Journal Archive

Editorial

Non-viral vectors for gene therapy

Editorial

Nejat Düzgüneş

Nejat_Duzgunes

Of the 2210 gene therapy clinical trials reported until July 2015, only 115 were carried out by the use of cationic lipid-mediated transfection or “lipofection” [1]. Some trials (387) employed plain plasmid DNA. Most of the trials utilized viral vectors, including adenovirus, adeno-associated virus, vaccinia virus, retroviruses and lentivirus, since they are considered to be highly efficacious compared to non-viral vectors in gene delivery. The immunogenicity of viral vectors, however, is a serious concern. The death of an 18-year-old patient with partial ornithine transcarbamylase deficiency who received 6 x 1011 particles/kg of adenovirus type 5 encoding human ornithine transcarbamylase led to reconsideration of the facile use of viral vectors [2,3]. Another consideration beyond the safety issue is the immunity developed against viral vectors that may preclude their repeated use.

DOI: 10.18609/cgti.2016.013
Citation: Cell Gene Therapy Insights 2016; 2(1), 1-3.
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Commercial Insights

Commercial Insight – February 2016

Alan Boyd, Mark Curtis & Rahul Sarugaser

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:

After a prolonged process, Astellas was successful in bringing its takeover bid of Ocata to a close this past month. Shareholders pushed back on several occasions in attempt to thwart the bid, requiring Astellas to extend the period within which shareholders could tender shares on two occasions. Ultimately, a majority of shareholders accepted the $8.50 per share offered by Astellas, giving them a 79% premium to market as of the day the bid was announced. Shareholders argued the offer didn’t reflect additional assets in the Ocata portfolio outside the core focus on ophthalmology. Ocata was one of the original pioneers in the RM space, having setup shop in the mid 90’s. Despite a few bumps in the road the company endured more than 20 years. The acquisition by Astellas, while met with some resistance, will hopefully ensure Ocata’s assets are developed swiftly and brought to market.

GENE THERAPY:

Funding continues to be a hot-topic again this month and the recent IPOs in New York from both AveXis and Proteostasis have shown that the IPO window is still just about open. The other piece of financial news was that Renova Therapeutics has just received a substantial grant from the NIH to support its gene therapy development in heart failure. There is much debate about whether it is best to still try for an IPO at this time or wait till the markets improve, but I think this news from these three companies still shows that as a growing company you will take funding from wherever you can get it despite the difficulties. If the IPO window does firmly get closed off for the while, companies should not forget that grants are a good alternative source too.

DOI: 10.18609/cgti.2016.005
Citation: Cell Gene Therapy Insights 2016; 2(1), 5-18.
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Clinical Trial Insights


Interview

Dr James Shapiro: the hype, hope & reality of cell therapy for diabetes

Video Interview

Dr James Shapiro was born in Leeds, England, son of a family doctor. He studied Medicine in Newcastle and trained in Surgery in Bristol. He developed a longstanding interest in islet transplantation as a medical student. He has been on Faculty at the UofA since 1998. James led the team that developed and tested the “Edmonton Protocol” and was the lead author on their seminal NEJM paper in 2000. This protocol revolutionized the treatment for Type 1 Diabetes, as for the first time a series of patients were able to completely stop their life-sustaining insulin injections. He is currently leading a National Canadian project in ex vivo organ transplant repair and has active clinical trials in Edmonton evaluating caspase inhibitors and new subcutaneous devices for islet transplantation. He is leading diabetes clinical trials in stem cell transplantation and regenerative medicine.

DOI: 10.18609.cgti.2016.015
Citation: Cell Gene Therapy Insights 2016; 2(1), 37-43.
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Obituary


Conference Insight

Cell and Gene Therapy World

Emily Culme-Seymour, Alexey Bersenev & Colin Lee Novick

CONFERENCE INSIGHT

Washington DC Phacilitate cell and gene therapy conference

On January 28, 2016, the National Oceanic and Atmospheric Administration announced that the January 22–24 snowstorm that hammered the US Eastern shoreline, was a Category 4 (or “Crippling”) on their Northeast Snowfall Impact Scale and that it was also the fourth largest to impact the northeast of the United States since 1950. Among the major metropolitan areas that were affected, the nation’s capital, Washington DC, was one of the hardest hit. The Phacilitate Cell & Gene Therapy World 2016 event, which had been set to take place in DC on January 25–27, caught the aftermath of the storm on the chin and due to some extraordinary work by the event organizers, Washington DC city officials, and the numerous attendees who braved the weather, the event got underway.

