Foreword


Editorial

Lentiviral vectors in hematopoietic stem cell therapies: mainstay technology, or simply a bridge to gene editing?

Spotlight Article

EDITORIAL

Marc Moore & John R Counsell

Critical Role of Automation in the Manufacture of Cell & Gene Therapies

Hematopoietic stem cells (HSCs) are quiescent progenitors to a range of blood and immune cell lineages with the propensity to repopulate these cellular niches. This makes them attractive as a cell-based therapy for lysosomal storage disorders [1,2], hemoglobinopathies [3] and primary immune deficiencies [4,5]. Indeed, allogenic identical HLA-matched HSC engraftment has been a mainstay therapeutic approach in the field since the 1960s. However, such cases of HLA matches are rare and finding suitably matched donor’s remains challenging. Furthermore, in many cases of allogenic HSC transplantation, acute graft versus host disease (GVHD) remains a significant concern. This has fuelled the shift towards use of autologous HSC engraftment, in which the patient’s own cells have functional gene expression restored ex vivo before reintroduction.

Published: 20 Nov 2018
DOI: 10.18609/cgti.2018.092
Citation: Cell Gene Therapy Insights; 2018; 4(10), 925-932.
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Interview

Capacity or capability? Getting your priorities right in viral vector manufacturing

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Interview

JAN THIRKETTLE

Latest Developments in Viral and Non-Viral Vector Manufacturing

Jan Thirkettle

JAN THIRKETTLE is Chief Development Officer at Freeline, a Syncona-funded start-up focussed on liver-directed AAV gene therapy. Jan has extensive experience in the development and deployment of novel platforms including natural product and enzyme derived NCEs, biologics and gene therapies. Prior to joining Freeline Jan led the establishment of GSK’s Cell & Gene Therapy platform and was responsible for CMC/supply for Strimvelis, the first ex vivo gene therapy to receive an EU Marketing Authorisation Application. He has held industry positions spanning from discovery to commercial manufacturing, but is most passionate about late-state development, new technology introduction and project delivery. Jan holds an MA in Chemistry and a PhD in Biological Chemistry from Oxford University.

DOI: 10.18609/cgti.2018.093
Citation: Cell Gene Therapy Insights 2018; 4(10),933-938
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Joined-up thinking: success criteria for tomorrow’s viral vector production platforms

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Interview

PHIL VANEK

the Latest Developments in Viral & Non-Viral Vector Manufacturing

Phil VAnek GE

Phil is General Manager of GE Healthcare’s Cell and Gene Therapy business development and strategy, a business formed to address the unique challenges of cell and gene therapy manufacturing and distribution. Prior to joining GE, Phil was Head of Business Development for Cell Therapy, and later Head of Innovation for Lonza’s life science business. Phil’s career has included a number of innovation, business and market development roles at Becton Dickinson, Invitrogen, and Life Technologies, as well as two start-up biotechnology companies in the Washington, DC area. Additionally, Phil was an Instructor for Johns Hopkins University Advanced Academic Programs teaching Biotechnology Marketing in the Masters of Biotechnology / MBA program. Phil received his Ph.D. in Biochemistry and Molecular Biology from Georgetown University Medical Center and subsequently held an IRTA fellowship at the National Cancer Institute in the Laboratory of Molecular Oncology and the Hollings Cancer Center in Charleston, South Carolina. Phil is an active board member of the Alliance for Regenerative Medicine and the ARM Foundation, as well as the Centre for Commercialization of Regenerative Medicine (CCRM) in Toronto. Additionally, Phil serves on several advisory boards in both not-for-profit and for-profit organizations and associations. Phil has published a number of industry position pieces and serves on the Editorial Board of Cell and Gene Therapy Insights.

DOI: 10.18609/cgti.2018.101

Citation: Cell Gene Therapy Insights 2018; 4(10),873-877.
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Applying learnings from the bioprocess development of Luxturna™

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Interview

J FRASER WRIGHT

the Latest Developments in Viral & Non-Viral Vector Manufacturing

J Fraser Wright

J Fraser Wright received his PhD in 1989 from the University of Toronto, Department of Biochemistry for work characterizing the interaction of complement with IgM, and completed post-doctoral studies at INSERM/CENG Grenoble, France in molecular immunology focused on antigen processing and presentation. He was awarded an CRCS/ MRC Scholarship gaining faculty appointment at the University of Toronto. In 1996 he moved to industry, first as a Scientist at Pasteur Sanofi working on the development of cancer immunotherapeutics, and then as Director of Development and Clinical Manufacturing at Avigen, a pioneering gene therapy company developing rAAV based investigational products for hemophilia and Parkinson’s Diseases. In 2004 he returned to academia, establishing the Clinical Vector Core at the Center for Cellular and Molecular Therapeutics at Children’s Hospital of Philadelphia, gaining faculty appointment at the University of Pennsylvania Perelman School of Medicine as professor of Pathology and Laboratory Medicine. Dr. Wright has contributed to several clinical development programs in gene therapy, including those for Luxturna and Kymriah, gene therapy products that were licensed in 2017, the first gene therapies for a genetic (RPE65 deficiency) and non-genetic (CAR-T immunotherapy) disease, respectively, approved in the United States. He is a Co-founder of Spark Therapeutics, served as Chief Technology Officer at Spark and subsequently Axovant Sciences, and is Principal at Wright Biologics Consulting.

