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

Periodic Reporting for period 3 - PREMSTEM (Brain injury in the premature born infant: stem cell regeneration research network)

Reporting period: 2023-01-01 to 2024-06-30

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 5y. Preterm birth causes more deaths than malaria or pneumonia, resulting in the loss of 77 million 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). 10% of infants born before 33 weeks develop cerebral palsy (CP), and 35% have persisting cognitive and neuropsychiatric deficits, including ASD and ADHD. 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. The lifetime costs for provision of care for one child affected by CP is 1.3 million US$.

PREMSTEM is a collective of world leading clinicians, researchers, stakeholder advocacy groups and industrial partners 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-MSC) 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 have tested the optimal dose, route and timing of H-MSC delivery for neuroprotection in two small animal models of EoP based on postnatal inflammation and in utero periventricular haemorrhage. We have demonstrated the superiority of the intranasal (versus intravenous) delivery route at a late stage with robust regeneration being afforded in both models.
In WP2, we are using two large animal models of EoP (chorioamnionitis and birth-asphyxia models) to study the short- term and long-term effects of H-MSC. The ovine studies have been successfully performed for the short and long-term chorioamnionitis model cohorts and the short-term birth asphyxia model cohort. Analysis of histopathological alterations, MRI data as well as motor and cognitive functions is ongoing in order to examine the neuroprotective effect of H-MSC.
In WP3, we are assessing the potential beneficial effects of H-MSC on multiple target cells important during EoP using in vitro co-culture systems. We have shown beneficial effects of H-MSC on all target cells including immunomodulatory effects on peripheral immune cells and microglia, rescue effects on challenged neurons, maturation and survival effects on challenged oligodendrocytes, and boosting and differentiating effects on neural stem cells. We also studied if two preconditioning protocols (hypoxic exposure (HP-H-MSC) or creatine preloading (CP-H-MSC)) could yield superior H-MSC effects compared to naïve H-MSC actions. We observed superior effects of HP-H-MSC on neurons and neural stem cells, and superior effects of CP-H-MSC on oligodendrocytes, neural stem cells and microglia. We will finalize all in vitro experiments to generate data needed for the final regeneration matrix of WP3.
In WP4, we are using five rodent models involving the four major current paradigms of EoP: inflammation, fluctuation of oxygen concentrations combined with inflammation, placental dysfunction and periventricular haemorrhage. We found clear-cut model-related differences in neuronal and glial injury and differences in neural cell maturation which are counterbalanced by H-MSC treatment. All models assessing microglia and astrocyte responses showed an increased local inflammatory response, ameliorated by H-MSC.
In WP5, functional ultrasound (fUS) and ultrasound localization microscopy (ULM) have been implemented in 3D for whole-brain imaging in rodents, and applied for preliminary investigations of vascular alterations in mouse models of neuroinflammation.
WP6 strives for visibility and impact of PREMSTEM and builds on previously applied methods to create interest for the project’s overall cause. The co-creation process was completed and a report which will be available to the public has been compiled. The Patient/Consumer Advisory Board has contributed to the project and given valuable insight. The exploitation and sustainability strategy has been updated, reviewed and presented internally.
In WP7, we organized two annual General Assembly meetings and five Executive Committee meetings. We prepared and submitted on behalf of the consortium two progress and financial reports to the EC.
In WP8, the PREMSTEM consortium ensures the continuous addressing of ethical questions.
There is no effective therapy for 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 has a dissemination and exploitation strategy to increase 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.
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