Periodic Reporting for period 1 - REGENERAR (IMPROVING THE EFFECTIVENESS AND SAFETY OF EPIGENETIC EDITING IN BRAIN REGENERATION)
Periodo di rendicontazione: 2024-03-01 al 2025-02-28
The central nervous system has a limited capacity for self-repair. Therefore, technologies to replace lost neurons after an injury, including stroke or neurodegenerative diseases, are of great need. The project REGENERAR aims to develop a non-viral delivery formulation up to TRL4 for the delivery of a brain reprogramming formulation.
In the first step, the safety and targeting of the formulation will be tested in vitro. In the second step, the in vivo safety, elimination, targeting and cell reprogramming will be evaluated. In addition, toxicological studies will be performed in GLP conditions to evaluate both in vivo systemic and local (brain) effects of the formulation. The development of the non-viral formulation will take into account the contributions of key stakeholders in the area of gene editing, health institutions, and patient associations, among others. A roadmap will be developed for upscaling innovation to higher TRL.
The objectives of the project can be summarised as below:
• Development of a non-viral formulation for brain cell reprogramming
• Proof-of-concept demonstration of brain cell reprogramming both in vitro and in vivo
• Advancement of knowledge and education in cellular reprogramming
The consortium includes six partners from three European Member states, including 2 academic institutions (UC, Portugal and HMGC, Germany), 1 research institute (Fraunhofer Institute, Germany), 1 biotech SME (SINGLE, Sweden), 1 large company (Hovione, Portugal) and 1 project management company (SPI, Portugal). Consortium partners have expertise in different fields, including brain drug delivery protein production and cellular reprogramming, production of nanoparticles under GLP conditions, spatially resolved transcriptomics, and safety and toxicity studies.
In the first step, the safety and targeting of the formulation will be tested in vitro. In the second step, the in vivo safety, elimination, targeting and cell reprogramming will be evaluated. In addition, toxicological studies will be performed in GLP conditions to evaluate both in vivo systemic and local (brain) effects of the formulation. The development of the non-viral formulation will take into account the contributions of key stakeholders in the area of gene editing, health institutions, and patient associations, among others. A roadmap will be developed for upscaling innovation to higher TRL.
The objectives of the project can be summarised as below:
• Development of a non-viral formulation for brain cell reprogramming
• Proof-of-concept demonstration of brain cell reprogramming both in vitro and in vivo
• Advancement of knowledge and education in cellular reprogramming
The consortium includes six partners from three European Member states, including 2 academic institutions (UC, Portugal and HMGC, Germany), 1 research institute (Fraunhofer Institute, Germany), 1 biotech SME (SINGLE, Sweden), 1 large company (Hovione, Portugal) and 1 project management company (SPI, Portugal). Consortium partners have expertise in different fields, including brain drug delivery protein production and cellular reprogramming, production of nanoparticles under GLP conditions, spatially resolved transcriptomics, and safety and toxicity studies.
During the initial reporting period, the consortium commenced project activities by recruiting staff, installing new equipment, and establishing methodologies and protocols related to Work Packages (WP) 1, 2, and 3. A strong emphasis was placed on communication, dissemination, exploitation activities (WP5), and project management (WP6). The consortium successfully developed an epigenetic editing system delivered via a non-viral strategy. We demonstrated the ability to target formulations more specifically to glial cells and advanced safety assessments in neural cell models, including neurons, microglia, and astrocytes. In vitro safety studies, conducted in accordance with ISO 10993-5:2009(E) guidelines, showed that at tested concentrations, the formulation did not significantly impact cell viability, with over 85% of cells remaining viable after 24 hours. Furthermore, the consortium demonstrated effective gene editing capabilities in cell monolayer cultures. Progress was also made in generating reporter mouse models to facilitate in vivo monitoring of the epigenetic reprogramming potential of the formulations. Toxicity assessments against immune cells in blood are underway. Key findings from these activities have been published in prestigious journals such as Angewandte Chemie, Nature Communications, and Nucleic Acids Research.
To maximize project visibility and impact, a comprehensive communication and dissemination strategy was implemented. This included launching a project website, developing dissemination materials, and publishing three high-impact scientific articles. The consortium participated in eight international scientific meetings, organized a multi-stakeholder workshop, and held bilateral meetings with industry representatives, patient advocacy groups, and healthcare professionals. Additional outreach activities encompassed dissemination via LinkedIn and X (formerly Twitter), engagement at public events (e.g. schools, European Researchers' Night), press releases, and the production of a project explanatory video.
