Sangamo Biosciences Inc (SGMO)

[jondoeuk]

Most recombinase-based genome insertion systems require large double-stranded DNA (dsDNA) donors that are often long. But in mammalian cells large cytosolic dsDNA is a danger signal. Key innate immune sensors include pathways related to the cGAS-STING pathway. Different pathways are activated, including the interferon pathway and cells shut down translation or undergo apoptosis (programmed cell death). This means editing efficiency collapses.

This led to INSTALL (Integration through Nucleus-Synthesized Template Addition of Large Lengths), which avoids dsDNA-triggered innate toxicity and is compatible with recombinases https://www.nature.com/articles/s41586-026-10241-z

However, efficiency is still a huge problem, with less than 1% of mouse liver cells showing successful DNA integration. So INSTALL today is still an order of magnitude or more below where it needs to be. Even if LNP delivery works all the steps involved multiply inefficiency. As for recombinase activity, all the steps have failure probabilities.

While the study uses standard LNPs designed for delivering mRNA, the vehicle can be optimised. Also, if recombinases become at least 10-100x more active, which could be possible with groups using ML/AI models, INSTALL-type systems could suddenly cross therapeutic thresholds.

So INSTALL is a big advance but not a near-term clinical solution.