Periodic Reporting for period 1 - EURAS (EUropean network for neurodevelopmental RASopathies)
Reporting period: 2023-06-01 to 2024-11-30
RASopathies are a group of genetic diseases caused by mutations in genes encoding components and regulators of the cellular RAS signalling pathway, resulting in increased signalling through this pathway. RAS signalling regulates cell division, growth, differentiation and survival in proliferative cells. In neurons, the non-proliferative cells of the brain, RAS signalling controls the wiring of neuronal networks, synaptogenesis and neurotransmission, critically shaping executive and cognitive brain functions. Reflecting the universal importance of RAS signalling across cell types, RASopathies display a wide range of symptoms, including growth retardation, cardiovascular defects, skin and musculoskeletal abnormalities, and neurocognitive impairment of various degree. The physical manifestations of the diseases can be life-threatening, but are reasonably manageable with multidisciplinary symptomatic treatments. However, there is a lack of therapies that specifically target the neurocognitive symptoms that are prominent in RASopathies such as Syngap1-related syndrome, cardio-facio-cutaneous syndrome and Costello syndrome. In addition, seizures, intellectual disability, autism, emotional and behavioural disorders often co-occur in these conditions, which complicates the correct classification and treatment of neurocognitive features and creates a lifelong burden for affected individuals and their caregivers.
The EURAS project addresses this gap. It brings together partners with a proven multidisciplinary track record who will contribute their expertise and cutting-edge technologies to achieve a common goal: the development of new effective therapies and operative disease management for neurodevelopmental RASopathies. The EURAS consortium covers clinical work, disease modelling, molecular, cellular and systems neurobiology, technology development, drug screening and drug delivery. In addition, a patient organisation is a formal partner of the EURAS consortium, acting as a link to the national patient organisations from 13 countries in Europe and beyond. The direct link with the patient organisation provides EURAS partners with exceptional access to patient cohorts and enables the patient organisation to actively shape the research undertaken within the project.
EURAS has set itself a number of objectives to achieve its goals. With strong support from patient organisations and in close collaboration between bioinformaticians and clinicians, EURAS implements a new registry based on reporting by patients and their caregivers to collect data on disease characteristics and treatment effects. Collected datasets will be subjected to state-of-the-art multi-level bioinformatic analysis to assess treatment efficacy and stratify patient cohorts. New disease models will be generated and characterised to cover disease variability, to elucidate the pathophysiology of RASopathies and to identify cellular/molecular 'disease signatures' that will be used as biomarkers for drug screening and therapy validation. Phenotypic screening of drug libraries, supported by high resolution and high content automated pipelines, will be performed on differentiated electrically active rodent and patient iPSC-derived neurons. Preclinical proof-of-concept studies will be conducted using repurposed drugs and antisense oligonucleotides to achieve reversal of neurological and behavioural symptoms in animal models. To provide less invasive treatments for patients, new technologies for efficient delivery of treatments to the brain will be developed and validated. Finally, EURAS will establish a pan-European patient network to improve awareness and communication among affected families and facilitate their access to knowledge and therapies.
Overall, EURAS will bring about a step change in the implementation of less invasive treatments for patients, improve awareness and information sharing, and bring new state-of-the-art knowledge and therapies to patients and their families. In addition, many other diseases will benefit from the transferability of EURAS results. In this way, EURAS will make a lasting difference to people's lives and strengthen the expertise of healthcare systems in Europe and around the world.
The EURAS project addresses this gap. It brings together partners with a proven multidisciplinary track record who will contribute their expertise and cutting-edge technologies to achieve a common goal: the development of new effective therapies and operative disease management for neurodevelopmental RASopathies. The EURAS consortium covers clinical work, disease modelling, molecular, cellular and systems neurobiology, technology development, drug screening and drug delivery. In addition, a patient organisation is a formal partner of the EURAS consortium, acting as a link to the national patient organisations from 13 countries in Europe and beyond. The direct link with the patient organisation provides EURAS partners with exceptional access to patient cohorts and enables the patient organisation to actively shape the research undertaken within the project.
EURAS has set itself a number of objectives to achieve its goals. With strong support from patient organisations and in close collaboration between bioinformaticians and clinicians, EURAS implements a new registry based on reporting by patients and their caregivers to collect data on disease characteristics and treatment effects. Collected datasets will be subjected to state-of-the-art multi-level bioinformatic analysis to assess treatment efficacy and stratify patient cohorts. New disease models will be generated and characterised to cover disease variability, to elucidate the pathophysiology of RASopathies and to identify cellular/molecular 'disease signatures' that will be used as biomarkers for drug screening and therapy validation. Phenotypic screening of drug libraries, supported by high resolution and high content automated pipelines, will be performed on differentiated electrically active rodent and patient iPSC-derived neurons. Preclinical proof-of-concept studies will be conducted using repurposed drugs and antisense oligonucleotides to achieve reversal of neurological and behavioural symptoms in animal models. To provide less invasive treatments for patients, new technologies for efficient delivery of treatments to the brain will be developed and validated. Finally, EURAS will establish a pan-European patient network to improve awareness and communication among affected families and facilitate their access to knowledge and therapies.
