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As companies look to bring gene therapy production to scale, there has been increased focus on innovation in manufacturing.

For hematopoietic stem cell (HSC) gene therapies, production requires creating specialized viral vectors, harvesting the patient’s living cells, transferring the cells to a manufacturing facility to be gene-modified by the viral vector, and then cryopreserving the cells and transferring them 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,” says Dr. Bobby Gaspar, chief executive officer and co-founder of Orchard Therapeutics. “While this approach sufficed for the relatively small number of patients we were treating, it soon became clear that delivery of these medicines to a larger 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.”

Five years later, the company has built a pipeline of investigational HSC gene therapies for rare diseases, and is now in the early days of expanding its focus to less rare conditions like Crohn’s disease, frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).

The ability to deliver these therapies will require a faster, more efficient production process. For its part, Orchard is looking at a number of tools to innovate in manufacturing, including:

Creating stable cell producer lines – 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 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 game-changers in the ability to generate lentiviral vectors. By introducing all the vector components stably into a clonal cell line, the high-titer vector can be made consistently and efficiently without the need for the extra transfection step.

Advancing transduction enhancers – Transduction enhancers are chemical agents that boost uptake of lentiviral vector into cells. Hematopoietic stem cells have historically been a difficult cell type to transduce, which requires the production of large quantities of viral vectors. Research is underway to identify transduction enhancers that can facilitate the same output of gene-transduced cells using a much smaller amount of viral vector.

Automating cell handling – Cell handling today is a manual process, 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 manufacturing, while ensuring adherence to exacting manufacturing standards.

Orchard is focusing now on stable producer lines with the ultimate goal of a fully automated process. These disruptive technologies will make the manufacturing of cell and gene therapy products faster, more reliable and more efficient.

A wave of innovation is expected to revolutionize manufacturing of gene therapies.  Click here to learn more about Orchard’s approach.