Progress and challenges in viral vector manufacturing

Abstract

Promising results in several clinical studies have emphasized the potential of gene therapy to address important medical needs and initiated a surge of investments in drug development and commercialization. This enthusiasm is driven by positive data in clinical trials including gene replacement for Hemophilia B, X-linked Severe Combined Immunodeficiency, Leber's Congenital Amaurosis Type 2 and in cancer immunotherapy trials for hematological malignancies using chimeric antigen receptor T cells. These results build on the recent licensure of the European gene therapy product Glybera for the treatment of lipoprotein lipase deficiency. The progress from clinical development towards product licensure of several programs presents challenges to gene therapy product manufacturing. These include challenges in viral vector-manufacturing capacity, where an estimated 1-2 orders of magnitude increase will likely be needed to support eventual commercial supply requirements for many of the promising disease indications. In addition, the expanding potential commercial product pipeline and the continuously advancing development of recombinant viral vectors for gene therapy require that products are well characterized and consistently manufactured to rigorous tolerances of purity, potency and safety. Finally, there is an increase in regulatory scrutiny that affects manufacturers of investigational drugs for early-phase clinical trials engaged in industry partnerships. Along with the recent increase in biopharmaceutical funding in gene therapy, industry partners are requiring their academic counterparts to meet higher levels of GMP compliance at earlier stages of clinical development. This chapter provides a brief overview of current progress in the field and discusses challenges in vector manufacturing.

Current challenges in biotherapeutic particles manufacturing

“…production as well as the high costs of the high-quality DNA and transfection reagents that are required. This leads to the evaluation of stable producer cell lines as an alternative for viral vectors production [11], that is also challenging since the virus themselves are toxic to the producer cells. Tomás et al recently developed a new lentivirus stable producer cell line -LentiPro26-A59, that constitutively produces titres above 10 6 TU.mL −1 .day −1 , aiming for clinical gene therapy applications [12].…”

Novel approaches to hemophilia therapy: successes and challenges

“…A promising strategy has to consider both the prevalence of NAbs to the vector capsid and the vector therapeutic dose, because the latter will impact both the rates of capsid-mediated immune responses and the manufacturing limitations associated with large-scale production. 71 Transient immunosuppression may not be efficacious in some situations as reported. 61 A better understanding of why the capsid-mediated toxicity occurs at significantly different vector doses for a given AAV serotype is needed.…”

Targeting Splicing in the Treatment of Human Disease

“…Problems with scaling up production processes and high economic costs are also barriers that need to be improved when considering viral vectors to treat diseases. Several recent reviews covering specific aspects of the use of viral vectors for gene therapy have been published elsewhere [75,79,80]. Aspects such as the insert size, time-course of transgene expression, route administration, and gene targeting are of primary importance when choosing the right viral vector.…”