During the first reporting period, the following milestones have been successfully achieved: (i) kick-off meeting held and management structure established; (ii) online platform launched for data sharing and communication among partners; (iii) synthesis of formulations to deliver the epigenetic editing system; (iv) initial results of the in vitro delivery of the epigenetic editing system; (v) initial results related with the in vitro epigenetic reprogramming of brain cells; (vi) generation of a reporter mouse and (vii) organization of a multi-stakeholder workshop.
During this period the following deliverables have been successfully submitted: (i) D1 – Website and project logo; (ii) D2 – Ethics Report; (iii) D3 – Data Management Plan; (iv) D4 – Plan for dissemination and Communication Activities; (v) D5 – Plan for Exploitation Activities; (vi) D6 – Production of the epigenetic editing system.
To maximize project visibility and impact, a comprehensive communication and dissemination strategy was implemented. This included launching a project website, developing dissemination materials, and publishing three high-impact scientific articles. The consortium participated in eight international scientific meetings, organized a multi-stakeholder workshop, and held bilateral meetings with industry representatives, patient advocacy groups, and healthcare professionals. Additional outreach activities encompassed dissemination via LinkedIn and X (formerly Twitter), engagement at public events (e.g. schools, European Researchers' Night), press releases, and the production of a project explanatory video.
During the first reporting period, the following milestones have been successfully achieved: (i) kick-off meeting held and management structure established; (ii) online platform launched for data sharing and communication among partners; (iii) synthesis of formulations to deliver the epigenetic editing system; (iv) initial results of the in vitro delivery of the epigenetic editing system; (v) initial results related with the in vitro epigenetic reprogramming of brain cells; (vi) generation of a reporter mouse and (vii) organization of a multi-stakeholder workshop.
During this period the following deliverables have been successfully submitted: (i) D1 – Website and project logo; (ii) D2 – Ethics Report; (iii) D3 – Data Management Plan; (iv) D4 – Plan for dissemination and Communication Activities; (v) D5 – Plan for Exploitation Activities; (vi) D6 – Production of the epigenetic editing system.
The partners of REGENERAR have an established track record of achieving impact in health and disease, business and science. This is demonstrated by their relationships with a broad range of partners including national health authorities, clinical societies, expertise centers and patient-advocacy groups.
One of the impacts of the project is in the area of stroke. The cellular reprogramming in patients not able to recover functionally from a stroke episode has high social and economic impact. A report conducted by the University of Oxford showed that in 2017, nearly 9 million Europeans (32 countries) were living with stroke. The economic impact due to productivity losses (12 billion euros) and unpaid care provided to stroke survivors by loved ones (16 billion euros) reached the 28 billion euros. It is expected that the reverse in gliose in stroke survivors by cellular reprogramming will lead to saves (estimate) in the order of 2 billion euros in EU every year.
Another major impact of the project is in the are of neurodegenerative diseases. It is estimated that approximately 10 million Europeans live with AD and this number will grow significantly in the next years aligned with the ageing of the European population. In 2019, the European direct (does not include family costs) spending attributable to AD was 9 billion USD. It is expected that REGENERAR project will reduce the burden of AD in the order of 1 billion euros in EU every year (∼10% of the costs) through accelerating the clinical application of epigenetic reprogramming therapeutics using cutting-edge delivery tools with superior efficiency and safety.
One of the impacts of the project is in the area of stroke. The cellular reprogramming in patients not able to recover functionally from a stroke episode has high social and economic impact. A report conducted by the University of Oxford showed that in 2017, nearly 9 million Europeans (32 countries) were living with stroke. The economic impact due to productivity losses (12 billion euros) and unpaid care provided to stroke survivors by loved ones (16 billion euros) reached the 28 billion euros. It is expected that the reverse in gliose in stroke survivors by cellular reprogramming will lead to saves (estimate) in the order of 2 billion euros in EU every year.
Another major impact of the project is in the are of neurodegenerative diseases. It is estimated that approximately 10 million Europeans live with AD and this number will grow significantly in the next years aligned with the ageing of the European population. In 2019, the European direct (does not include family costs) spending attributable to AD was 9 billion USD. It is expected that REGENERAR project will reduce the burden of AD in the order of 1 billion euros in EU every year (∼10% of the costs) through accelerating the clinical application of epigenetic reprogramming therapeutics using cutting-edge delivery tools with superior efficiency and safety.