Logan Thrasher Collins: The Trojan Horse That Could Fix Gene Therapy | Frameshifts Episode #14

On this show, we’ve talked a lot about gene editors. These are little molecular machines derived from or inspired by the Nobel-prize winning CRISPR system that put gene editing on the radar of the general public. Once these editors get into a cell, they can cut out DNA, change the DNA sequence, insert entire copies of genes or delete faulty genes that cause illness. Think of them as tools to cut, paste, backspace and overwrite the code of life. But the primary challenge with these gene editors, besides off-target edits and low-but-steadily-improving editing efficiencies, is that they need to get *into* the cell to be able to do *anything*. Getting gene editors into cells is an entire field of biomedical engineering called gene delivery. And in comparison to the rapidly flourishing field of gene editor tech dev, the field of gene delivery is both under-appreciated and relatively stagnant. And that’s a massive problem. Because without effective delivery vectors, gene editors are limited to a very small number of conditions for which our delivery vectors happen to be okay at. Current clinical successes are concentrated in situations where delivery is unusually favorable: \* Liver diseases, where lipid nanoparticles can efficiently deliver cargo to hepatocytes after IV injection \* Blood disorders and some hematological cancers, where cells can be removed from the patient, genetically modified ex vivo using lentiviruses and then re-injected into the patient (e.g. HSC therapy for sickle cell anemia or CAR-T therapy for leukemia) \* Diseases that only require a very small percentage of cells to be edited in order to be functionally cured \* A limited number of tissues, such as the retina or CNS where viral vectors can achieve therapeutically meaningful gene transfer That's the ceiling today. But if we crack delivery, the potential of this field is disgustingly profound. Gene Delivery Vector + Gene Editor = Gene Therapy If humanity can solve both sides of this equation, we can, *literally*, cure *anything*. You have a genetic disease? Here’s an injection that gives all of your cells the healthy copy of the corrupted gene you inherited from your parents. You’re prone to cardiovascular disease? Here’s an injection that gives you new human-designed molecular machines that clear out your clogged arteries. You have a family history of cancer? Here’s an injection that replaces your genome maintenance and DNA machinery with engineered supernatural versions that can protect your cells from cancer-causing mutations for at least 1000 years. Worried about keeping up in a world of artificial superintelligence? Here's an injection that carries the morphological instructions for a population of your cortical neurons to rewire themselves for compatibility with high-bandwidth brain-machine interfaces, connecting you directly into Dario or Sam’s frontier models. Now, I know a lot has to go right for humanity to achieve mastery over the code of life and transcend the limits imposed by “fit enough to have offspring” evolutionary biology. So I’ll get my head out of the clouds for a moment. Currently, the most clinically successful delivery vehicle in the emerging field of gene therapy is a family of viral variants that we call Adeno-Associated Viruses, or AAVs. AAVs are DNA viruses that scientists have hijacked to make little viral couriers that carry a working gene into your cells. Within this group are many serotypes and engineered capsid variants, each with tropism for specific organs and tissue types. Significantly oversimplifying: AAV9 can penetrate the brain, AAV8 is strongly liver-tropic and other capsids are tuned for tissues like skeletal muscle or retina. But somewhere between a third and two-thirds of people already have antibodies against AAVs, left over from ordinary childhood infections with the wild versions. If you’re one of them, a gene therapy that could save your life may simply not be available to you, because your immune system will neutralize the courier before it arrives. And even if you’re in the clear, most AAV therapies work exactly once. The first dose teaches your body to recognize the vector, so a second one gets destroyed the moment it touches your immune system. For a whole field built on delivering genes into people, the delivery itself is one of the deepest unsolved problems there is. Logan Thrasher Collins has spent his career on that problem. As a PhD student in biomedical engineering at Washington University in St. Louis, he invented a new gene-delivery modality called vaultAAV, which does something a bit strange: it hides the AAV inside a protein vault. Wow. Incredible. But what the hell is a protein vault? Vaults are odd, barrel-shaped organelles *our own cells churn out* in huge numbers, and nobody is entirely sure what they’re for. What Logan realized is that because the body recognizes a protein vault as *self*, they act as immunologically invisible Trojan horses. Cells take them up, the vault disassembles in the acidifying endosome, and the AAV escapes to deliver its DNA to the nucleus, all without the immune system ever getting a look at the AAV courier hiding inside. In this episode, Logan walks us through his entire scientific journey, from designing an aggregating antimicrobial peptide as a high school science fair project (which won the top prize at ISEF and got a minor planet named after him), to the insight that connected the protein vault literature with the AAV field’s antibody problem. We discuss the full landscape of gene delivery: AAVs, adenoviruses, LNPs, virus-like particles, and why the field’s relationship with each vector is driven more by reputation and vibes than by rigorous analysis of dosing and safety data. Logan also explains why vaultAAVs may enable something no other approach can: redosability. Currently, AAV capsids are engineered with surface mutations to escape antibodies, but each new variant can only be used once before the immune system learns the new epitope. Vault-shielded AAVs, because their outer surface is self, could theoretically be administered multiple times, allowing lower doses, reduced toxicity and lower manufacturing costs. Logan has since taken the vaultAAV work out of the lab and into a company. He co-founded Cathedral Therapeutics, a gene-delivery engineering company, alongside Prof. David Curiel, MD, PhD at Washington University, to build exactly this kind of stealth delivery system. In this episode, we also get into: \* How 30 to 60% of people are locked out of AAV gene therapy by the time they reach adulthood \* How hiding a virus inside one of your own organelles gets it past the immune system \* Why vaultAAVs don’t just dodge antibodies but also boost transduction up to 5x (in some cell lines) \* Why gene therapies cost $850K to $3.5M a dose, and how synthetic biology could make them cheap \* How a high-school science fair peptide led to Logan getting a minor planet named after him \* How we can engineer adenoviruses to cross the blood-brain barrier in order to treat neurodegenerative disease and mental illnesses \* What it means that our cells are full of a mysterious organelle nobody can fully explain Gene editing technologists like David Liu, Feng Zhang and my friends in the AbuGoot lab have spent two decades proving that CRISPR-based systems can fix faulty genes. The much harder problem is how we can get gene therapies into everyone who needs them, and eventually make them as safe, cheap and ubiquitous as Ozempic. To do that, we need to be able to inject them more than once, and get them to our target tissues without the immune system getting in the way. That’s the problem Logan is working on. Watch on YouTube, listen on Apple Podcasts or Spotify. **GUEST INFORMATION:** \* Logan Thrasher Collins, PhD, Washington University in St. Louis \* Cathedral Therapeutics \* VaultAAV preprint \* Synthetic Biology for AAV Manufacturing \* X (Twitter) **CONNECT WITH US:** \* Website \* Substack \* YouTube \* X (Twitter) \* LinkedIn \* TikTok Get full access to Frameshifts with Benjamin Arya at frameshifts.bio/subscribe