Programmable Genomic integration (PGI): a technology that enables the integration of large DNA sequences at specific genomic locations

Tome Biosciences is leading the field of programmable genomic integration (PGI). Building on founding technologies obtained from MIT and Replace Therapeutics, Tome has developed and refined PGI resulting in stable integration of multiple kilobases of DNA at user-defined locations. Integrase-mediated PGI (I-PGI) uses a Cas9 nickase with a writing enzyme (reverse transcriptase or ligase) to write an integrase recognition site (‘beacon’) at a user-defined location in the genome. Beacon placement (BP) is followed by integrase-mediated integration of donor DNA. I-PGI enables therapeutic correction of genetic diseases through the insertion of functional genes at the endogenous location without dependency on a double-strand break (DSB) and is not dependent on homology-directed repair (HDR). This technology is agnostic to the size of the DNA template and, due to the orthogonal nature of the integrase: beacon system and lack of DSBs, this technology can be used to generate complex cell therapies via multiplex large gene insertion.

This presentation will focus on an overview of PGI and highlight the progress Tome has made in developing this technology into medicine for patients in need. We will present data showing efficient PGI in primary human cells (iPSCs, Primary Human Hepatocytes (PHH)), as well as our current progress in translating PGI into rodent and non-human primates (NHP).

Tome is developing this technology to treat a wide variety of both rare and common diseases. For in vivo gene therapy applications, PGI will enable the integration of a healthy copy of a gene at the endogenous location, meaning that a single product will work for the majority of the patient population, regardless of the specific mutation. For cell therapy applications, PGI enables the development of highly edited cell therapies, opening the door to a new generation of medicine specifically designed for common diseases such as autoimmunity.

Learning Objectives:
PGI is a new technology that combines site specificity of integrases with Cas9-based genome editing to allow large gene insertion/replacement at user-defined locations.