Addressing the Current Limitations of AAV Gene Therapies

December 3, 2022

The transformational potential of AAV gene therapies has been limited by challenges of delivering genetic material to the cells where they need to go, gene expression, immunity, and the complexity of manufacturing them. Apertura Gene Therapies is seeking to simultaneously engineering AAV capsids, genetic regulatory elements, and payloads to overcome these limitations. We spoke to Joseph La Barge, CEO of Apertura, about its platform technologies, how they work, and the potential for next-generation gene therapies to transcend the limits of first-generation AAV therapies.


Daniel Levine: Joe, thanks for joining us.

Joseph La Barge: Thanks Danny. Pleasure to be here.

Daniel Levine: We’re going to talk about genetic medicines, Apertura Gene Therapy, and its efforts to address existing limitations of gene therapies in terms of gene delivery and expression. Let’s start with the limitations though. What are the limitations of existing gene therapies and what are you doing to seek to address those?

Joseph La Barge: I think gene therapy as a modality has seen a tremendous amount of progress over the last 10 years. We’ve seen lifesaving and life altering treatments such as Zolgensma not only approved, but actually successfully commercialized. But alongside those successes, there have been a uniform set of challenges that have plagued the entire field of gene therapy, resulting in SAEs and clinical holds across the entire sector. Now we believe that these challenges largely stem from the field’s reliance on naturally occurring serotypes of AAV viruses. Naturally occurring viral vectors are a bit of a blunt instrument. They do a great job of delivering their genetic payload broadly throughout the body, but aren’t very particular about going where we want them to go. And they have difficulty accessing hard to reach tissue types, such as crossing the blood brain barrier to approach CNS tissues. And they typically are recognized by the body’s immune system since many of us have been exposed to these serotypes throughout our lifetimes. At Apertura, we’re focused on overcoming these challenges by designing viral vectors that target specific tissues, and that hopefully have a more favorable immune signature than naturally occurring AAVs. These engineering efforts should enable us to use lower doses of AAV gene therapies, and importantly open up opportunities to address diseases of difficult to reach tissue types.

Daniel Levine: The company was founded on a pair of platform technologies developed at the Broad Institute of MIT and Harvard and the Harvard Medical School. Walk me through the two platforms. How do they work and what do they enable you to do?

Joseph La Barge: Sure. So to make an effective gene therapy, we believe it’s critical to start with the end in mind and design the therapy to best address the particular indication we’re seeking to address. The platforms we license allow us to innovate inside and outside the capsid to do exactly that. The capsid engineering platforms licensed from the Broad came from the laboratory of Ben Deverman. These platforms addressed the manufacturability, tissue targeting, and immune innovation properties of the gene therapy product. While we’re taking this platform in a number of directions, I will highlight two approaches that Ben and his team have discussed publicly earlier this year. In May, at ASGCT, Ben’s team disclosed a machine learning approach that we call fit for function that allows us to simultaneously engineer multiple properties of the AAV capsid at the same time. In contrast, most other capsid engineering approaches focus on one attribute at a time. Fit for function allows us to use machine learning models to dial the requirements for different characteristics up and down. At the same time, to fit the need of a specific therapeutic profile, we can toggle manufacturability, targeting specific cell types, de-targeting specific organs, and alter the performance across species. In another approach, at the beginning of November, Ben’s team posted a paper on Bio Archive outlining another machine learning approach for engineering AAV capsids. This time we’re focused on generating capsids with specific capsid receptor interactions. This is an approach that homes in on specific known receptors to increase AAV tropism. And the platform we licensed from the laboratory of Mike Greenberg of the Harvard Medical School focuses on gene regulatory elements, or GREs. GREs are little snippets of DNA that regulate how the AAV payload is expressed. The work at Mike’s team previously described as a platform called PESCA, allows them to develop a GRE, which ensures that only specific cell types can read the instructions delivered by the AAV. This allows us to sidestep the ubiquitous promoters used by earlier generations of gene therapies that have caused complications due to high levels of expression in off-target cells. We’re working towards designing GREs to decide which cells express a payload, how much they express and when they express it.

Daniel Levine: There’s been a fair bit of activity in the gene therapy space around next generation vectors. How does combining these two platforms compare to what other companies are doing now?

Joseph La Barge: Drug development is complex and patients are clearly waiting and I’m delighted by the number of companies in the gene therapy space working to bring more treatments to patients. With regard to Apertura, I think we are differentiated in that our platforms utilize machine learning to gain insights in designing genetic medicines and transforming the current trial and error approach into a data driven process. We believe that there are real synergies in applying both our engineering efforts to innovate inside and outside AAV capsids and that by combining these two platforms, we should be able to address some of the current challenges in the gene therapy field and ultimately unlock opportunities to provide treatments for patients in need.

Daniel Levine: What’s the case for using engineered AAV capsids rather than just using naturally occurring ones?

Joseph La Barge: Yeah, so as I indicated at the start of our conversation, naturally occurring serotypes are really a rather blunt instrument. They deliver their genetic payload broadly throughout the body. They have difficulty accessing hard to reach tissues and are typically recognized by the body’s immune system. In contrast, engineered capsids hold the promise of being more targeted. We’ve demonstrated compelling proof of concept data showing that the ability to engineer capsids that can be administered intravenously are a thousand fold more effective at crossing the blood brain barrier than AAV9 and naturally occurring serotype. Another important attribute of engineered capsids is the ability to create caps that detarget tissues where we don’t want them to go, such as the liver. Through our machine learning models, we can do both targeting and detargeting simultaneously.