DOI: 10.18609.cgti.2016.011
Citation: Cell Gene Therapy Insights 2016; 2(1), 23-36
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Expert Insight

Spotlight on the cell & gene therapy manufacturing pathway

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Chris Mason & Elisa Manzotti

Foreword

The cell and gene therapy sector has recently seen an influx of investment and interest from Big Pharma and venture capital companies, in part due to the promising early clinical data from immunotherapies such as CAR T cells and engineered T cells. However, a number of key questions and challenges remain on the path to successful commercialization.

DOI: 10.18609/cgti.2016.017
Citation: Cell Gene Therapy Insights 2016; 2(1), 75-76.Open access

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Evolving product attributes through the lens of MSC translation

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Robert Deans

EXPERT INSIGHT

Mesenchymal stem cell therapeutics have entered the home stretch for market approval, with academic and corporate sponsors reporting mid- to late-phase clinical results which will be highly impactful on commercialization of this product class. How well have translational expectations been borne out? Are there lessons learned from a retrospective perspective that can improve or accelerate successful development? Have baseline product attributes been forecast accurately? This discussion emphasizes the dynamic state of product attributes and integrating bedside-to-bench clinical data, and as well identifies the value of product attributes tied to investment and capital needs to bring these therapies to standard of care.

Submitted for review: Feb 18 Published: Mar 21 2016; DOI: 10.18609.cgti.2016.010
Citation: Cell Gene Therapy Insights 2016; 2(1), 77-83.
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Drivers and methodologies for making cell therapy process changes

Spotlight Article

Gregory Russotti

EXPERT INSIGHT

Cell therapies are a new and exciting modality with the potential to treat a variety of severe unmet medical needs. Although the types of cell therapies currently in clinical development encompass a wide range of cell types with various functions, they all can be classified as highly complex biological products that are challenging to characterize. As is the case with all complex biological products, the processes by which they are produced, to some degree, define the product such that process changes must be highly scrutinized before they can be implemented. In order to make process changes for a cell therapy product, one must employ a combination of strong analytical tools, a thorough understanding of how the cell is intended to function as a therapy, detailed process characterization which elucidates how process parameters affect product attributes, and sound engineering principles to understand how the chemical and physical parameters of the process can be controlled to yield a comparable product after the process change.

Submitted: January 7 2016 Published: March 21 2016; DOI: 10.18609.cgti.2016.003
Citation: Cell Gene Therapy Insights 2016; 2(1), 85-94.
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Centralized or decentralized manufacturing? Key business model considerations for cell therapies

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Nicholas Medcalf

expert insight

The choice of manufacturing strategy for cell-based therapeutics is one that is best made early in product development. Expense and delay may result from any additional bridging studies following changes to manufacturing process design late in development. The chosen strategy will be strongly influenced in turn by the preferred business model. Business models may favor either centralized or distributed manufacture. There are advantages and disadvantages to each and variants may be suitable in certain circumstances. An appropriate choice depends upon a combination of regulatory, economic and supply-chain factors. In this article the factors are examined and described in the context of hypothetical examples. In general the degree of decentralization will depend on a balance of manufacturing features. The investment risk of building a centralized facility at the projected capacity, the cost of managing quality and the cost or quality implications of long-distance cold supply chains must be considered. No single business model will suit all cases. For any innovation the decision must be based on an operational analysis at the projected capacity required.

Submitted for review: Dec 1 2015 Published: Mar 21 2016
DOI: 10.18609.cgti.2016.012; Citation: Cell Gene Therapy Insights 2016; 2(1), 95-109
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Translational cell & gene therapy collaborations: accelerating time to market

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Cindy Collins

INNOVATOR INSIGHT

In recent years, cell and gene therapies have moved out of the realm of science fiction and now seem within reach. Indeed, they have made remarkable progress as novel medicines for effective, personalized treatment of some of today’s most difficult diseases, extending the potential and promise of precision medicine. In addition to the not-insignificant scientific obstacles of delivering safe and effective treatments, there is also the challenge of cost efficient production and logistics that now needs to be addressed through scaling, automation, and continuous process improvement. These and other factors will determine the success of effectively translating these remarkable therapies from the clinic to the mainstream. At GE, we’re working to bring all of these solutions together to help our customers focus on delivering the best possible therapies to market.

