Joseph La Barge has been mulling over the limitations of gene therapy for some time. So, when he left his position at Spark Therapeutics, having watched the company grow from its start in borrowed offices at Children’s Hospital of Philadelphia as employee number five to post-acquisition by Roche, he dove into the world of gene therapy delivery vehicles.
“Finding better delivery vehicles through engineering efforts is going to be a critical next step for gene therapies, moving the technology from the field of 1.0 to 2.0 and beyond and unlocking indications, particularly in the central nervous system (CNS) and other hard-to-reach tissues,” La Barge told GEN Edge.
While there’s been a lot of effort both by academics and companies now over probably a collective decade or so to try to engineer capsids, many of the methods used to date have been very brute force, focused on iterative screening of large libraries, typically first in a mouse model and then moving to a nonhuman primate model.
“I think that strategy is flawed in that even if you believe the premise that 99% of the nonhuman primate genome is pretty identical to the human genome, that 1% difference can make a big change and a big impact as you were looking for translation from animal models to humans,” said La Barge.
La Barge joined Apertura Gene Therapy as CEO in the middle of 2022 after becoming completely captivated with the young biotechnology company’s platform for engineering capsids that target human cells.
“Apertura’s approach is to engineer from the outset capsids that will interact specifically with human receptors… to assess function against those human receptors,” said La Barge. “I think that has a couple of advantages. One, we know its mechanism of action and why it’s working and not working. Two, it is highly probable that we think it will ultimately translate to humans and be transparent.”
A year and a half later, La Barge and Apertura have unveiled their proprietary engineered adeno-associated virus (AAV) capsids that bind to the human Transferrin Receptor 1 (TfR1), which mediates crossing of the blood-brain barrier (BBB) to enable gene therapy delivery throughout the CNS. Behind these TfR1 capsids, Apertura announced the advancement of two programs for undisclosed neurologic conditions.
The Vector Engineering Lab at the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, under the direction of Ben Deverman, PhD, developed the technology on which Apertura’s TfR1 capsids are based.
Apertura’s approach to engineering capsids is unique in that they do not decorate a chosen capsid with antibodies or recognition molecules that facilitate cell targeting. Nor do they necessarily use AAV serotypes that are known to be able to target particular tissue types. They also don’t screen as large of a pool of capsids they can get their hands on, hoping to find some “perfect” hits that check off all the boxes.
To engineer an Apertura capsid, the company starts by screening variants with modifications to the native structure of the capsid for binding properties to the receptor they’re looking to target. These results are put through proprietary machine learning tools to identify “production fit” variants, precisely selecting at the front end of their engineering efforts to work with only capsids that can be manufactured.
“What we’ve also seen over the last number of years is that you can engineer these things so they become fragile, fall apart, and don’t package,” said La Barge. “Finding something that works and then belatedly finding out that you can’t manufacture it is not where anyone wants to be.”
Then, through various generative AI, site saturation mutagenesis, and other techniques, the team at Apertura continues to tweak and make additional modifications to their candidate capsids.
So, whereas a traditional method may start with a really large library and then continue to narrow that funnel down to one, Apertura is using a library that may not be huge upfront that gets narrowed to subsets and then is expanded for a second round of screening for a handful of lead capsids.
Apertura’s TfR1 capsid works without interfering with transferrin binding, resulting in transcytosis of the capsid and delivery to the CNS. Administered intravenously, Apertura’s TfR1 capsids have demonstrated high efficiency at crossing the BBB at dose levels 40-fold lower than current CNS-targeted gene therapies and broad distribution and transduction in both neurons and astrocytes while also reducing distribution of the capsids to the liver.
“We’ve taken the approach of first solving the delivery challenge,” said La Barge. “We know we are transducing upwards of 60% of neurons and over 80% of astrocytes. What opportunity does that open for going after various indications? We’re thinking about it that way. We will continue to look at it through those lenses and think about the various receptors that we may be engineering capsids to bind and what opportunities that will open up.”
Brought into focus
With their receptor-based approach, La Barge said that Apertura is building out its pipeline, seeing many opportunities in the CNS, skeletal muscle tissue, and kidney, and is also engaging in business development discussions for out-licensing capsids for other indications that they wouldn’t pursue themselves wholly.
“We are actively screening the landscape and thinking about what other indications, either our TfR1-binding capsids or other ones we’re developing, could be used for,” said La Barge. “We will continue to build a pipeline, but at the same time, we’ll be looking to license them to partners as well.”
According to La Barge, the lowest hanging gene therapy fruit is gene replacements and not indications where extremely titrated expression is needed, like Rett syndrome, where gene expression needs to be dialed to a specific therapeutic level to both have an effect and avoid serious adverse events.
Having spent time previously at Spark, La Barge also had the patient population size in mind when choosing indications.
“While Luxterna was a huge success from the gene therapy perspective and for the patients who received it, from a commercial perspective, it was challenging because there were a very small number of prevalent patients—few are born every year,” said La Barge. “So, it gets to the point where it can’t support the commercial infrastructure.”
On the flip side, La Barge said that Apertura has no intention of becoming a contract development and manufacturing organization (CDMO) for manufacturing capsids. As Apertura advances its lead programs towards IND-enabling studies, La Barge said they will look to partner with a CDMO for GMP and clinical-grade manufacturing.
“I think there’s going to be an abundance of CDMO capacity,” said La Barge. “I’m not in a hurry to drop $100 million on building a facility before we have high confidence.”
When put into the context of the challenging capital markets over the past two years, La Barge is very proud of Apertura’s progress, which Deerfield Management Company has backed from the beginning.
“It is good to have a supporter and investor like Deerfield in our corner,” said La Barge. “We’re hoping that 2024 starts to shake some of the other capital loose and things become a little better for the biotech industry in general.”
Either way, don’t expect to see Apertura drawing up plans for a manufacturing facility soon. They have a long way to go before one of their engineered capsids is taken through the regulatory process, either in-house or out-licensed, and succeeds as the vehicle for a safe, effective, and commercially viable gene therapy. But you have to get a man on base to start, and that’s what they’ve shown today.