Abstract
Lentiviral vectors are increasingly the gene transfer tool of choice for gene or cell therapies, with multiple clinical investigations showing promise for this viral vector in terms of both safety and efficacy. The third-generation vector system is well-characterized, effectively delivers genetic material and maintains long-term stable expression in target cells, delivers larger amounts of genetic material than other methods, is non-pathogenic and does not cause an inflammatory response in the recipient. This report aims to help academic scientists and regulatory managers negotiate the governance framework to achieve successful translation of a lentiviral vector-based gene therapy. The focus is on European regulations, and how they are administered in the United Kingdom, although many of the principles will be similar for other regions including the United States. The report justifies the rationale for using third-generation lentiviral vectors to achieve gene delivery for in vivo and ex vivo applications; briefly summarises the extant regulatory guidance for gene therapies, categorised as advanced therapeutic medicinal products (ATMPs); provides guidance on specific regulatory issues regarding gene therapies; presents an overview of the key stakeholders to be approached when pursuing clinical trials authorization for an ATMP; and includes a brief catalogue of the documentation required to submit an application for regulatory approval of a new gene therapy.
Highlights
THE ESTABLISHMENT OF GENE THERAPY as a clinical technique has provided a revolutionary approach to a wide range of previously untreatable diseases
In the case of gene therapies, study guidance is in line with normal pharmaceuticals provided by ICH M3.25 Toxicity should be assessed for the whole gene therapy medicinal product (GTMP), including the transgene product, any vector-related non-therapeutic gene products, and any impurities present in the viral preparation
A significant decrease in infectious titer was observed in lentiviral particles pseudo-typed with VSV-G when stored at 4°C instead of -80°C, with an approximately 50% reduction in functional titer every 3 days.[34]
Summary
THE ESTABLISHMENT OF GENE THERAPY as a clinical technique has provided a revolutionary approach to a wide range of previously untreatable diseases. The aim is to help to establish thirdgeneration lentivirus as a viral vector of choice for clinical applications in gene therapy by providing initial justification that such vectors can meet the standard principles for preclinical safety testing and providing a route for translational teams to collect information in order to risk assess a new GTMP.[25]. In the case of gene therapies, study guidance is in line with normal pharmaceuticals provided by ICH M3.25 Toxicity should be assessed for the whole GTMP, including the transgene product, any vector-related non-therapeutic gene products, and any impurities present in the viral preparation For this reason, it is best to run toxicity experiments on trial batches of viral vector identical to the intended clinical-grade product, produced by the same GMP manufacturing facility, and using the same GMP manufacturing platform.
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