REPLIBIO

Gene therapy, which aims to correct diseases by modifying patients’ genetic material, is booming. But this medical revolution faces a major obstacle: the large-scale, affordable production of the necessary therapeutic tools. In particular, the plasmids (small circular DNA fragments) used in these treatments are expensive to manufacture and, in most cases, do not replicate in human cells, limiting their efficacy and duration of action.
To overcome these challenges, the REPLIBIO project, the fruit of collaboration between the Institute of Human Genetics (IGH), Genethon and the Centre de Biologie Structurale (CBS), is proposing an innovative solution: to create plasmids capable of replicating autonomously in human cells. This advance could transform the production of gene therapies, particularly those using AAV (adeno-associated virus) vectors, the most widely used today.
The main scientific challenge is to understand and control the mechanisms of DNA replication in human cells, in order to adapt them to therapeutic plasmids. To this end, the IGH benefits from a vast collection of human replication origin sequences identified by the Méchali team and protected by two patents. These origins are active when inserted elsewhere in the genome, and can confer autonomous replication to plasmids. They are being used to design a new type of vector: non-viral, self-replicating and more efficient. This will massively reduce the quantity of plasmids needed to produce AAVs, while increasing production reliability and quality. The CBS is contributing its expertise in advanced microscopy to observe the behavior of the new plasmids in the cell nucleus. Généthon, for its part, will play a key role in plasmid design and manufacture, as well as in bioproduction quality control.
The expected results are major: more efficient production of gene therapies will bring down costs, make these treatments more accessible to patients, and repatriate part of the production to France, thereby strengthening health sovereignty. It will also pave the way for new therapeutic applications in oncology and the development of DNA vaccines.
The REPLIBIO project’s main lines of research are:
1. Design of new self-replicating plasmids based on human replication origins.
2. Optimization of replication according to the type of producing cell, integrating key genomic and epigenetic elements.
3. Improved targeting of plasmids to areas of the nucleus favorable to replication.
4. Modification of cell lines used in production to reduce their rejection of foreign DNA.
5. Real-time plasmid visualization using state-of-the-art microscopy.
6. Integration of Genethon’s know-how into industrial production lines.
In short, REPLIBIO offers breakthrough innovation in the field of gene therapy, combining fundamental research, biological engineering and biomanufacturing to develop the safer, more effective and more accessible treatments of tomorrow.