Special Issue "Feature Papers"

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A special issue of Biomedicines (ISSN 2227-9059).

Deadline for manuscript submissions: closed (31 October 2013)

Special Issue Editor

Guest Editor
Prof. Dr. Kenneth Cornetta (Website)

Department of Medical and Molecular Genetics, Indiana University School of Medicine, USA
Interests: gene therapy; lentiviral vectors; retroviral vectors; safety of gene therapy; vector production and certification

Special Issue Information

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. For the first couple of issues the Article Processing Charge (APC) will be waived for well-prepared manuscripts. English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Published Papers (7 papers)

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Research

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Open AccessArticle Development and Evaluation of Quality Metrics for Bioinformatics Analysis of Viral Insertion Site Data Generated Using High Throughput Sequencing
Biomedicines 2014, 2(2), 195-210; doi:10.3390/biomedicines2020195
Received: 25 September 2013 / Revised: 26 March 2014 / Accepted: 28 April 2014 / Published: 6 May 2014
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Abstract
Integration of viral vectors into a host genome is associated with insertional mutagenesis and subjects in clinical gene therapy trials must be monitored for this adverse event. Several PCR based methods such as ligase-mediated (LM) PCR, linear-amplification-mediated (LAM) PCR and non-restrictive (nr) [...] Read more.
Integration of viral vectors into a host genome is associated with insertional mutagenesis and subjects in clinical gene therapy trials must be monitored for this adverse event. Several PCR based methods such as ligase-mediated (LM) PCR, linear-amplification-mediated (LAM) PCR and non-restrictive (nr) LAM PCR were developed to identify sites of vector integration. Coupling the power of next-generation sequencing technologies with various PCR approaches will provide a comprehensive and genome-wide profiling of insertion sites and increase throughput. In this bioinformatics study, we aimed to develop and apply quality metrics to viral insertion data obtained using next-generation sequencing. We developed five simple metrics for assessing next-generation sequencing data from different PCR products and showed how the metrics can be used to objectively compare runs performed with the same methodology as well as data generated using different PCR techniques. The results will help researchers troubleshoot complex methodologies, understand the quality of sequencing data, and provide a starting point for developing standardization of vector insertion site data analysis. Full article
(This article belongs to the Special Issue Feature Papers)
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Review

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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 1 | 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 [...] Read more.
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 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 1 | 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 [...] Read more.
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 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
Cited by 3 | PDF Full-text (342 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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 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 [...] Read more.
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 Decoding the Pluripotency Network: The Emergence of New Transcription Factors
Biomedicines 2013, 1(1), 49-78; doi:10.3390/biomedicines1010049
Received: 23 October 2013 / Revised: 10 December 2013 / Accepted: 11 December 2013 / Published: 16 December 2013
Cited by 1 | PDF Full-text (275 KB) | HTML Full-text | XML Full-text
Abstract
Since the successful isolation of mouse and human embryonic stem cells (ESCs) in the past decades, massive investigations have been conducted to dissect the pluripotency network that governs the ability of these cells to differentiate into all cell types. Beside the core [...] Read more.
Since the successful isolation of mouse and human embryonic stem cells (ESCs) in the past decades, massive investigations have been conducted to dissect the pluripotency network that governs the ability of these cells to differentiate into all cell types. Beside the core Oct4-Sox2-Nanog circuitry, accumulating regulators, including transcription factors, epigenetic modifiers, microRNA and signaling molecules have also been found to play important roles in preserving pluripotency. Among the various regulations that orchestrate the cellular pluripotency program, transcriptional regulation is situated in the central position and appears to be dominant over other regulatory controls. In this review, we would like to summarize the recent advancements in the accumulating findings of new transcription factors that play a critical role in controlling both pluripotency network and ESC identity. Full article
(This article belongs to the Special Issue Feature Papers)
Open AccessReview Beyond Gene Delivery: Strategies to Engineer the Surfaces of Viral Vectors
Biomedicines 2013, 1(1), 3-16; doi:10.3390/biomedicines1010003
Received: 4 November 2013 / Revised: 22 November 2013 / Accepted: 26 November 2013 / Published: 4 December 2013
PDF Full-text (448 KB) | HTML Full-text | XML Full-text
Abstract
Viral vectors have been extensively studied due to their great transduction efficiency compared to non-viral vectors. These vectors have been used extensively in gene therapy, enabling the comprehension of, not only the advantages of these vectors, but also the limitations, such as [...] Read more.
Viral vectors have been extensively studied due to their great transduction efficiency compared to non-viral vectors. These vectors have been used extensively in gene therapy, enabling the comprehension of, not only the advantages of these vectors, but also the limitations, such as the activation of the immune system after vector administration. Moreover, the need to control the target of the vector has led to the development of chemical and non-chemical modifications of the vector surface, allowing researchers to modify the tropism and biodistribution profile of the vector, leading to the production of viral vectors able to target different tissues and organs. This review describes recent non-genetic modifications of the surfaces of viral vectors to decrease immune system activation and to control tissue targeting. The developments described herein provide opportunities for applications of gene therapy to treat acquired disorders and genetic diseases and to become useful tools in regenerative medicine. Full article
(This article belongs to the Special Issue Feature Papers)
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