DOI: 10.18609/cgti.2018.096

Citation: Cell Gene Therapy Insights 2018; 4(10), 969-976.
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Transmission Electron Microscopy: a Critical Component of the Vector Analytical Toolkit

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Interview

VANESSA CARVAHLO

Latest Developments in Viral and Non-Viral Vector Manufacturing

VANESSA CARVALHO is a Senior scientist at Vironova AB, Stockholm, Sweden. During her PhD at TUDelft, The Netherlands, she worked on membrane protein structural characterization using several electron microscopy techniques. Before her PhD Vanessa worked in different research groups mainly using protein purification and X-ray crystallography techniques. Vanessa has a master’s degree in molecular biology from the Aveiro University in Portugal and a bachelor degree in Anatomical Pathology from the Polytechnic Institute of Porto in Portugal. Her profound knowledge in structural biology and electron microscopy bring valuable contributions to the development of image analysis solutions and innovations at Vironova.

DOI: 10.18609/cgti.2018.084
Citation: Cell Gene Therapy Insights 2018; 4(10), 947-950.
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AAV meets exosomes: at the cutting edge of cardiovascular gene therapy

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Interview

ROGER HAJJAR

the Latest Developments in Viral & Non-Viral Vector Manufacturing

Roger Hajjar

Roger Hajjar is an internationally renowned scientific leader in the field of cardiac gene therapy for heart failure. His laboratory focuses on molecular mechanisms of heart failure and has validated the cardiac sarcoplasmic reticulum calcium ATPase pump, SERCA2a, as a target in heart failure, developed methodologies for cardiac directed gene transfer that are currently used by investigators throughout the world, and examined the functional consequences of SERCA2a gene transfer in failing hearts. His basic science laboratory remains one of the preeminent laboratories for the investigation of calcium cycling in failing hearts and targeted gene transfer in various animal models. The significance of Dr. Hajjar’s research has been recognized with the initiation and recent successful completion of phase 1 and phase 2 First-in-Man clinical trials of SERCA2a gene transfer in patients with advanced heart failure under his guidance and the start of an international phase 2b/3 trial (August 2012). This product would be the first gene therapy therapeutics for heart failure and would potentially benefit millions of patients.

DOI: 10.18609/cgti.2018.97

Citation: Cell Gene Therapy Insights 2018; 4(10), 877-881.
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Keeping viral vector manufacturing in-house: strategic considerations for gene therapy biotechs

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Interview

TIMOTHY J MILLER

Latest Developments in Viral and Non-Viral Vector Manufacturing

Tim Miller Abeona

TIMOTHY J MILLER PhD, is co-Founder, President and Chief Scientific Officer of Abeona Therapeutics Inc. He has over 20 years of business development, scientific research, product development and clinical operations expertise, with a focus on transitioning novel biotherapeutics through pre-clinical phases and Phase 3 human clinical trials. As a C-level executive in public and private companies, he has driven multiple inflection points through innovation and operational excellence in rare disease companies. Dr Miller was President and CEO of Red5 Pharmaceuticals from 2013 until 2015 and was CEO-in-Residence at BioEnterprise Inc. in 2015. He was Senior Director of Product Development at SironRX Therapeutics from 2010 to 2013. Between 1996 and 2010 Dr Miller held various positions at several biotech companies focusing on gene therapy and regenerative medicine. Dr Miller earned his PhD in Pharmacology with a focus on gene therapy/cystic fibrosis from Case Western University. He also holds a BS in Biology and MS in Molecular Biology from John Carroll University (Cleveland, OH, USA).

DOI: 10.18609/cgti.2018.095
Citation: Cell Gene Therapy Insights 2018; 4(10),965-968
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Scaling up gene therapy manufacturing for multinational pivotal trials & commercialization

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Interview

KRZYSZTOF REGULSKI

the Latest Developments in Viral & Non-Viral Vector Manufacturing

Krzysztof Regulski, PhD, is a CMC Manager at GenSight Biologics. He manages CMC activities and leads Process Development of GS030 Product associated to optogenetic therapy for retinitis pigmentosa. He has been working in biotechnology industry since 2007, having experience in Bioprocess and QC Methods Development & Validation, Technology Transfer to CMO’s and Project Management. Before joining GenSight Biologics, Dr. Regulski was formerly Head of Bioprocess and Analytical Development at Pherecydes Pharma (Romainville, France). He received his Master’s degree in Industrial Biotechnology from Poznan University of Life Sciences (Poland) and a PhD in Biochemistry and Microbiology from University of Paris-Sud (France).

