Unlocking the Blood-Brain Barrier: Yale Ventures’ D2B3 Revolution
Written by Nurşen Öğütveren, Yale SOM '26
An Urgent Need
Right now, a patient is suffering from a debilitating brain disease. In a nearby lab, a promising drug candidate exists that might cure their condition. Doctors could administer the drug, but it would be of no use. The life-saving drugs cannot reach their target because the blood-brain barrier (BBB) stands in the way. This natural defense mechanism, while essential for protecting the brain from pathogens and harmful substances, also prevents potentially life-saving drugs from reaching their target. But now, a team at Yale has the potential to revolutionize the field with D2B3, a groundbreaking drug delivery technology that temporarily and reversibly opens the BBB.
A Groundbreaking Discovery
Anne Eichmann, a professor at Yale and co-director of the Yale Cardiovascular Research Center (YCVRC), has been at the forefront of this discovery. Trained under the renowned French biologist Nicole Le Douarin, Eichmann's early scientific work focused on the developmental mechanisms of blood vessels. "I began my career working on chicken embryos, not with the intent to develop pharmacological tools, but to understand mechanisms of development," says Eichmann.
It was while exploring the signaling consequences of a particular receptor in endothelial cells that a serendipitous discovery was made. "My postdoc, Kevin Boyé, who is the inventor of all this, put an additional loading control into his Western blot. He used CLDN5, which is a major tight junction protein in the brain. But then we saw that there was so much less CLDN5 in the mutant!" A follow-up experiment in mice confirmed the finding and discovered a leak of the BBB in addition to a decrease in CLDN5.
Eichmann’s team had discovered a receptor critical to maintaining the BBB. They aptly named it the "Guardian receptor" Crucial in maintaining the BBB, the Guardian receptor laid the groundwork for D2B3, a spin-out of Yale University that leverages this mechanism for safely opening the BBB.
From the moment you have a tool that works in a mouse to the moment where you inject this tool into a person, there is a huge gap you have to bridge. Yale Ventures has been a wonderful help in facilitating this.
The Science Behind D2B3
D2B3 uses an antibody tool to specifically inhibit the binding of the guardian ligand to its receptor. This interaction between receptor and ligand is crucial for maintaining the BBB. By temporarily blocking this interaction, D2B3 can open the BBB for a brief period, allowing drugs to pass through and reach the brain. The antibody is unstable, ensuring the barrier can close again, thus minimizing potential risks. With no such tool available, D2B3's patented antibody to reversibly open the BBB is positioned to transform how drugs are delivered to the brain.
Eichmann compares D2B3 with existing mechanical means of opening the BBB, such as focused ultrasound. "In the case of a diffuse brain tumor, this focused ultrasound approach is not so attractive. Whereas, our antibody-based technology targets all 400 miles of capillaries in the brain. That should be a lot more effective." The D2B3 team is comparing the two technologies side-by-side in ongoing experiments with a collaborator that specializes in focused ultrasound mediated BBB-disruption.
Our antibody-based technology targets all 400 miles of capillaries in the brain.
Building the Business
To bring this potentially powerful platform to market, Dr. Manuel Mohr, a biotechnologist with a background in gene therapy and tool development, joined the D2B3 project while working as a Blavatnik Fellow for Life Science Entrepreneurship at Yale Ventures.
Mohr’s passion for helping to develop technologies at early-stage biotechnology companies Scribe Therapeutics and Cell Infinity Bio provided the perfect launching pad for his role leading business strategy for the young company D2B3. As a Blavatnik Fellow at Yale Ventures, Mohr chose to work on D2B3 over many other projects. "It's amazing science -- period," he says, "It's not every day you come across a project where the science is responding to such a big unmet medical need, and at the same time is so diligently executed. Having a huge problem and a phenomenally well-executed solution staring you in the face is an opportunity you can't miss out on."
It's amazing science -- period. It's not every day you come across a project where the science is responding to such a big unmet medical need, and at the same time is so diligently executed.
Connecting Through Yale Ventures
Mohr and Eichmann both credit the team at Yale Ventures with their early success. "Yale Ventures has been absolutely amazing," says Mohr, "They've been supportive in countless ways. There's the financial support from the Blavatnik Award, but there's so much more. This is a business of connections and social engineering. Through Yale Ventures, we were introduced to many senior experts and experienced biotech executives that have provided invaluable advice and hands-on assistance in setting up D2B3."
Eichmann adds to this saying, “From the moment you have a tool that works in a mouse to the moment where you inject this tool into a person, there is a huge gap you have to bridge. Yale Ventures has been a wonderful help in facilitating this. They help us with necessary business advice, planning a clinical trial, navigating discussions with the FDA, figuring out what we need to show them to bring this into the clinic, etc. I'm so appreciative of being able to work with them."
