Latus Bio finds a better way to deliver genes to cells deep in the brain to help patients with neurodegeneration

Progress in a given innovation sector tends to leap ahead once prac­ti­tioners can settle on a few key workhorse tech­nolo­gies. HTML and HTTP were the founding protocols of the web, for example, and Chinese hamster ovary cells (CHO) are the universal choice for manu­fac­turing recombinant biologic medicines like antibody drugs. In the field of gene therapy, which fixes mutated genes causing diseases, biologists have been engaged in a quarter-century-long search for a precise, effective vehicle (called a vector) for getting genetic payloads into the cells they want to reprogram. 

Finally, a workhorse gene therapy technology is emerging — a vector created from the chassis of recombinant adeno-associated viruses, or rAAVs. Recognized decades ago as a non-pathogenic way to deliver therapeutic genes without causing DNA damage, the first AAV vectors were built by deleting parts of the gene for the viruses’ shells or capsids. Now Latus Bio, a DCVC Bio portfolio company, has found a way to tailor AAVs to vastly dial up their safety and cost-effec­tive­ness and allow them to become precise, potent tools for the industry.

In a Nature Commu­ni­ca­tions paper published May 19, a group including several Latus scientists showed that one of their novel viruses, called AAV-DB‑3 — created using Latus’s proprietary platform for generating rAAVs with customized shells or capsids — outper­formed an earlier type of vector called AAV5 by a factor of more than 100, measured according to their effec­tive­ness at delivering reporter genes to neurons deep in the brains of rhesus macaque monkeys. That’s significant because those same brain areas in humans are the locus of the genetic errors that lead to Huntington’s disease, and because previous generations of rAAVs developed to treat neurode­gen­er­a­tive problems have had to be delivered at such high doses that they proved toxic. 

“These findings suggest that AAV-DB‑3 and other capsid variants from our screening platform could prove to be highly promising vectors for a broad range of neurode­gen­er­a­tive disorders that affect deep brain and associated cortical brain regions,” Dr. Beverly Davidson, founder of Latus and chair of its scientific advisory board, said in an announce­ment accom­pa­nying the paper. 

Last week, a team led by Davidson also published a separate paper in Science Trans­la­tional Medicine, showing that another novel capsid variant, AAV-Ep+, outper­formed naturally occurring AAVs at delivering therapeutic genes to cells lining the ventricular systems of the brain and spinal cord of primates and mice. That means the equivalent cells in humans might be made to serve as protein production depots to treat neurode­vel­op­mental and neurodegenerative disorders.

Gene therapy — the effort to replace or mitigate missing or mutated genes in diseases caused by single-gene defects — is a compelling idea that was held back by the lack of suitable delivery vehicles. The first adenovirus vectors researchers tried on human patients in the late 1990s and early 2000s caused fatal immune problems that stalled progress for a decade or more. The goal since then has been to find vectors that work with greater specificity (reaching only the targeted tissues) and at much lower doses.

The specificity of an rAAV — which types of cells it can ​“infect,” and how much of its curative payload it can deliver — is determined by the structure of its capsid, the icosahedral shell that protects its DNA or RNA cargo. Davidson, working from her lab at the Children’s Hospital of Philadel­phia, developed a way to generate millions of types of rAAVs with different capsids, then screen the variants to choose the ones that are best at penetrating specific types of neurons in the brains of non-human primates. 

That’s how Latus identified AAV-Ep+ and AAV-DB‑3. To gauge the latter’s effec­tive­ness, researchers injected AAV-DB‑3 carrying fluorescent reporter genes into the left side of monkeys’ brains, in an area called the globus palladus. (In humans, this region is inter­con­nected with key areas that degrade because of mutant huntingtin, causing the symptoms seen in Huntington’s patients.) On the right side, they injected an identical dose of AAV5 carrying similar reporter genes. A few weeks later, the monkeys were euthanized and their brains were analyzed to see how many neurons had taken up the vectors and started expressing fluorescent proteins. The researchers saw that expression of the fluo­res­cence transgene was 92 to 531 times higher on the left side, depending on the specific brain region observed. The result suggests that AAV-DB‑3 could be used to safely deliver therapies that help slow the rate of expansion of the repeating three-nucleotide sequence (CAG) found in the mutant huntingtin gene, at doses low enough to avoid toxicity. 

And that’s exactly what Latus intends to do, by loading up the vector with microRNAs designed to block MSH3, a protein thought to help cause the CAG sequence to multiply out of control. In time, the company will ask the FDA for permission to start clinical trials testing whether — as Latus believes — its capsid will be faster and easier to inject into the brains of human Huntington’s patients than the AAV5-based capsids that competing gene therapy companies such as uniQure are deploying. Because of its higher potency, the cost and time to manufacture quantities sufficient for treatment will also be far lower.

Down the road, Latus’s underlying technology for generating better capsid variants could help the company deliver cures for genetic diseases affecting many other tissues, inside and outside the brain. As we discuss in our upcoming Deep Tech Oppor­tu­ni­ties Report for 2025, we need to move to a healthcare system that supports increases in early diagnostics and curative therapies where they are possible. Latus Bio is working hard on this ideal, and we look forward to seeing their first clinical data later this year.