Periodic Reporting for period 2 - PREMSTEM (Brain injury in the premature born infant: stem cell regeneration research network)
Periodo di rendicontazione: 2021-07-01 al 2022-12-31
In 2010, the Global Burden of Disease Study estimated that preterm birth was the commonest cause of death and disability in children under the age of 5 years. Preterm birth causes more deaths than malaria or pneumonia, resulting in the loss of 77 million Disability Adjusted Life Years (DALYs). In the developed world the incidence of prematurity is increasing: with rates currently at 7% of all births in the EU. Most of these infants survive, but morbidity is very high, predominantly due to neurological damage or Encephalopathy of Prematurity (EoP). To highlight the severity of this neurological injury, almost 10% of infants born before 33 weeks develop cerebral palsy, and approximately 35% have persisting cognitive and neuropsychiatric deficits, including autism spectrum disorder and attention deficit disorder later in life. Even modest reductions in gestational length have significant adverse effects; for example, increasing a child’s need for special educational support. As such, prematurity is a significant problem for the provision of long-term educational and health care. The emotional costs of EoP to individuals and their families is immeasurable, but the lifetime costs for provision of care for one child affected by cerebral palsy is approximately 1.3 million US dollars.
PREMSTEM is a collective of world leading clinicians, researchers, stakeholder advocacy groups and an industrial partner with well-established experience in neonatology and drug development. PREMSTEM is focussed on delivering to the clinic a novel regenerative therapy to reduce the enormous emotional and economic burden of EoP. We aim to validate umbilical cord derived human mesenchymal stem cells (H-MSCs) as a regenerative therapy for EoP to improve the quality of life for these infants and reduce the societal costs of their special needs.
PREMSTEM is a collective of world leading clinicians, researchers, stakeholder advocacy groups and an industrial partner with well-established experience in neonatology and drug development. PREMSTEM is focussed on delivering to the clinic a novel regenerative therapy to reduce the enormous emotional and economic burden of EoP. We aim to validate umbilical cord derived human mesenchymal stem cells (H-MSCs) as a regenerative therapy for EoP to improve the quality of life for these infants and reduce the societal costs of their special needs.
In WP1, we established the most neuroprotective strategies for human mesenchymal stem cells (H-MSC) treatment in two small animal models of encephalopathy of prematurity (EoP). We determined the optimal treatment regime using neuropathology and mathematical approaches.
In WP2, ovine studies have been successfully performed for the infection ventilation cohort.
In WP3, we are studying the potential beneficial effects of H-MSC on multiple target cells important during EoP (i.e. peripheral blood cells, neurons, oligodendrocytes, neural stem cells and microglia) using cultures. We have demonstrated beneficial effects of H-MSC on several target cells so far. In the upcoming period we will investigate whether the optimized H-MSC will yield superior effects on the target cells.
In WP4, using 5 small clinically relevant animal models of EoP, our goal is to characterize the neuroregenerative effects of H-MSC both at the short-term and long-term levels. Despite some initial challenges in the inflammation-based models, we made very good progress in all five animal models, demonstrating a clear phenotype of the models so that in-depth characterization of H-MSC treatment has started in almost all models.
In WP5, we have implemented new functionalities (super-resolution imaging) in the preclinical research prototype built in RP1. The multiplane ultrasound probe for 3D functional and super-resolution imaging has been tested and validated in rodents.
WP6 aims at increasing impact of PREMSTEM. The activities within WP6 continue to raise awareness and promote the project content. During this reporting period, a wide range of content mainly addressed to a lay audience has been produced and translated into several languages. The Patient/Consumer Advisory Board (PCAB) continues to be engaged within the project and contributes to several communication and co-creation activities. The co-creation process is advancing and several workshops with a wide range of external stakeholders have taken place. The first draft version of an exploitation and sustainability strategy has been circulated internally.
In WP7, the coordinator and IT organised 2 annual meetings and 3 ExCom meetings. They prepared and submitted on behalf of the consortium two progress and financial reports to the EC (Period 1 and 2).
In WP8, PREMSTEM ensures the continuous addressing of ethical questions.
In WP2, ovine studies have been successfully performed for the infection ventilation cohort.
In WP3, we are studying the potential beneficial effects of H-MSC on multiple target cells important during EoP (i.e. peripheral blood cells, neurons, oligodendrocytes, neural stem cells and microglia) using cultures. We have demonstrated beneficial effects of H-MSC on several target cells so far. In the upcoming period we will investigate whether the optimized H-MSC will yield superior effects on the target cells.
In WP4, using 5 small clinically relevant animal models of EoP, our goal is to characterize the neuroregenerative effects of H-MSC both at the short-term and long-term levels. Despite some initial challenges in the inflammation-based models, we made very good progress in all five animal models, demonstrating a clear phenotype of the models so that in-depth characterization of H-MSC treatment has started in almost all models.
In WP5, we have implemented new functionalities (super-resolution imaging) in the preclinical research prototype built in RP1. The multiplane ultrasound probe for 3D functional and super-resolution imaging has been tested and validated in rodents.
WP6 aims at increasing impact of PREMSTEM. The activities within WP6 continue to raise awareness and promote the project content. During this reporting period, a wide range of content mainly addressed to a lay audience has been produced and translated into several languages. The Patient/Consumer Advisory Board (PCAB) continues to be engaged within the project and contributes to several communication and co-creation activities. The co-creation process is advancing and several workshops with a wide range of external stakeholders have taken place. The first draft version of an exploitation and sustainability strategy has been circulated internally.
