Some genes are too large to fit into AAV vectors. UCB, Novartis back $57M idea to deliver them in parts instead
Of all the major limitations of adeno-associated viruses (AAV) as a vector for gene therapy, one is particularly well-known and indisputable: They can only carry a transgene up to a certain size. Design a payload larger than 4.7kb, and there’s simply no way you can fit everything in.
That’s why gene therapy developers working on, say, Duchenne muscular dystrophy have come up with workarounds, such as creating shortened versions of the target gene.
But a Spanish biotech believes there’s an alternative: What if you can deliver the full gene in two parts?
SpliceBio has raised close to $57 million (€50 million) from UCB Ventures, Ysios Capital, New Enterprise Associates, Gilde Healthcare, Novartis Venture Fund and Asabys Partners to test the concept, starting with a rare genetic disease of the eye.
The big idea here is protein splicing. Miquel Vila-Perelló, co-founder and CEO, began studying protein segments known as inteins while working as a research scholar with Princeton’s Tom Muir.
Since their discovery in the late 1990s, inteins have been explored for various applications in bioconjugation and protein reconstitution, Vila-Perelló said. But they largely failed to catalyze reactions as efficiently as researchers were hoping.
Building on close to two decades of work by Muir, “we basically evolved or developed, engineered novel inteins that are engineered that overcome the limitations of the natural ones,” he said.
Applied to gene therapy, it translates to two different AAV vectors each encoding for roughly half the protein you want, with an intein tagged to each. Once the body churns out the desired protein, the inteins bind the two fragments to form a full-length protein — then get cleaved off.
“Through our platform technology, we can go after targets that, you know, that were kind of off the picture for gene therapy … because these genes were too large,” Vila-Perelló said. “So these diseases were kind of ruled out or people were trying these rather convoluted approaches of the mini-genes or different strategies that have not really panned out.”
Working out of Barcelona with a team of 10 — they hope to double the headcount with the new round — Splice has nominated a lead program in Stargardt disease. A common form of juvenile macular dystrophy, Stargardt is “a very prevalent disease for a rare disease,” said CBO Gerard Caelles, with more than 80,000 estimated patients in the US and EU. The condition is caused by a loss of function mutation in the ABCA4 gene, which is 6.8kb large.
While other scientists have proposed a dual-vector approach to AAV gene therapy, they relied on DNA recombination to piece the full protein together.
“We estimate that from 20% up to 50% of all monogenic diseases could benefit from our technology,” Caelles said.
With co-founder Silvia Frutos heading the platform technology as CTO/COO, Splice hopes to spend the next two or three years taking the lead candidate toward the clinic while expanding the pipeline, initially in ophthalmology but perhaps expanding to other organs as well.
By that time, Vila-Perelló hopes the booming field may have solved some of the other limitations and issues — including serious safety concerns — around AAV.
“In the future, we expect that there’s gonna be some improvements in vectors that could make systemic delivery less problematic, so that people don’t need to resort to the high doses,” he said.