Journal Archive

Editorial

The road to gene therapy for recessive dystrophic epidermolysis bullosa

Editorial

M Peter Marinkovich, Ngon T Nguyen & Zurab Siprashvili

MullerKleinHeckmann

The road towards development of an optimal gene therapy for recessive dystrophic epidermolysis bullosa has been long and many lessons have been learned along the way. This editorial highlights the key advances and challenges in the field as it progress towards clinical translation.

DOI: 10.18609/cgti.2017.011
Citation: Cell Gene Therapy Insights 2017;3(2),75-81.
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Cell and gene therapy: scaling up and moving to mass production

Nigel Whittle, Sagentia

Editorial

Nigel Whittle

There is tremendous clinical promise in the application of therapies based on administering cells to patients to treat a wide range of diseases. In order to fulfil this promise, it is important that manufacture of these therapies can be ‘industrialized’ through transfer into a commercial setting in a scalable and cost-effective manner. This editorial provides an overview of the key challenges and new opportunities for the successful commercialization of cell therapies.

DOI: 10.18609/cgti.2017.010
Citation: Cell Gene Therapy Insights 2017;3(2): 329-333.

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Commercial Insights

Cell & Gene Therapy Commercial Insight – February 2017

Mark Curtis & Richard Philipson

Providing a critical overview of the sector’s commercial developments – M&As, licensing agreements & collaborations, financial results, IPOs and clinical/regulatory updates, with commentary from our Expert Contributors.

CELL THERAPY:

Kite Pharma delivered new pivotal data this month that showed that there was a limited drop in complete response rate between 3 and 6 months in ZUMA-1, a study investigating lead candidate axicabtagene ciloleucel in patients with aggressive NHL. While there was a substantial drop in complete response rate in the first 3 months of the study, this decline softened over time, adding some confidence the therapy can be a cure for this form of lymphoma. While more follow-up will be required to substantiate durability, it certainly strengthens the case for approval at the FDA. While Kite’s launch of its first autologous CAR product becomes imminent, other developments continue to appear in off-the-shelf approaches to cell-based immunotherapy.

GENE THERAPY:

Exciting news this month in the field of hereditary muscle diseases! A collaboration led by the University of Washington has demonstrated preclinical proof of concept for systemically delivered, AAV-based gene therapy in dogs with X-linked myotubular myopathy. In addition, there is good news for boys with Duchenne muscular dystrophy, with Exonics announcing the award of seed funding to support preclinical development of its CRISPR/Cas9 technology, which could offer a one-off, curative treatment for the disease. Other interesting developments include the award of Breakthrough Therapy designation by FDA for UniQure’s AAV-5 treatment for hemophilia B, based on emerging clinical data from its ongoing, dose-ranging Phase 1–2 study. It’s always encouraging to receive ‘validation’ of clinical data from a regulatory authority with this type of designation!

DOI: 10.18609/cgti.2017.019
Citation: Cell Gene Therapy Insights 2017; 3(2), 83-94.

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Expert Insight

Next-generation gene therapy vectors: alternative approaches to vector design and application

Spotlight Article

Foreword

Next-Generation Vectors

Richard P Harbottle

Richard-Harbottle

This issue of Cell and Gene Therapy Insights will focus on alternative next-generation vectors for gene therapy and the genetic modification of cells. Rather than discussing the use of attenuated viruses, which are the most commonly used vector system, this issue comprises reviews and commentary on a range of alternative vectors that are being developed and which provide properties, capabilities and utility not available with typically used retrovirus and lentivirus, adenovirus or adeno-associated virus vectors.

DOI: 10.18609/cgti.2017.015
Citation: Cell Gene Therapy Insights 2017;3(2),159-164.
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Recent advances in non-viral vectors for gene therapy & vaccination

Spotlight Article

Editorial

Next-Generation Vectors

Clague P Hodgson, Aaron E Carnes & James A Williams

MullerKleinHeckmann

While the majority of gene therapy vectors are derived from viruses, their use introduces the issues of immunogenicity, carcinogenicity, insertional mutagenesis and reversion to replication competency. In addition, viral vectors often come with manufacturing bottlenecks such as scalability and processing. In order to avoid the problems associated with viral vectors, investigators turn to the use of naked DNA, usually in the form of non-integrating bacterial plasmids, which have now been used in 427 clinical trials.

DOI: 10.18609/cgti.2017.012
Citation: Cell Gene Therapy Insights 2017;3(2),95-101.
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Minicircles: next-generation gene vectors

Spotlight Article

Expert Insight

Ram Shankar, Marco Schmeer & Martin Schleef

Next Generation Vectors

Plasmid DNA is commonly used in vaccination, cell and gene therapy, and as a basic substance in viral vector and RNA production. Backbone sequences in a plasmid vector are only needed for amplification in bacterial cultures. Since the uncontrolled expression of these sequences may have profound detrimental effects, for example, the dissemination of antibiotic resistance genes, an important goal in vector development is to produce supercoiled DNA lacking such bacterial backbone sequences. One elegant approach is minicircle (MC) DNA, consisting almost only of (therapeutically) active gene cassette. Over the past few years, MCs have proven to be a reliable tool for efficient transgene expression in eukaryotic cells both in vitro and in vivo as well as for ex vivo modification for cell therapy or lately even for the generation of induced pluripotent stem cells. Recent trends and progress in pre-clinical studies suggest that the time has come for preparation of such minimalistic vectors to a High Quality Grade to enable for example the production of viral vectors for gene therapy. Furthermore, significant developments in transfection efficiency of non-viral vectors suggest that GMP grade MCs conformant to regulatory guidelines would be needed in the near future for direct clinical applications. This article provides an overview of the advantages and drawbacks of different approaches to produce MC DNA, their applications, and finally describe current and future developments.

