Bioprocessing and Bioproduction Trends in Cell and Gene Therapies

Cell and gene therapies hold great promise for treating human diseases, for which current therapeutics are lacking. However, the research and development process for delivering these therapies to the clinic is complex, comprising various bioprocessing and bioproduction steps that must be fulfilled and optimized to ensure the safety and efficacy of the final product. The process continues to evolve to meet increasing demand and to overcome unexpected obstacles, such as the impact of the COVID-19 global pandemic on supply chains and manufacturing efforts in the biotech and biopharma industries.

在这次采访中捷克葡萄牙直播Teknova首席科学官Neal Goodwin博士与尼尔·古德温（Neal Goodwin）进行了交谈，以了解有关细胞和基因治疗领域中当前的生物处理和生物生产趋势的更多信息。古德温还讨论了COVID-19大流行对生物制药部门的影响，并强调了该行业在这个关键时期如何团结起来为疫苗开发做出贡献。

Molly Campbell (MC): You have 20 years of experience working in biotechnology and therapeutics. Can you talk about the evolution of the field through this time?

Neal Goodwin (NG):It has been a great 20 years! The human genome release is one of the most dramatic events during those 20 years. Once we had the human genome at our disposal, the field burgeoned. We've seen targeted therapeutics make a significant impact in personalized healthcare – imatinib, erlotinib, and the new KRAS inhibitors, among other targeted therapeutics for oncology, come to mind. Also, the first immuno-oncology therapeutics are now positively affecting large numbers of patients – which is terrific.

The ability to move into gene therapy and address severe genetic disorders and conduct gene replacement therapy is fantastic. The progress in gene delivery viral vectors and non-viral nanoparticle delivery contributed to the rapid advancement of prominent COVID-19 vaccines. The mRNA-based vaccines and non-viral nanoparticle-based gene delivery technologies have validated a promising approach to gene therapy that is being expanded to rare genetic diseases. The ability to mass-produce mRNA vaccines demonstrated the feasibility of mRNA treatments and gene therapies for more widespread use for treating broader therapeutic targets and conditions.

MC: Can you talk to us about some of the current trends you are seeing in the bioprocessing and bioproduction space?

ng：First of all, there is a considerable demand for bioprocessing and commercial production of viral and non-viral vectors.These efforts must support what is now well over 1,000 clinical development programs in gene therapy alone. There is a need to develop better individualized processes that are readily scalable for GMP production matched to specific therapeutics. This effort will require the implementation of new strategies, new technologies, and increased global manufacturing capacity. It is an exciting place to be, but there is a great deal of development left to achieve streamlined processes and optimized capacity.

MC：细胞和基因疗法是关键的新兴市场。从实验室到临床测试并最终授权，开发这些产品时存在哪些主要挑战？

ng：有很多要求 - 我将尝试将它们缩小到一些基本要点。一些自体细胞疗法要求细胞进行基因修饰的离体。这种遗传修饰通常是用病毒载体进行的，至关重要的方面是基因（即活性药物成分）向细胞的递送。需要更先进的慢病毒矢量系统，这些系统可用于全身基因输送。

Among the non-cellular gene delivery segment, adeno-associated virus (AAV) vector gene delivery is the most widely used viral gene delivery platform. AAV production relies on the efficient expression in human cell lines of plasmids that encode viral packaging, capsid and replication genes, and expression plasmids encoding the therapeutic gene. One of the drawbacks of AAV vectors employed for gene therapy is they generally cannot deliver larger gene fragments required for optimal treatments. So, better viruses or non-viral gene delivery systems are needed.

In turn, choosing the best cell manufacturing conditions that provide the most efficient viral vector production is essential. A key challenge is how to scale up with reproducibility and efficiency.

MC: How can we look to overcome the challenge of scale-up in cell and gene therapies?

ng：由于治疗程序各自不同，因此对单个程序的适应过程至关重要。一些策略专注于将基因递送到自体细胞或同种异细胞中，这些细胞被扩展并移植到患者中.相比之下，other strategies require direct delivery of viral or non-viral gene therapy products into patients. In viral gene delivery, matching the most suitable virus to achieve the best target tissue tropism is essential. To date, AAV has been successfully used in two FDA-approved gene therapies, with many in advanced clinical trials. Traditionally, there have been few available AAV serotypes available for gene delivery. However, now we can use a directed evolution approach to manipulate and generate AAV capsids that have better target tissue tropism with reduced host immunogenicity.

Concerning AAV production, the purification processes of viruses need optimized, which is a focus of Teknova. We are barcoding different AAV serotypes with specific processes to achieve higher purity and viral vector yield.

MC: How has the COVID-19 impacted the biotech sector?

ng：COVID-19 motivated and united the biotech sector. It remains a worldwide effort where enormous challenges are being addressed rapidly and collaboratively. The field appears more collaborative, almost cheering once competitive firms and laboratories. Teknova experienced this by retooling and supplying GMP viral transport media for COVID-19 testing and providing the global research community with research reagents and custom GMP manufactured products. This transformation is something that instils pride.

MC: How do you envision the biotech sector will change over the next few years? Are there any areas, aside from cell and gene therapies, that excite you?

ng：生物技术部门的态度比20年前更加积极，更有信心，这种精神使我们能够解决曾经被认为是无法解决的问题。

最令人兴奋的生物技术进步领域之一是精确治疗。例如，要克服的困难障碍是治疗与特定突变体相关的癌症KRAS等位基因较高的癌症。多家公司最近将精密治疗剂用于后期临床试验，以精确治疗这种历史上不可治疗的癌症类型。我认为这种态度将继续。

我期望看到进展的另一个领域是基因治疗递送，它将越来越多地进化出非病毒递送技术。这种演变将允许精确靶向治疗剂的递送，无疑通过此过程改善了人类健康。