Overall, EURAS will bring about a step change in the implementation of less invasive treatments for patients, improve awareness and information sharing, and bring new state-of-the-art knowledge and therapies to patients and their families. In addition, many other diseases will benefit from the transferability of EURAS results. In this way, EURAS will make a lasting difference to people's lives and strengthen the expertise of healthcare systems in Europe and around the world.
In its first 18 months of operation, EURAS has achieved a number of important results:
EURAS established a clear organizational framework, guidelines and all support mechanisms. This is a prerequisite for a smooth and coordinated project workflow in EURAS. The established regular monitoring ensured that objectives and milestones were met on time. Importantly, a continuous risk analysis and transparent conflict management structures were established and proved to be effective in identifying and communicating deviations in a timely manner so that effective corrective actions could be developed quickly and in a coordinated manner.
Important organizational, legal, technical and scientific steps were executed to establish and exploit PATRAS and to create an international patient network that will be instrumental to reach, inform and recruit PATRAS participants. The PATRAS A and PATRAS B studies have recruited 316 and 306 participants, respectively. The domain-specific set of common data elements (DCDE) for neurodevelopmental RASopathies was defined and published.
An effective workflow was established to provide all EURAS partners with standardized human cell lines and mouse models for disease modelling of RASopathies and drug screening. The working and master cell bank has been established centrally for existing iPSC lines and made available to EURAS partners. Several independent iPSC lines for CS were generated by gene editing to facilitate implementation of disease-specific neurons and brain organoids within project. A novel mouse model with brain-specific expression of the CFC mutation was established and validated.
Studies in human in vitro and mouse in vivo disease models were initiated to identify disease-related phenotypes that will be used as biomarkers for drug screening and for evaluation of treatment effects. First robust phenotypes have been identified in cellular and animal disease models.
The work towards identification of effective ASOs and drug candidates that restore, at least in part, healthy phenotypes in disease models of RASopathies was initiated. ASOs applicable to restore physiological signalling, which is increased in RASopathies, were developed. Considerable work was invested to establish workflow for drug screening, including establishment of scalable conditions and workflows for reproducible iPSC differentiation and culturing.
Important steps towards new brain delivery strategies have been made through the development of new drug encapsulation technologies and antisense oligonucleotides.
Patient organisation representatives have been appointed to the EURAS Patient Board to facilitate the exchange and awareness of affected families and to increase the project's outreach within Europe and worldwide. The network of patient organisations is also essential for effective and timely recruitment of participants for the PATRAS surveys.
EURAS established a clear organizational framework, guidelines and all support mechanisms. This is a prerequisite for a smooth and coordinated project workflow in EURAS. The established regular monitoring ensured that objectives and milestones were met on time. Importantly, a continuous risk analysis and transparent conflict management structures were established and proved to be effective in identifying and communicating deviations in a timely manner so that effective corrective actions could be developed quickly and in a coordinated manner.
Important organizational, legal, technical and scientific steps were executed to establish and exploit PATRAS and to create an international patient network that will be instrumental to reach, inform and recruit PATRAS participants. The PATRAS A and PATRAS B studies have recruited 316 and 306 participants, respectively. The domain-specific set of common data elements (DCDE) for neurodevelopmental RASopathies was defined and published.
An effective workflow was established to provide all EURAS partners with standardized human cell lines and mouse models for disease modelling of RASopathies and drug screening. The working and master cell bank has been established centrally for existing iPSC lines and made available to EURAS partners. Several independent iPSC lines for CS were generated by gene editing to facilitate implementation of disease-specific neurons and brain organoids within project. A novel mouse model with brain-specific expression of the CFC mutation was established and validated.
Studies in human in vitro and mouse in vivo disease models were initiated to identify disease-related phenotypes that will be used as biomarkers for drug screening and for evaluation of treatment effects. First robust phenotypes have been identified in cellular and animal disease models.
The work towards identification of effective ASOs and drug candidates that restore, at least in part, healthy phenotypes in disease models of RASopathies was initiated. ASOs applicable to restore physiological signalling, which is increased in RASopathies, were developed. Considerable work was invested to establish workflow for drug screening, including establishment of scalable conditions and workflows for reproducible iPSC differentiation and culturing.
Important steps towards new brain delivery strategies have been made through the development of new drug encapsulation technologies and antisense oligonucleotides.
Patient organisation representatives have been appointed to the EURAS Patient Board to facilitate the exchange and awareness of affected families and to increase the project's outreach within Europe and worldwide. The network of patient organisations is also essential for effective and timely recruitment of participants for the PATRAS surveys.
None of the planned results have yet been achieved.