inside tumors, amplifying their cytotoxicity and simultaneously reversing the tumor immune suppression. Among different viruses, recombinant adenoviruses designed to replicate selectively in tumor cells have been clinically tested by intratumoral or systemic administration. Limited efficacy has been associated to poor tumor targeting, intratumoral spread, and virocentric immune responses. A deeper understanding of these three barriers will be required to design more effective oncolytic adenoviruses that, alone or combined with chemotherapy or immunotherapy, may become tools for oncologists. Full article
(This article belongs to the Special Issue Gene Therapy Used in Cancer Treatment)
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Open AccessReview Stem Cell Banking for Regenerative and Personalized Medicine
Biomedicines 2014, 2(1), 50-79; doi:10.3390/biomedicines2010050
Received: 19 November 2013 / Revised: 10 January 2014 / Accepted: 17 February 2014 / Published: 26 February 2014
Cited by 2 | PDF Full-text (301 KB) | HTML Full-text | XML Full-text
Abstract
Regenerative medicine, tissue engineering and gene therapy offer the opportunity to treat and cure many of today’s intractable afflictions. These approaches to personalized medicine often utilize stem cells to accomplish these goals. However, stem cells can be negatively affected by donor variables such
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Regenerative medicine, tissue engineering and gene therapy offer the opportunity to treat and cure many of today’s intractable afflictions. These approaches to personalized medicine often utilize stem cells to accomplish these goals. However, stem cells can be negatively affected by donor variables such as age and health status at the time of collection, compromising their efficacy. Stem cell banking offers the opportunity to cryogenically preserve stem cells at their most potent state for later use in these applications. Practical stem cell sources include bone marrow, umbilical cord blood and tissue, and adipose tissue. Each of these sources contains stem cells that can be obtained from most individuals, without too much difficulty and in an economical fashion. This review will discuss the advantages and disadvantages of each stem cell source, factors to be considered when contemplating banking each stem cell source, the methodology required to bank each stem cell source, and finally, current and future clinical uses of each stem cell source. Full article
(This article belongs to the Special Issue Feature Papers)
Open AccessReview Product-Related Impurities in Clinical-Grade Recombinant AAV Vectors: Characterization and Risk Assessment
Biomedicines 2014, 2(1), 80-97; doi:10.3390/biomedicines2010080
Received: 13 December 2013 / Revised: 20 February 2014 / Accepted: 20 February 2014 / Published: 3 March 2014
Cited by 2 | PDF Full-text (246 KB) | HTML Full-text | XML Full-text
Abstract
Adeno-associated virus (AAV)-based vectors expressing therapeutic genes continue to demonstrate great promise for the treatment of a wide variety of diseases and together with other gene transfer vectors represent an emerging new therapeutic paradigm comparable in potential impact on human health to that
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Adeno-associated virus (AAV)-based vectors expressing therapeutic genes continue to demonstrate great promise for the treatment of a wide variety of diseases and together with other gene transfer vectors represent an emerging new therapeutic paradigm comparable in potential impact on human health to that achieved by recombinant proteins and vaccines. A challenge for the current pipeline of AAV-based investigational products as they advance through clinical development is the identification, characterization and lot-to-lot control of the process- and product-related impurities present in even highly purified preparations. Especially challenging are AAV vector product-related impurities that closely resemble the vector itself and are, in some cases, without clear precedent in established biotherapeutic products. The determination of acceptable levels of these impurities in vectors prepared for human clinical product development, with the goal of new product licensure, requires careful risk and feasibility assessment. This review focuses primarily on the AAV product-related impurities that have been described in vectors prepared for clinical development. Full article
(This article belongs to the Special Issue Feature Papers)
Open AccessReview Feasibility of Applying Helper-Dependent Adenoviral Vectors for Cancer Immunotherapy
Biomedicines 2014, 2(1), 110-131; doi:10.3390/biomedicines2010110
Received: 20 December 2013 / Revised: 25 February 2014 / Accepted: 26 February 2014 / Published: 10 March 2014
Cited by 1 | PDF Full-text (742 KB) | HTML Full-text | XML Full-text
Abstract
Adenoviruses (Ads) infect a broad range of tissue types, and derived vectors have been extensively used for gene therapy. Helper-dependent Ad vectors (HDAds), devoid of viral coding sequences, allow for insertion of large or multiple transgenes in a single vector and have been
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Adenoviruses (Ads) infect a broad range of tissue types, and derived vectors have been extensively used for gene therapy. Helper-dependent Ad vectors (HDAds), devoid of viral coding sequences, allow for insertion of large or multiple transgenes in a single vector and have been preclinically used for the study of genetic disorders. However, the clinical application of Ad vectors including HDAds for genetic disorders has been hampered by an acute toxic response. This characteristic, while disadvantageous for gene replacement therapy, could be strategically advantageous for the activation of an immune response if HDAds were used as an adjunct treatment in cancer. Cancer treatments including immunotherapy are frequently limited by the inhibitory environment produced by both tumors and their stroma, each of which express numerous inhibitory molecules. Hence, multiple inhibitory mechanisms must be overcome for development of anti-tumor immunity. The large coding capacity of HDAds can accommodate multiple immune modulating transgenes that could produce a combined effect to overcome tumor-derived inhibition and ensure intratumoral effector T-cell proliferation and function. In this review, we discuss the potential advantages of HDAds to cancer immunotherapy based on potent host immune responses to Ads. Full article
(This article belongs to the Special Issue Gene Therapy Used in Cancer Treatment)
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