This company is not going to be out of opportunities anytime soon!
Applications and Potential
The implications of D2B3 are vast. “We can deliver anything from small molecules to peptides to nanobodies, growth factors, scFvs, affinity agents, and so much more.," says Mohr, "This company is not going to be out of opportunities anytime soon." But despite a seemingly endless landscape to delve into, Eichmann and Mohr see eye-to-eye on the initial area of focus. Eichmann says, "Brain tumors would probably be our first indication. Brain tumors, such as glioblastoma, have a median survival rate of a few months, even with chemotherapy and radiation treatment, which is the current standard of care. And that standard of care has not changed in the past 15 years."
Mohr discusses this further saying, "There are drugs available that we know would work if they could only reach their target, so that's low-hanging fruit. We have mapped out that space extensively, so we also know there are economic factors supporting our decision to go after brain tumors. We take advantage of the established clinical trial endpoints and can reference a lot of existing experience and clinical data."
Beyond neuro-oncology, Eichmann and Mohr are also excited about the potential for patients and families affected by neurodevelopmental disorders, for which current treatments are invasive and uncomfortable. A veteran in the gene therapy space, Mohr relates, "Many ASO and siRNA assets have hit the clinic and show great efficacy, but they currently have to be administered directly into the spinal cord.
"As a patient with a severe disease, you might consider doing a highly invasive injection route like this once or twice, but especially in the neurodevelopmental space, we're looking at treatments that involve regular injections on a weekly or monthly basis for years and years of a child's development. This is a very difficult decision for parents of the affected children."
Crossroads
Despite its promise, D2B3 faces several challenges. Critical decisions about co-developers, investors, and collaborators must be made, and the path to clinical testing in humans is still long and uncertain. Eichmann says, "I think the biggest challenges still lie ahead of us. Turning this lab discovery into a treatment in humans is going to take time, a lot of effort, and a lot of learning on everybody's part. But we're excited to proceed."
Mohr also comes into the sea of opportunities with enthusiasm restrained by practicality. "I will never stop being a scientist. I will always have an insatiable curiosity for exciting new biology and I would love to pursue all of these opportunities. Sometimes this conflicts with an economically-focused, well-balanced company. So, I take it one decision at a time."
With ongoing studies and collaborations, the team aims to transition from preclinical trials to human trials in the near future. "A lot of pharma companies are interested in the opportunity that this might hold for the drug candidates in their pipelines. And we're talking to several of them; we have more interest than is probably wise for a small startup to entertain," says Mohr, "We can be selective in who to partner with and hope to be able to close a co-development deal with a pharma company within the next 12 months or so."
What do Eichmann and Mohr believe is the key to a winning team? "Diversity," says Mohr, "The biggest impact on a team's productivity is its diversity. Bringing diverse perspectives together turbo charges its creative output. [...] We hope that also holds for our investors. We assess investors for being a good addition to the team, beyond just bringing in money."
Turning this lab discovery into a treatment in humans is going to take time, a lot of effort, and a lot of learning on everybody's part. But we're excited to proceed."
Big Picture
The D2B3 team is made primarily of first-time founders, but they are driven by heartfelt commitment and backed by experienced advisors. Eichmann says, "We're doing research because we want to improve human health. This technology really has the potential to do that, and that's why I decided I was going to embark on this business journey. I'm very excited about this process; and I think it's one of the most fun things I've done in my career." Mohr echoes this sentiment saying, "We found startups and biotech companies to make a difference in the world and to make the world a better place. [...] We have big aspirations, but we need to start small."
One thing that has accelerated impact and timelines for D2B3 is their recent win at the $100,000 Alexandria LaunchLabs 2024 Innovation Prize. Mohr says, "This award really allows us to build our own lab presence sooner rather than later, so we can explore a lot of other indication spaces and de-risk with early in-vivo proof-of-concept experiments. We know it works in brain cancer, but what else can it do?. These data sets will allow us to support our conversations with various pharma partners and investors to raise program-specific funding." Eichmann adds, "We are optimizing the antibody and doing studies in non-human primates so we can be confident it also works in a larger animal and, ultimately, in humans."
The development of D2B3 at Yale Ventures exemplifies the transformative power of innovative research combined with strategic support. Despite the challenging work ahead, the D2B3 team is navigating each step of the process with thoughtfulness, long-term vision, and flexibility. Having helped grow 2 successful startups before, Mohr shares his insights. "There will always be challenges ahead, and staying open-minded, flexible and resilient to all of those curveballs is the only way to prevail." With any luck, this Yale Ventures-backed innovation will soon be en route to provide hope for those suffering from untreatable brain diseases.