Daniel Levine: And how does this open up the potential for reaching new tissue? Is it just a trial and error approach, or are there specific things you’re doing to target specific tissue?

Joseph La Barge: Yeah, so that’s really the power of the machine learning platform in that as we examine the amino acid sequence of capsids right within a library, we can deeply examine the library at its core and analyze which sequences of amino acids might drive higher tropism of specific tissue, while at the same time decreasing tropism for other organ types. And so, it really provides a very finely tuned and known dataset that we can toggle up and down to go after specific tissue types and really in a very directed and data driven way, rather than a more random trial and error approach.

Daniel Levine: As you’ve alluded to using a natural AAV vector, one of the issues is that you will train the immune system to respond to it. What’s the potential for developing redosable gene therapies through your approach?

Joseph La Barge: Great question. I like to tell my team that we and the field need to walk before we run here. You know, our underlying hope for gene therapy is that we can effectively treat people’s disease with one dose. That seems to be holding true with treatments such as Luxturna, but only time will tell. Engineering capsids to avoid preexisting neutralizing antibodies or the body’s immune system and being able to re-dose would be the holy grail. It’s something we will absolutely be focused on and I think the field will ultimately solve this challenge. And I think what is really unique and interesting is during the past two years through this pandemic, we’ve seen a virus that is incredibly adept at mutating to avoid neutralizing antibodies in the body. So, the trick will be figuring out how to apply that to AAV technology to allow patients that have high titers of neutralizing antibodies or people that have already been dosed with a gene therapy to be re-dosed.

Daniel Levine: Gene therapies are expensive and difficult to manufacture. Do your platform technologies do anything to make these products easier to produce or lower the cost of manufacturing?

Joseph La Barge: Absolutely. One of the core tenets of our platform is ensuring the caps we are engineering are highly manufacturable. The attributes that I discussed earlier regarding being able to more effectively target tissue types should mean that we can lower doses, which improves the safety profile of the therapy, while also reducing the cost of manufacturing a dose. And I would also note that even separate from what we’re doing here at Apertura, the gene therapy manufacturing landscape is evolving and improving from the early days when we were using roller bottles and adherence cell culture processes. These processes will only get more efficient and cost effective over time.

Daniel Levine: What’s the business model? The company talks about working closely with academic and biopharmaceutical partners. Is the focus on partnering with others who will perform clinical development and commercialization, or do you expect to take your own pipeline of gene therapies forward?

Joseph La Barge: We believe in doing what is ultimately best for patients and that will benefit Apertura and the gene therapy industry as a whole. Now, partnering with other biotech and pharma companies as well as academic researchers to make our platform technologies available to a broad segment of the gene therapy industry will help move the field forward and will ultimately get more treatments to patients faster. But we are also going to be simultaneously focusing on building our own pipeline of product candidates using the engineered capsids and novel GREs that will be developing through our platforms.

Daniel Levine: Given the broad applicability of your platform technology, how are you prioritizing indications you’ll pursue and where are you beginning?

Joseph La Barge: We have a process underway to identify and select the indications that we’ll go after ourselves. We’ll look to target indications where the disease biology is reasonably well understood and the technical feasibility of addressing that indication is tractable. We believe our platforms will open opportunities to address areas of high unmet need as well as more effectively address indications that have shown only modest clinical benefit in development to date.

Daniel Levine: Apertura is backed by Deerfield; launched in April with $67 million in funding. How far will existing funding take you and how are you thinking about additional fundraising?

Joseph La Barge: Yeah, I don’t want to specifically say how far Deerfield’s funding will take us, but suffice it to say it provides a really solid foundation to reach some critical milestones and demonstrating the power of our platforms. And I’m sure as you know, Danny, gene therapy and biotech in general are capital intensive businesses and we’ll absolutely be looking to raise additional capital as we progress the business. And it is great to have such a robust start to the company with an investor like Deerfield backing Apertura.

Daniel Levine: You were brought in as CEO in July. Listeners may remember you from the gene therapy company, Spark Therapeutics where you served as chief business officer, and one of the few companies with a commercial gene therapy product. What did you learn from your experience At Spark that you’re bringing to Apertura?

Joseph La Barge: Well, I was actually one of the first employees at Spark when I joined in 2013. And when I left at the end of 2021, we were just shy of 900. And I think through that tenure, one of the things that made Spark the success that it is, was our relentless focus on culture and keeping the patient as our north star of the work that we were doing, valuing high science and really cultivating an environment that truly embodied collaboration. We had this saying at Spark that we don’t follow footsteps, we create the path. And I think we demonstrated that spirit with the approval of Luxturna as the first gene therapy for genetic disease in the U.S. and not only getting it through the regulatory hurdles, but creating novel reimbursement structures for commercialization to pave the way for more gene therapies to come. And I’m looking, really looking forward to bringing the learnings from Spark and growing that company and bring that energy and commitment to Aperture.

Daniel Levine: Joseph La Barge, CEO of Apertura Gene Therapy. Joe, thanks so much for your time today.

Joseph La Barge: Thanks so much Danny. It was a pleasure.

This transcript has been edited for clarity and readability.


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