It's the VBSA's 2019 holiday BioBeer at Queen City Brewery with the usual enthusiastic bio and tech crowd. A small group of us duck past the bar to circle up on the production floor. We're a mixed group, from former IBMers with no background in biotech, to a PhD candidate conducting her own research into a variety of 21st century biotechnologies. We're looking for a little peace and quiet to hear Russell Beste, Vice President of Industry Affairs for the VBSA, talk about gene therapy (GT).
GT is a relatively new therapy that remarkably enables the ability to fix a person with genetic disease by inserting copies of the DNA permanently into a patients stem cells. In this way, a person born with defective DNA can be fixed (rather than continuously treating their symptoms arising from their defective DNA, throughout their lives).
This remarkable therapy is just being commercialized for the first time, and are now beginning to be approved by the FDA and EMA. This field is rapidly expanding, and there are now over 250 GT products in Phase II clinic and beyond. "Usually we scale commercial biotechnology product using large stainless steel vessels, like that," says Russell, pointing to one of the large, gleamingly pristine stainless steel beer vessels that surround us. "For GT however, each patient provides their own raw materials, so the challenge is not to scale up but rather scale out thousands of small manufacturing processes, each one dedicated solely to a particular individual using their own raw material ("their own DNA").
Russell explains the basic idea "modern" manufacturing process behind lentiviral vector, an important gene therapy technique that is modified to provide a gene delivery. The goal of gene therapy is to replace broken or missing DNA in a patient's cells in order to cure a genetic disease. But under normal circumstances, cells don't want to pick up strange DNA. If there's anything that's good at sneaking DNA into cells, it's lentiviruses (HIV is a notable member of this group). Scientists use the envelope, basically the empty shell, of lentivirus to sneak DNA into a patient's stem cells.
Russell then dives deep into the manufacturing steps needed to make this all happen through several discrete steps: 1) a plasmid DNA is created that contains critical gene sequences including the gene of interest (GOI), then subsequently scaled up to create multiple copies of a variety of genetic sequences including the GOI; 2) in a separate subsequent operation, the plasmid with the GOI, along with other plasmids containing various genetic sequences that code for LentiVector (LV) are grown and multiplied using HEK cells, which become transfected and in the process of being transfected created millions of LentiViral Particles (containing the LV shell (the LV shell is similar in composition to the shell of an aids virus and as such is very good at getting DNA into a human being's stem cells), along with critical DNA plasmids coding to help the patient); 3) the patient stem cells are removed, then grown in the presence of the LV particles, which transduce the patient stem cells by using the LV shell to enter the stem cell and deposit critical DNA sequences including the GOI intended to fix the patient. During this time, the GOI inserts itself into the patients stem cells, thereby transducing the patient stem cell to now produce and copy the previously defective GOI; 4) The transduced stem cells that now contain the GOI are then injected back into the patient, thereby permanently "fixing" the patient!
If all goes well, the patient's cells will incorporate the new DNA, often a functional copy of a gene that is "broken" or missing in the patient, and new cells with the new DNA will proliferate in their body, correcting their illness. Gene therapy is a whopping half million per treatment, but it permanently cures diseases that have long been uncurable.
While gene therapy can be a miracle cure for debilitating diseases, its fundamentally patient-focused model presents unique manufacturing challenges. Every treatment is essentially unique, since stem cells from each specific patient are part of the treatment, making gene therapies difficult to mass produce. The shelf life for a treatment is currently often just 12-24 hours, so shipping from a single manufacturing location may be prohibitive.
The former IBM engineers ask about the legal ramifications of manufacturing and quality control processes with gene therapies. How do patents work on a technology were each version of the product is a one-off? Is each patient case a patent? Russell explains that so far everyone is working on a generous basis because of the huge opportunity gene therapy breakthroughs represent. "It's going to change the world for sure," he sums up with confidence. "Though the field is ripe for many new scale up technologies that will make this currently very expensive therapy more practical and affordable."
Keep an eye out for more bioscience talks led by the VBSA! Dates TBD and posted on our events page.