DOI: 10.18609/cgti.2018.100

Citation: Cell Gene Therapy Insights 2018; 4(10), 1015-1018.
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Conference Insight

The Growing Promise of Gene Therapy Approaches

NIH/FDA August 20, 2018 Workshop Synopsis

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CONFERENCE INSIGHT

R Jude Samulski, Jacob M Smith, Joshua C Grieger, Ken Cornetta, Richard Snyder

the Latest Developments in Viral & Non-Viral Vector Manufacturing

Recently, the gene therapy community had a unique opportunity of assembling at the NIH August 20-21 for a workshop based on the “The Growing Promise of Gene Therapy Approaches.“ Timely & important presentations describing various research advances, transformative clinical observations, and programmatic efforts to support future initiatives were discussed with eager enthusiasm. We were extremely fortunate in that one session, (of which I was requested to chair) was completely dedicated to the topic of Gene Therapy Vector Production. This report provides an overview of the key discussion points and take-aways from this important meeting.
Published: Dec 8 2018
DOI: 10.18609/cgti.2018.104

Citation: Cell Gene Therapy Insights 2018; 4(10), 1043-1049.

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Expert Insight

Challenges and progress in lentiviral vector bioprocessing

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EXPERT INSIGHT

Eugenio Macchiarulo, Phil Bassett & Mark Dudley

Cell and gene therapies provide potential treatment alternatives to conventional medicine, opening a new era of targeted medicine for patients with cancers and rare diseases. Chimeric antigen receptor (CAR) T-cell therapies, some of which have been granted FDA approval, and TCR T-cell therapy, amongst which specific peptide enhanced affinity receptor (SPEAR) T cells are in Phase 1–2 trials, are two immunotherapy options that are shaping the future of medicine. In both CAR and TCR T-cell therapies, a patient’s own T cells are engineered ex vivo to express the therapeutic gene, often using lentiviral vectors. As a consequence, both approaches face similar process challenges in getting treatment to patients. Herein, we examine challenges and progress in lentiviral vector bioprocessing.

Submitted for peer review: Sep 5 2018 Published: Nov 30 2018 DOI:10.18609/cgti.2018.091
Citation: Cell Gene Therapy Insights 2018; 4(10), 915-925.
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Standardizing viral vector manufacture: maximizing production with the TRiP SystemTM

Spotlight Article

INNOVATOR INSIGHT

Dan Farley

the Latest Developments in Viral & Non-Viral Vector Manufacturing

The use of viral vectors to create novel gene- and cell-based medicines is now a reality. As gene therapy matures into a new era, the industry will need to adopt improvements to viral vector manufacturing to meet the demand for GMP grade material. The activities of process optimisation/characterisation with any given viral vector entering into clinical development are considerable. The cell culture (Upstream) and purification/concentration (Downstream) aspects of this process are multi-faceted. The amount of vector produced during Upstream can vary depending on the transgene encoded, especially if the active protein is expressed in the production cell when constitutive or leaky tissue specific promoters are employed. Oxford BioMedica has developed the Transgene Repression In vector Production (TRiP) System™ to recover vector titers compromised by transgene expression. The system utilises the bacterial protein TRAP and its short RNA binding sequence – inserted within the transgene leader sequence – to repress transgene mRNA translation during vector production only, leaving expression unaffected in target cells. The TRiP System™has been used to fully recover titers of Lenti-, Adeno- and AAV-based vectors, and is expected to be universally applicable to any viral vector/vaccine platform. We anticipate that the TRiP System™ will enable new gene therapies to be considered, and assist those already in development to become commercially viable. Given that only TRAP and the viral proteins of the vector platform being employed will be expressed during Upstream, the TRiP System™ opens the door to ‘plug-and-play’ manufacturing, greatly minimising the burden of process development within a given pipeline.

Submitted for review: Oct 15 2018 Published: Nov 30 2018
DOI:10.18609/cgti.2018.099
Citation: Cell Gene Therapy Insights 2018; 4(10), 983-994.
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Logistics by design: a framework for advanced therapy developers to create optimal Logistics Platforms

EXPERT INSIGHT

Simon Ellison*, Ryan McCoy*, Marc Bell, Kelly Frend & Stephen Ward

Advanced therapeutic medicinal products (ATMPs) are delivering a new wave of treatment options for unmet healthcare needs. Their impact however, will be severely truncated if supply chain infrastructure is unable to robustly and cost-effectively connect patient to product. Guaranteeing logistical success is becoming an ever-increasing focal point as the field rapidly delivers. Establishing a seamless development approach, including logistics, will be critical in delivering a successful commercial logistics strategy. Paramount to facilitating ATMP commercial realisation is a support structure for logistics planning. In this article we present ‘Logistics by Design’ (LbD) – a framework for logistics-based decision making, based in-part, on Quality by Design principles. This is accompanied by case studies that illustrate the value in applying LbD principles early in the development lifecycle, thereby de-risking the probability of logistics strategy failure.
* Joint First Authors

Submitted for review: Oct 8 2018 Published: Dec 6 2018

DOI: 10.18609/cgti.2018.102
Citation: Cell Gene Therapy Insights 2018; 4(10), 1019-1040.
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