Submitted for review: Feb 28 2017 Published: June 6 2017
DOI: 10.18609/cgti.2017.020
Citation: Cell Gene Therapy Insights 2017;3(2), 285-300.
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Non-viral gene transfer with Sleeping Beauty system to engineer T cells for hematologic malignancies and solid tumors

Spotlight Article

Expert Insight

Hiroki Torikai, Judy S Moyes & Laurence JN Cooper

Next generation vectors

The manipulation of genes has progressed to human application thanks in part to viral-based vectors that transduce a therapeutic gene and sustain its long-term expression. The adoptive transfer of genetically modified T cells against cancer highlights the potential for gene therapy to cure human disease refractory to conventional therapy. The improvements in the genetic manipulation of clinical-grade cells has widened possible treatment options with the realization that personalized gene therapy will be needed in which the introduced gene matches the needs of a particular patient. To match this growing need for individualized therapeutic genes, we have developed a rapid, robust and low-cost approach for clinical translation. This is based on a DNA plasmid-based transposon/transposase, termed the Sleeping Beauty (SB) system. The SB system stably introduces therapeutic genes, such as chimeric antigen receptors (CARs), into clinical-grade T cells and allows for long-term expression of the introduced transgene. Our first-in-human clinical trial of SB-mediated CAR-expressing T cells targeting B-cell malignancies established the safety, feasibility and efficacy of the SB system. This clinical application of the SB system is the foundation for future use of this tool to personalize genetically modified T cells targeting hematologic malignancies and especially solid tumors.

Submitted for review: Mar 13 2017 Published: May 25 2017
DOI: 10.18609/cgti.2017.017
Citation: Cell Gene Therapy Insights 2017;3(2), 301-311.
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Sleeping Beauty transposon vectors for therapeutic applications: advances and challenges

Spotlight Article

Expert Insight

Suneel A Narayanavari & Zsuzsanna Izsvák

Next-Generation Vectors

Transposable elements are natural, non-viral gene delivery vehicles capable of mediating stable genomic integration. The Sleeping Beauty (SB) transposon has the ability to cut-and-paste the ‘gene of interest’ into the genome, providing the basis for long-term, permanent transgene expression in transgenic cells and organisms. The SB transposon system is relatively well characterized, and has been extensively engineered for efficient gene delivery and gene discovery purposes in a wide range of vertebrates, including humans. The SB system is a safe and simple-to-use vector that enables cost-effective, rapid preparation of therapeutic doses of cell products. Recently, there has been a growing interest in using the SB system for therapy as evidenced by the large number of pre-clinical studies. SB moved swiftly from pre-clinical to clinical trials in almost a decade. In this article, we highlight the advancements and challenges associated with the SB system in various therapeutic applications. We also provide an overview that has been exploited by spin-off companies based on the SB system.

Submitted for review: Feb 21 2017 Published: Mar 30 2017
DOI: 10.18609/cgti.2017.014
Citation: Cell Gene Therapy Insights 2017;3(2),131-158.
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Specifically integrating vectors for targeted gene delivery: progress and prospects

Spotlight Article

Expert Insight

Adrian Kovač & Zoltán Ivics

Next-Generation Vectors

Integrating vectors based on viruses or transposons are efficient gene delivery vehicles and promising tools for gene therapy. While different vector systems have different preferences and biases when it comes to target site selection, integration can always occur at vast numbers of potential sites throughout the human genome. This can result in unpredictable expression of the transgene (position effects), and can disrupt host genes or regulatory elements (genotoxicity), thereby potentially causing malignant transformations. Our knowledge about the natural target site selection properties of these gene insertion systems can be translated into artificial, experimental retargeting with the goal of introducing a bias into their insertion profiles. Here, we provide an overview of naturally occurring targeting mechanisms of viruses and transposons, and of the different molecular strategies that have been followed to manipulate their target site selection to derive stably integrating vectors with enhanced safety profiles.

Submitted for review: Jan 13 2017 Published: Mar 30 2017
DOI: 10.18609/cgti.2017.013
Citation: Cell Gene Therapy Insights 2017;3(2),103-123.
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Advances in the development of parvovirus-based anti-cancer therapies

Spotlight Article

Interview

Next-Generation Vectors

Dr. Antonio Marchini

Avery-Posey

Antonio Marchini is a Principal Investigator at the German Cancer Research Center (DKFZ, Heidelberg, Germany) and Head of the Laboratory of Oncolytic Virus Immuno Therapeutics (LOVIT), a newly established joint research unit between the Luxembourg Institute of Health and DKFZ. His team focuses on the development of new anticancer strategies based on oncolytic autonomous parvoviruses (PVs) with the ultimate goal to move them into the clinic. Major areas of research are: i) generation of innovative oncolytic vectors: retargeted PVs, chimeric vectors of adenovirus-PV genomes, PVs expressing sh/miRNAs; ii) design and assessment of novel combination therapies using PVs together with other anticancer agents such as apoptosis inducers, immune checkpoint blockade and/or epigenetic modulators of gene expression. He earned his PhD at the University of Heidelberg in 2001, working on the identification of new cellular proteins interacting with human papillomavirus 16 E7 oncoprotein. Before becoming Principal Investigator, he worked as a Postdoc Scientist at the University of Heidelberg on the characterization of the cellular functions of the SHOX homeodomain protein.

DOI: 10.18609/cgti.2017.016
Citation: Cell Gene Therapy Insights 2017; 3(2),125-130.
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