I’m writing a series of blogs with insights from inside the gene therapy world. Starting with the analogy of the airplane industry, I highlighted how decades of sustained innovation can translate big ideas impacting everyday life. This theme was kicked off several weeks ago here.
In the case of ex vivo gene therapy, ensuring proper “take off” and then reaching a stable “cruising altitude” can be achieved via optimization of the following four levers:
- Vector copy number (VCN)
- Transduction efficiency
- Cell dose and
These levers enable gene therapy developers to tune the gene therapy to sustainably deliver the amount of potency required to durably impact various diseases.
Successful flights navigated from the gene therapy cockpit
The path has been blazed by pioneers like The San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) funded latterly by GSK, as well as University College London with Orchard Therapeutics, and bluebird bio. Each of these leaders made refinements to their gene therapy platforms to enable them to be adapted to specific diseases.
Let’s consider how bluebird bio was successful with this. According to publicly available information, bluebird bio upgraded their vector design, improved transduction efficiency and protein expression levels, and modified the dose of busulfan - a drug that is given to condition, or make space in, the bone marrow. By the time the company presented early data from the sickle cell program at ASH in 2017, bluebird bio’s CMO was able to state that “changes made to the HGB-206 protocol and to our manufacturing process are having a favorable impact on engraftment of the gene-modified stem cells.”
So let’s look some more at these complementary levers. A gene therapy cockpit might look something like this:
VCN and Transduction Efficiency
In this analogy, “power” equates to potency. Increasing the number of stem-cell daughter cells with a normal copy of the gene(s) increases the power of gene therapies.
For the drug product, two levers increase potency. Transduction efficiency is the percentage of the patient’s CD34+ stem cells that contain at least one integrated transgene, and VCN is the average number of copies of the transgene integrated into a patient’s cells.
Cell dose and Conditioning
“Lift” equates to a critical mass of modified cells engrafting. The conditioning regimen exposes a patient’s bone marrow to a chemotherapeutic agent. The more space made in the bone marrow and the appropriate duration of its existence, the greater the potential engraftment of the modified cells. The goal of this engraftment is to enable lifelong expression of a protein, such as an enzyme.
We anticipate that even more innovative conditioning regimens will be available in the future. They could include using antibody-drug conjugates that recognize and selectively remove bone marrow stem cells. These targeted conditioning agents may help broaden the use of ex vivo gene therapies to an even wider range of disease indications.
Finally, vector design will continue to evolve. Those elements range from codon optimization, to insulators, promoters, tags and signal peptide sequencing. For example, tag technology involves genetically engineering the transgene to produce a fusion protein with a tag that enables increased secretion from CD34+ nucleated daughter cells and uptake into target cells. Because the efficiency of protein secretion is strongly determined by its signal peptide, we are exploring a number of signal peptide sequences.
Forging ahead on our journey
AVROBIO expects to transition to our optimized platform in 2019 with enhancements across many of the levers discussed above. As excited as we are to elevate our game with the goal of advancing our optimized platform into the clinic, we doubt very much that the early aviation engineers rested on their laurels. Similarly, we are committed to continued R&D and process development work as we advance. Some of these are minor process changes while others represent more meaningful leaps forward. Collectively, they push us towards delivering on our mission of “Curing Rare Disease in a Single Dose”.
P.S. I’ll retire the aviation analogy soon. When it runs out of … runway.