Periodic Reporting for period 1 - BOOST (Backbone-Optimized OligonucleotideS for Therapeutics)
Okres sprawozdawczy: 2024-04-01 do 2026-03-31
Therapeutic oligonucleotides are a promising class of medicines that can regulate disease related genes and offer new treatment options for many genetic and rare disorders. Their wider use is limited because they require chemical modifications to stay stable and active in the body. These modifications are technically demanding and slow to produce, increasing development time and manufacturing costs.
The BOOST project set out to overcome this challenge by creating a new generation of chemically modified oligonucleotides with improved biological performance. Its goal was to develop innovative backbone structures suitable for antisense oligonucleotides and siRNA, two key technologies in modern genetic medicine. By enabling faster and more efficient chemical modification, BOOST aimed to support the development of more accessible and affordable RNA based therapies.
The project designed new chemical reagents and applied them during solid phase oligonucleotide synthesis, the standard method used to produce therapeutic oligonucleotides. It then evaluated how the new backbone structures behave in biological environments and explored how additional functional groups, such as targeting molecules or imaging dye, can be attached to create more precise and versatile therapeutic tools.
BOOST successfully demonstrated that these new backbone designs can streamline chemical modification and expand the functional possibilities of therapeutic oligonucleotides. This provides a foundation for developing next generation RNA medicines with improved stability, reduced production costs, and enhanced targeting capabilities.
The project is expected to contribute to EU priorities in health innovation, competitiveness, and sustainable production. By reducing chemical waste and energy use during synthesis, BOOST also supports greener manufacturing practices. Overall, the project advances the long term goal of making genetic medicines more efficient, affordable, and widely accessible.
The BOOST project set out to overcome this challenge by creating a new generation of chemically modified oligonucleotides with improved biological performance. Its goal was to develop innovative backbone structures suitable for antisense oligonucleotides and siRNA, two key technologies in modern genetic medicine. By enabling faster and more efficient chemical modification, BOOST aimed to support the development of more accessible and affordable RNA based therapies.
The project designed new chemical reagents and applied them during solid phase oligonucleotide synthesis, the standard method used to produce therapeutic oligonucleotides. It then evaluated how the new backbone structures behave in biological environments and explored how additional functional groups, such as targeting molecules or imaging dye, can be attached to create more precise and versatile therapeutic tools.
BOOST successfully demonstrated that these new backbone designs can streamline chemical modification and expand the functional possibilities of therapeutic oligonucleotides. This provides a foundation for developing next generation RNA medicines with improved stability, reduced production costs, and enhanced targeting capabilities.
The project is expected to contribute to EU priorities in health innovation, competitiveness, and sustainable production. By reducing chemical waste and energy use during synthesis, BOOST also supports greener manufacturing practices. Overall, the project advances the long term goal of making genetic medicines more efficient, affordable, and widely accessible.
The project carried out three main scientific activities: developing new chemical reagents, applying them in oligonucleotide synthesis, and evaluating the resulting structures. A custom heating device to improve synthesis efficiency was also developed as a key technical achievement.
First, the project designed and tested new reagents for backbone modification during solid phase synthesis. This work led to the discovery of a fast and reliable reagent class capable of introducing backbone modifications within seconds. These reagents are stable, easy to prepare, and compatible with a wide range of functional groups.
Second, the new reagents were used to synthesize both singly and multiply modified oligonucleotides, including a fully modified 20 mer. This demonstrated that the method supports high density backbone modification. The newly developed heating device further improved synthesis efficiency by reducing reagent consumption and shortening reaction times.
Third, the modified oligonucleotides were evaluated for their physical and biological properties. Single modified strands showed excellent stability under physiological conditions and normal base pairing behaviour. When incorporated into siRNA, the new backbone structure maintained gene silencing activity without detectable toxicity. Multiply modified oligonucleotides were also produced and tested, and in vitro evaluation of multi modified siRNAs is ongoing.
Overall, the project achieved its scientific objectives by establishing a rapid and versatile back-bone modification method, demonstrating its compatibility with therapeutic oligonucleotides, and developing tools that improve the efficiency and sustainability of oligonucleotide production. These outcomes provide a strong basis for future development and exploitation of next generation RNA based therapeutics.
First, the project designed and tested new reagents for backbone modification during solid phase synthesis. This work led to the discovery of a fast and reliable reagent class capable of introducing backbone modifications within seconds. These reagents are stable, easy to prepare, and compatible with a wide range of functional groups.
Second, the new reagents were used to synthesize both singly and multiply modified oligonucleotides, including a fully modified 20 mer. This demonstrated that the method supports high density backbone modification. The newly developed heating device further improved synthesis efficiency by reducing reagent consumption and shortening reaction times.
Third, the modified oligonucleotides were evaluated for their physical and biological properties. Single modified strands showed excellent stability under physiological conditions and normal base pairing behaviour. When incorporated into siRNA, the new backbone structure maintained gene silencing activity without detectable toxicity. Multiply modified oligonucleotides were also produced and tested, and in vitro evaluation of multi modified siRNAs is ongoing.
Overall, the project achieved its scientific objectives by establishing a rapid and versatile back-bone modification method, demonstrating its compatibility with therapeutic oligonucleotides, and developing tools that improve the efficiency and sustainability of oligonucleotide production. These outcomes provide a strong basis for future development and exploitation of next generation RNA based therapeutics.
The project introduced a fast, stable, and easily accessible reagent class for oligonucleotide backbone modification. Their ability to react within seconds under standard synthesis conditions removes a major bottleneck in producing modified oligonucleotides and enables high density modification, including a fully modified 20 mer. Incorporation into siRNA preserved knockdown activity without cytotoxicity, confirming biological compatibility and expanding the design space for therapeutic nucleic acids.
A second key result is the development of a heating device that halves reagent consumption and synthesis time, improving efficiency and sustainability. Together, the chemistry and device form a technological platform that supports more cost effective production of RNA based medicines and enables the attachment of diverse ligands, dyes, and biomolecules for applications in diagnostics, imaging, and targeted delivery. A priority patent application was filed, and the work has already attracted interest from academic and industrial groups.
The expected impact includes faster development of oligonucleotide based therapies, reduced manufacturing costs, and broader access to genetic medicines. The results also support EU priorities in innovation, competitiveness, and greener production through reduced reagent use and waste.
To ensure further uptake, key needs include extended biological evaluation in disease relevant models, demonstration and scale up studies for industrial translation, continued IP support, and engagement with regulatory frameworks. Collaboration with pharmaceutical developers, oligonucleotide manufacturers, and academic partners will be essential for validating the method across applications and integrating it into existing production pipelines.
A second key result is the development of a heating device that halves reagent consumption and synthesis time, improving efficiency and sustainability. Together, the chemistry and device form a technological platform that supports more cost effective production of RNA based medicines and enables the attachment of diverse ligands, dyes, and biomolecules for applications in diagnostics, imaging, and targeted delivery. A priority patent application was filed, and the work has already attracted interest from academic and industrial groups.
The expected impact includes faster development of oligonucleotide based therapies, reduced manufacturing costs, and broader access to genetic medicines. The results also support EU priorities in innovation, competitiveness, and greener production through reduced reagent use and waste.
To ensure further uptake, key needs include extended biological evaluation in disease relevant models, demonstration and scale up studies for industrial translation, continued IP support, and engagement with regulatory frameworks. Collaboration with pharmaceutical developers, oligonucleotide manufacturers, and academic partners will be essential for validating the method across applications and integrating it into existing production pipelines.