Next generation gene writing platform to cure genetic and oncological diseases

Projektinformationen

FiCAT

ID Finanzhilfevereinbarung: 101188324

DOI

10.3030/101188324

EK-Unterschriftsdatum 19 Dezember 2024

Startdatum 1 Dezember 2024

Enddatum 30 November 2026

Finanziert unter

• The European Innovation Council (EIC)

Gesamtkosten

Keine Daten

EU-Beitrag

€ 2 496 375,00

Koordiniert durch

INTEGRA THERAPEUTICS S.L.
Spain

Periodic Reporting for period 1 - FiCAT (Next generation gene writing platform to cure genetic and oncological diseases)

Berichtszeitraum: 2024-12-01 bis 2025-11-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

The current landscape of gene therapy, while holding immense promise for curing severe genetic diseases, is heavily constrained by the reliance on traditional viral vectors. These vectors pose significant challenges, including safety risks such as immunogenicity and the potential for insertional mutagenesis, alongside difficulties in achieving cost-effective, large-scale manufacturing. These limitations ultimately restrict the broad and safe application of life-changing curative treatments for patients.

The FICAT (Find-Cut And-Transfer) project is driven by the ambition to establish a new paradigm and radically change this landscape. The overall objective is to develop and validate a novel, highly efficient, and non-viral Gene Editing System that completely bypasses the safety issues and manufacturing constraints of viral vectors. FICAT utilizes a cutting-edge non-viral delivery system based on lipid nanoparticles (LNPs) combined with a proprietary, highly efficient integrase enzyme. This unique combination is engineered to achieve stable, long-lasting gene expression in target cells, overcoming the major drawback of transient gene expression seen in many other non-viral methods.

FICAT's pathway to impact is designed to be transformative. By offering a safer, non-immunogenic and scalable platform, the project aims to significantly lower the production costs of gene therapies, thereby enhancing global accessibility for patients and sustainability for healthcare systems. Our initial focus is a first-in-human clinical demonstration for a liver disorder, which will serve to validate the platform's universal potential for treating a wide array of monogenic diseases. This work directly addresses a strategic European Union priority: the urgent need for faster, safer and more affordable advanced therapeutic medicinal products (ATMPs).

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

The project commenced with the established scientific foundation of the proprietary FiCAT. This is a breakthrough non-viral Gene Editing System, which uniquely combines the precision of RNA-guided nucleases with the high efficacy of programmable transposases to achieve safe, precise, and stable integration of therapeutic DNA into the genome.

Key preparatory work successfully validated the platform’s capacity for large-gene insertion, demonstrating the ability to integrate DNA cargos up to 22 kb ex vivo and 11 kb in vivo. This capability was confirmed through in vivo therapeutic proof-of-concept studies, where the 9.2kb LAMA2 gene was inserted in an animal model for congenital muscular dystrophy type A, resulting in improved life expectancy and mobility. The non-viral delivery system, based on advanced Lipid Nanoparticles (LNPs), was also established as an efficient, virus-free approach for large-size genome engineering with demonstrated robust efficiency in targeting the liver.

The current work is structured around two main technical objectives. The first one is focused on optimization and IND-enabling studies, including refining the FiCAT gene writing formulation, adapting optimal LNP delivery solutions and improving transgene expression levels specifically for liver diseases. The second objective aims to execute the in vivo platform validation and PoC for the first clinical target: a liver disorder. This critical work involves comprehensive toxicity and efficacy studies in animal models using the full-length gene, aiming to confirm stable, durable therapeutic gene expression and to assess redosing potential, thereby paving the way for clinical trial application.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

FiCAT has demonstrated significant potential as a versatile, non-viral solution for precise and stable genetic modifications across various biological contexts. The key findings are summarized below:

- Robust and Precise Genomic Integration: Current results confirm that FiCAT can handle substantial non-viral donor DNA sizes, facilitating the delivery of complex therapeutic cargos in primary human cell lines with high on-target precision.
- Effective In Vivo Delivery Performance: Utilizing a refined Lipid Nanoparticle (LNP) delivery system, FiCAT has achieved in vivo editing rates that are highly competitive with existing benchmarks.
- Durable and Stable Expression Profiles: Unlike transient non-integrative approaches, FiCAT-mediated integration ensures stable and long-term transgene expression.
- Enhanced Intracellular Transport: Significant progress has been made in overcoming the “nuclear barrier” by actively facilitating the translocation of genetic material from the cytosol to the nucleus.

The immediate priority of FiCAT lies in the completion of robust IND-enabling studies, which will serve as the foundation for our first-in-human trials. This transition is not merely a technical step but a regulatory one; as we pioneer a novel non-viral in vivo gene writing platform, we must work proactively with governing bodies to help establish a clear and supportive regulatory framework that recognizes the unique safety profile of non-viral delivery.

Finally, the ultimate success of FiCAT is inextricably linked to its industrial scalation. To truly achieve the cost-reductions that make gene therapy accessible, we are focused on securing the strategic investment necessary for commercial-scale manufacturing of LNP components.

Figure 3. Key Competitive Advantages of the FiCAT Gene Writing Platform.

Figure 2. Delivery Modalities for FiCAT.

Figure 1. FiCAT components.