With a rich background in medical robotics and IoT applications, James Maitland has dedicated his career to the intersection of technology and medicine. Today, he shares his perspective on a pioneering collaboration that could redefine the future of cardiac gene therapy. We’ll explore how leveraging established medical devices like the Impella heart pump for targeted drug delivery aims to solve the persistent safety and efficacy challenges that have hindered the field, potentially heralding a new era of precision genetic medicine.
Your collaboration with Johnson & Johnson leverages the Impella heart pump for gene therapy. Can you walk us through the mechanics of this localized delivery, and how specifically does it aim to prevent the off-target effects and liver accumulation common with traditional AAV methods?
Absolutely. The concept is both elegant and powerful. For 30 years, the gene therapy field has wrestled with a fundamental challenge: how to get the therapeutic payload only where it’s needed. We’ve traditionally used systemic infusion, which is like sending a package through the general mail with a vague address. Our approach, using Johnson & Johnson’s Impella pump—the world’s smallest heart pump—is like using a dedicated courier to deliver it directly to the recipient’s hands. We use the device to create a contained circulatory loop, allowing us to administer the gene therapy directly to the cardiac tissue. This method concentrates the adeno-associated virus, or AAV, right at the heart, preventing it from circulating throughout the body and accumulating in the liver, which has been a major source of safety concerns.
Given recent safety events in the gene therapy space, including patient deaths from liver toxicity, how does concentrating AAV delivery directly to the heart mitigate these specific risks? What new safety and efficacy metrics will this localized approach allow you to measure in your studies?
The recent safety events, particularly the tragic patient deaths linked to liver toxicity from drugs like those from Sarepta Therapeutics, cast a long shadow over our field. They underscore the urgent need for a better delivery method. Our direct-to-heart approach is designed to tackle this head-on. By largely bypassing the liver, we aim to eliminate the primary cause of this systemic toxicity. It’s a fundamental shift in the safety paradigm. This precision allows us to move beyond just monitoring liver enzymes in the blood. We can now focus on metrics that truly matter for cardiac treatment: measuring the level of transgene expression directly within the heart muscle and correlating it with improved cardiac function, all while keeping the systemic exposure of the AAV to an absolute minimum.
This direct-to-heart method aims to substantially lower AAV doses. What magnitude of dose reduction do you anticipate is possible, and what are the cascading benefits of using less virus for minimizing immune responses and overcoming manufacturing challenges?
The goal is to “substantially reduce required AAV doses,” and while we are still in the preclinical stage, the logic is compelling. When you are not diluting the therapy across the entire body, you simply need far less of it to achieve a therapeutic effect in the target organ. This isn’t just a minor improvement; it creates a cascade of benefits. Firstly, a lower dose dramatically lessens the risk of triggering a powerful immune response, which can not only cause harm but can also render the therapy ineffective. Secondly, from a practical standpoint, manufacturing AAV vectors is a significant bottleneck for the entire industry. By using a smaller dose per patient, we can extend our limited manufacturing capacity, which could ultimately make these life-changing therapies more accessible to the people who need them.
As companies like Takeda and Biogen exit gene therapy due to persistent issues, Lexeo is advancing a new delivery platform. What gives you confidence this approach can succeed where others have stumbled, and how does partnering with an established device maker specifically de-risk your cardiac programs?
It’s certainly a sobering moment when you see major players like Takeda and Biogen pulling back. It forces you to ask hard questions. Our confidence stems from the belief that they were hitting a wall with the delivery system, not necessarily the therapeutic concept itself. We are not just creating another AAV; we are re-engineering the delivery process. Partnering with a proven leader like Johnson & Johnson to use their Impella technology is a massive de-risking strategy. We aren’t building a new device from scratch. We are leveraging a sophisticated, market-approved heart pump and applying it in a novel way. This allows our team at Lexeo, which just re-focused its pipeline with a $20 million investment into its lead cardiac programs, to focus on what we do best: the gene therapy science.
The Impella system’s controllers were subject to a Class I recall over cybersecurity. How does this history inform your preclinical planning, and what specific operational protocols are you implementing to ensure the integrity and safety of the device during these sensitive gene therapy procedures?
That Class I recall is a matter of public record, and it absolutely informs our approach. In medicine, especially when you’re on the cutting edge, you have to learn from every challenge. Even in our preclinical work, we build safety protocols as if we were in a human trial tomorrow. That history makes us hyper-vigilant about the integrity of the entire system. We are implementing stringent operational protocols that include running the device on isolated networks, performing exhaustive pre-procedural system checks, and having redundant monitoring in place. It’s about ensuring the device performs its designated function flawlessly, without any vulnerability, so that we can guarantee the precision and safety of these delicate procedures.
What is your forecast for the future of localized delivery systems in cardiac gene therapy?
I believe localized delivery is the key that will finally unlock the full promise of gene therapy, not just for the heart but for many other organs. For too long, we’ve been constrained by the trade-off between delivering a high enough dose to be effective and a low enough dose to be safe. Direct-to-organ delivery, using sophisticated medical technology, shatters that paradigm. We’re moving from a systemic sledgehammer to a biological scalpel. I forecast that over the next decade, we will see a surge in these combination therapies, where advanced devices and genetic medicines work in concert. This will be what finally allows us to treat complex genetic diseases that have remained stubbornly out of reach.
