New Gene-Writing Tool Helps To Develop Advanced Gene Therapies – Technology Networks

An international, multidisciplinary team of researchers from theTranslational Synthetic Biology Laboratoryat Pompeu Fabra University (Barcelona, Spain), led by Dr.Marc Gell, has published an article in the scientific journalNature Communicationsshowing the potential of Find Cut-and-Transfer (FiCAT) technology as a state-of-the-art tool forgene writingto develop advanced therapies that are safer and more effective in their future clinical application in patients withgenetic and oncological diseasesthat have few treatment options.

The UPF Translational Synthetic Biology Laboratory has been working on gene editing and synthetic biology applied to gene therapies since 2017. FiCAT technology is an important scientific breakthrough to overcome the current limitations of the technology used today for genome editing and gene therapy.

Human genome engineering has significantly progressed in the last decade with the development of new editing tools, but there was still a technology gap that would allow therapeutic genes to be transferred efficiently with few size limitations, comments Dr. Marc Gell, supervisor of the study.

In this work, the researchers develop an efficient and precise programmable gene writing technology based on the combination of modified proteins CRISPR-cas and piggy Bac transposase (PB), succeeding in inserting small and large fragments. Dr.Maria Pallars, co-first author of the study explains that: CRISPR stands out for its precision when editing small fragments. However, transposases allow us to insert large fragments but in an uncontrolled manner. We have combined the best of each technology.

In this way, FiCAT technology allows us to precisely insert large fragments of DNA into the genome. This means we can develop therapeutic solutions to diseases that currently have no treatment, such as Duchenne muscular dystrophy, or some cases of hereditary blindness, in which the affected gene is large in size, asserts Dr.Avencia Snchez-Mejas, a senior researcher with the group and co-supervisor of the work.

They tested the technology in human and mouse cell lines achieving efficiencies of 522% with minimal off-target insertions and have demonstrated on-target gene transfer in vivo in mouse liver and germline cells in mouse models. Lastly, they performed a directed evolution of FiCAT and further improved efficiency by 25-30%. We have been progressively modifying enzymes so that they acquire the function we were looking for, selecting the ones that displayed a better function, detailsDimitrije Ivani, co-first author of the article. Our work is a clear example that enzyme engineering in the context of genome editing has great potential, he concludes.

UPF has transferred FiCAT technology via the spinoffIntegra Therapeutics, founded in 2020 by the researchers Marc Gell and Avencia Snchez-Mejas, seeking to get this scientific knowledge and technological capacity to reach the biopharmaceutical industry to develop safe and efficient advanced technologies that reach patients. Recently, Integra Tx has obtained 4.5 million euros in funding from Advent France Biotechnology (France), Invivo Capital (Spain) and Takeda Ventures (USA).

The work published in Nature Communications was carried out with funding from the Societal challenges AEI, AGAUR- PRODUCTE, UPGRADE-Horizon 2020 of the European Commission; la Caixa CaixaImpulse Validate and CaixaImpulse Consolidate programmes; the Ramn Areces Foundation; and the Ramn y Cajal programme of the Spanish Ministry of Economy, Industry and Competitiveness.

Reference:Pallars-Masmitj M, Ivani D, Mir-Pedrol J, et al. Find and cut-and-transfer (FiCAT) mammalian genome engineering. Nat Commun. 2021;12(1):7071. doi: 10.1038/s41467-021-27183-x

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New Gene-Writing Tool Helps To Develop Advanced Gene Therapies - Technology Networks