Cellectis SA has announced the delivery of two meganucleases targeting the p53 gene to its partners in the NETSENSOR collaborative research project (part of the European Union's 6th Framework program).
NETSENSOR is a research consortium in the field of synthetic biology. Its purpose is to develop a system that detects a particular type of malfunction in the cell: alteration of the p53 protein function, observed in practically all cancers. The system developed by NETSENSOR not only detects the malfunction, but also reacts either by killing the cell or repairing it with a meganuclease.
The approach pursued by NETSENSOR is to build synthetic gene networks able to respond to alterations in cells. By carefully linking chosen genes and regulatory sequences, scientists are able to design and construct "gene networks" that can sense specific conditions or signals in the cell and respond either to detect them or counter their effects.
Within NETSENSOR, a multi-disciplinary team is working to develop one such network that will sense errors in p53 signaling - a pathway altered in almost all cancers - and respond either by killing the cell or by actually repairing detected mutations. The technology could have a wide range of applications - from diagnostics to gene therapy.
NETSENSOR brings together teams from Cellectis and several research institutes: the European Molecular Biology Laboratory (Heidelberg), Centro de Regulacion Genomica (Barcelona), Centro Nacional de Investigaciones Oncologicas (Madrid), and Medizinische Hochschule Hannover (Hannover).
The protein p53 was chosen as one of the program's primary targets because it is a major tumor suppressor. This protein is directly altered in ~50% of all cancers, while the other 50% carry alterations in genes or mechanisms that directly regulate p53. p53 acts as a checkpoint protein and also controls apoptosis (programmed cell death). Thus, it can prevent the proliferation of damaged cells by blocking their development or triggering apoptosis.
Meganucleases cleaving sequences from the p53 gene have been generated on Cellectis' high throughput screening platform. Meganuclease design relies on Cellectis' database of meganuclease variants, and on the know how accumulated over several years of meganuclease engineering, which enables the production of meganucleases with tailored specificity for most genes identified to date: indeed, targetable sequences are found once every one thousand base pairs on average.
These meganucleases will be first used in the repair process triggered by the gene regulatory network designed by NETSENSOR. Further characterization will be required to investigate the therapeutic potential of these meganucleases.