Published: Mar 21 2016
DOI: 10.18609.cgti.2016.009; Citation: Cell Gene Therapy Insights 2016; 2(1), 111-114
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Cell and gene therapy manufacturing: the necessity for a cost-based development approach

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Sarah Callens, Jahid Hasan, Ryan McCoy & Stephen Ward

EXPERT INSIGHT

“Money does not grow on trees, but it does make the world go round!”
Whilst you don’t have to be a botanist to appreciate the first half of this statement, it is only the purest of physicists that will disagree with the latter. The world of drug development, of which cell and gene therapies currently represent the forefront of scientific, clinical and business activity, is an expensive undertaking (where money trees are few and far between). Moreover, global healthcare providers have never been under greater pressure to reduce expenditure in order to meet ever decreasing budgets and an ever increasing patient population. So, whilst addressing unmet clinical needs or improving clinical efficacy does and should remain the primary driver of novel cell and gene therapy development, the expense of implementing such therapies from a manufacturing, logistical and clinical perspective is coming under greater scrutiny and mounting importance – the era of cost-based development is upon us and is central to the approach of the Cell and Gene Therapy Catapult.

Published: Mar 21 2016
DOI: 10.18609.cgti.2016.014; Citation: Cell Gene Therapy Insights 2016; 2(1), 115-120.
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Future Leader Perspective

Toward a scalable and consistent manufacturing process for the production of human MSCs

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Qasim A Rafiq

Future leader perspective

The development of novel, affordable and efficacious therapeutics will be necessary to ensure the continued progression in the standard of global healthcare. With the potential to address previously unmet patient needs as well as tackling the social and economic effects of chronic and age-related conditions, cell therapies will lead the new generation of healthcare products set to improve health and wealth across the globe. However, if many of the small to medium enterprises (SMEs) engaged in much of the commercialization efforts are to successfully traverse the ‘Valley of Death’ as they progress through clinical trials, there are a number of challenges that must be overcome. No longer do the challenges remain biological but rather a series of engineering and manufacturing issues must also be considered and addressed.

DOI: 10.18609.cgti.2016.008; Citation: Cell Gene Therapy Insights 2016; 2(1), 127-140
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Key considerations in optimizing pluripotent stem cell bioprocessing

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Iwan Roberts

future leader perspective

In the same paper in which the first successful derivation of human pluripotent stem cells was reported, they were already being postulated as a potentially unlimited source of cell transplantation material [1]. In the following years, an entire research field has evolved to seek ways to control and harness the complexity of PSCs, which has resulted in a slow but steady progression towards the clinic. Now it is the turn of bioprocess development to adapt existing tools and technologies, or develop totally novel approaches, to ensure the promise of these therapies can finally be delivered in a safe, efficacious and affordable manner.

Published: Mar 21 2016
DOI: 10.18609.cgti.2016.016; Citation: Cell Gene Therapy Insights 2016; 2(1), 131-136.
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Research Article

Characterization of Rhesus Macaque lung-resident multipotent stromal cells

Ryan W Bonvillain, Michelle E Scarritt, Nicholas C Pashos, Deborah E Sullivan, Aline M Betancourt, Fern Tsien, Ayesha P Umrigar, Andrew M Hoffman and Bruce A Bunnell

Research Article

Current lung regeneration strategies focus on the airway epithelium, pulmonary endothelium, and their putative progenitors; however, the supportive pulmonary stroma has been widely overlooked. Tissue-resident multipotent mesenchymal stem cells have recently been identified in a host of mammalian tissues including the lungs. In this report, we isolated lung-resident mesenchymal stromal cells from the non-human primate, rhesus macaque. These cells expressed cell surface markers consistent with those expressed by mesenchymal stem cells isolated from bone marrow, and they also demonstrated variable degrees of differentiation into bone, adipose, and cartilage. When cultured on Matrigel, the cells formed tubules, and when cultured on decellularized macaque lung scaffolds, the cells attached to the matrix with minimal apoptosis observed. Given the ease of isolation, characteristics similar to other mesenchymal stem cells, and engraftment to decellularized lung scaffolds, lung-resident mesenchymal stromal cells may be valuable in tissue engineering applications as well as other therapeutic strategies that employ mesenchymal stem cells.

Submitted for Review: Jul 27 2015; Published: Mar 21 2016 ; DOI: 10.18609.cgti.2016.002
Citation: Cell Gene Therapy Insights 2016; 2(1), 49-72.
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