In WP7, the coordinator and IT organised 2 annual meetings and 3 ExCom meetings. They prepared and submitted on behalf of the consortium two progress and financial reports to the EC (Period 1 and 2).
In WP8, PREMSTEM ensures the continuous addressing of ethical questions.
Progress beyond the state-of-the-art:
The current clinical situation for preterm born infants is that there are no effective options that specifically treat their brain injuries; in turn, we have a very limited ability to reduce or correct the poor neurological outcomes caused by EoP. Research expenditure focused on diseases and injury in neonates is vastly lower than in related adult disorders. It is estimated that of all the R&D money spent across the EU, only 1-4% is targeted to maternal and perinatal health.
PREMSTEM overcomes these hurdles to go beyond the state-of-the-art by applying the following approaches:
- Addressing the need for better testing processes – improving on the one protocol in one model approach. PREMSTEM will extensively screen the efficacy of H-MSC in a large battery of in vivo and in vitro animal models of EoP, using the ‘best in field’ mesenchymal stem cells.
- Addressing the need for better imaging modalities for patient identification, stratification and follow-up, using state-of-the-art high-resolution 3D imaging techniques.
- Addressing the need for rapid translation of preclinical studies: regulatory needs. PREMSTEM’s innovation plan includes a strong industry-academia partnership from the beginning of the project, ensuring compliance with regulatory guidelines for development, registration and commercialization of therapeutic products.
- Addressing the need for rapid translation of preclinical studies: setting the scene for health care professionals and related stakeholders. PREMSTEM includes a dissemination and exploitation strategy with the goal of increasing the visibility and impact of PREMSTEM on both public health and society, and most importantly, the fast tracking of bench to bedside research through strong industrial expertise in product development in neonatology and ATMPs.
Expected results:
- Identification of the most effective H-MSC neuroregenerative paradigm/s
- Short- and long-term outcomes of H-MSC treatment on neuroregeneration and immune function
- Creation of a statistically derived mechanistic model of H-MSC-induced neuroregeneration
- Expansion of our knowledge of the efficacy of our optimised H-MSC treatment
- Operational prototype for 2D ultrafast ultrasound imaging with advanced preclinical imaging modes
- Coherent and meaningful engagement of stakeholders
- Implementation of our Exploitation Roadmap and Business Plan
Impacts:
PREMSTEM will bring potential new regenerative therapies to address unmet clinical needs of large patient groups identified, with an obvious societal impact via its potential to help reducing morbidity associated with prematurity.
PREMSTEM will strengthen Europe's position in translational regenerative medicine by providing a road-map of the best practice in validating an efficacious stem cell-based therapy for a large heterogeneous patient group. This road-map will enable PREMSTEM’s approach of screening to be deployed for other conditions.
The current clinical situation for preterm born infants is that there are no effective options that specifically treat their brain injuries; in turn, we have a very limited ability to reduce or correct the poor neurological outcomes caused by EoP. Research expenditure focused on diseases and injury in neonates is vastly lower than in related adult disorders. It is estimated that of all the R&D money spent across the EU, only 1-4% is targeted to maternal and perinatal health.
PREMSTEM overcomes these hurdles to go beyond the state-of-the-art by applying the following approaches:
- Addressing the need for better testing processes – improving on the one protocol in one model approach. PREMSTEM will extensively screen the efficacy of H-MSC in a large battery of in vivo and in vitro animal models of EoP, using the ‘best in field’ mesenchymal stem cells.
- Addressing the need for better imaging modalities for patient identification, stratification and follow-up, using state-of-the-art high-resolution 3D imaging techniques.
- Addressing the need for rapid translation of preclinical studies: regulatory needs. PREMSTEM’s innovation plan includes a strong industry-academia partnership from the beginning of the project, ensuring compliance with regulatory guidelines for development, registration and commercialization of therapeutic products.
- Addressing the need for rapid translation of preclinical studies: setting the scene for health care professionals and related stakeholders. PREMSTEM includes a dissemination and exploitation strategy with the goal of increasing the visibility and impact of PREMSTEM on both public health and society, and most importantly, the fast tracking of bench to bedside research through strong industrial expertise in product development in neonatology and ATMPs.
Expected results:
- Identification of the most effective H-MSC neuroregenerative paradigm/s
- Short- and long-term outcomes of H-MSC treatment on neuroregeneration and immune function
- Creation of a statistically derived mechanistic model of H-MSC-induced neuroregeneration
- Expansion of our knowledge of the efficacy of our optimised H-MSC treatment
- Operational prototype for 2D ultrafast ultrasound imaging with advanced preclinical imaging modes
- Coherent and meaningful engagement of stakeholders
- Implementation of our Exploitation Roadmap and Business Plan
Impacts:
PREMSTEM will bring potential new regenerative therapies to address unmet clinical needs of large patient groups identified, with an obvious societal impact via its potential to help reducing morbidity associated with prematurity.
PREMSTEM will strengthen Europe's position in translational regenerative medicine by providing a road-map of the best practice in validating an efficacious stem cell-based therapy for a large heterogeneous patient group. This road-map will enable PREMSTEM’s approach of screening to be deployed for other conditions.