Next-Generation Gene Therapy Manufacturing: A Key to Long-Term Growth and Sustainability

By Bobby Gaspar, M.D., Ph.D.

The process of making personalized gene therapies is arguably the most complex pharmaceutical manufacturing process of any medicine to date. For hematopoietic stem cell (HSC) gene therapies, such as the ones Orchard is developing, production requires the creation of specialized viral vectors, the harvesting of a patient’s own living cells, the cells being transferred to a laboratory to be gene-modified by the viral vector, then their transfer back to the patient for infusion.

When I was an academic physician, we did these steps manually in our labs, which was incredibly labor-intensive. While this approach sufficed for the relatively small number of patients we were treating, it soon became clear to me that delivery of these medicines to a greater population of patients globally would require a more scalable and consistent manufacturing approach. That realization was part of what led me and others to found Orchard.

Now, five years into our growth as a company, we’ve built a pipeline of investigational HSC gene therapies for rare diseases that has shown the potential to really change the lives of patients. Today, we’re exploring the potential for HSC gene therapy in less rare indications as well. We have the opportunity now, while our patient populations remain small, to evaluate and implement new processes and new technologies to make our manufacturing as efficient as possible, so that we are ready for the growth in production needed to bring gene therapies to a larger number of patients in the future.

One element of our next-generation manufacturing plan is the creation of stable cell lines for viral vector production. Conventional manufacturing of lentiviral vectors is done by transiently transfecting producer cells, via genetic information carried on a plasmid, to produce the lentiviral particles. This approach is not ideal: it’s labor-intensive, prone to variability in its outputs, hard to scale up and expensive, with the need to generate plasmids on a regular basis. Stable cell producer lines (SCLs), by contrast, have the potential to be a ‘game-changer’ in our ability to generate lentiviral vectors. By introducing all the vector components stably into a clonal cell line, we can then make high-titer vector consistently and efficiently without the need for the extra transfection step. Orchard recently announced that we have entered into two worldwide license agreements with GlaxoSmithKline for use of their proprietary lentiviral stable cell line technology.

SCLs are just one key component of the manufacturing strategy that Orchard is building to ensure our therapies, when approved, are scalable to meet patients’ needs. We are also actively evaluating other promising technologies to increase manufacturing efficiency and scalability. One example is transduction enhancers – chemical agents that boost uptake of lentiviral vector into cells. Hematopoietic stem cells have historically been a difficult cell type to transduce, which necessitates the production of large quantities of viral vectors. Ongoing research at Orchard aims to identify transduction enhancers that can facilitate the same output of gene-transduced cells using a much smaller amount of viral vector.

Another area in which Orchard is investing is the development of automated cell handling processes. Cell handling today is very manual, requiring multiple steps of cell manipulation in sterile environments. Recent technological advances in closed system manufacturing and automated cell handling could offer significant efficiencies to our manufacturing process, while ensuring adherence to exacting manufacturing standards.

There is much work to be done to realize the full potential of HSC gene therapies, and manufacturing innovations will play an essential role in shaping the future of this class of medicines. Orchard is committed to continuing to lead advancements in this area, with the ultimate goal of expanding the reach of HSC gene therapies to all patients who could benefit.

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