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Brain injury in the premature born infant: stem cell regeneration research network

Periodic Reporting for period 1 - PREMSTEM (Brain injury in the premature born infant: stem cell regeneration research network)

Reporting period: 2020-01-01 to 2021-06-30

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.
In WP1, the goal is to establish how and when we should deliver H-MSCs. We use state-of-the-art mathematical approaches to combine the ‘how many X when X what route of delivery’ information to find out what combination has the best regenerative abilities. We are also testing where the cells go in the body of animal models (biodistribution).
In WP2, ovine studies have been successfully initiated. Protocols for in vivo and ex vivo functional tests, complex histology, and immune cell characterization are optimized and ready for implementation.
In WP3, we are looking at the beneficial effects of H-MSCs on multiple target cells important during EoP (i.e. peripheral blood cells, neurons, oligodendrocytes, neural stem cells and microglia) using in vitro cultures. We are finalizing the standardization and optimization of our protocols. The first results of H-MSCs on some target cells have been obtained.
In WP4, using five small clinically relevant animal models of EoP, our goal is to characterize the neuroregenerative effects of H-MSCs both at the short-term and long-term levels. We are currently working on the standardization of our protocols that will allow to carry the multidisciplinary experiments and analysis of the various models.
In WP5, we have developed a preclinical research prototype for in vivo ultrafast ultrasound imaging of the brain. The device enables to map the brain activity in rodents at a high spatiotemporal resolution and high sensitivity, and comes with a user-friendly acquisition software for an easy adoption by neuroscientists.
WP6 is dedicated to increasing the visibility and impact of PREMSTEM. Our communication strategy was finalised within the first year of the project and a frequent stream of content has been published on the website, Twitter, LinkedIn and youtube channels. The Patient/Consumer Advisory Board (PCAB) was established and already contributed to a variety of tasks. Co-creation work has been started with the consortium members and the PCAB. A roadmap for an exploitation and sustainability strategy has been finalised.
In WP7, the coordinator and IT organised the Kick off meeting, one SAB and EAB meeting and nine ExCom meetings. They prepared and submitted on behalf of the consortium an amendment of Grant Agreement for a partial take over.
In WP8, to fulfil the ethics requirements for PREMSTEM research activities, we have obtained all ethics and legal approvals and authorizations from the relevant authorities and institutions, and submitted all related deliverables to the EU Commission in 2020.
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

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.
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