The Pilot Experimental Study of the Neuroprotective Effects of Exosomes in Extremely Low Birth Weight Infants

Surviving extremely low birth weight (ELBW) infants are at risk of severe neurodevelopmental disability. Exosomes or extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) can mediate a variety of different effects, including synaptic plasticity, nutritional metabolic support, nerve regeneration, inflammatory response, anti-stress effect, cellular waste disposal, treating neurological injury, preventing hemorrhagic and ischemic brain lesions, playing an important role in health and neuroprotection in extremely premature newborns during neonatal intensive care.

The proposed blinded randomized controlled trial was designed to compare the effect of intranasal administration of exosomes on long-term neurodevelopmental outcome in ELBW infants.

ELBW infants will be randomized to receive (group 1) and not receive exosomes (control group).

Group 1 - Neonates will receive exosomes (1 dose will be obtained from a daily conditioned culture medium of 120 million MSCs) suspended in 500 µl of phosphate buffer in each nostril at 50 µl with an interval of 2-3 minutes. The therapeutic course will consist of 5 instillations with an interval of 1 days.

The primary outcome measure is the incidence of death, the incidence of survival with any of either severe intraventricular hemorrhage (IVH), cystic periventricular leukomalacia (PVL), or brain injury on cranial ultrasound and MRI or major neurodevelopmental impairment determined at 36 months of age corrected for prematurity (where major neurodevelopmental impairment is defined as any of the following: cognitive deficit, cerebral palsy, or severe visual or hearing impairment. Cognitive delay defined as mental developmental index (MDI) score of the Griffiths-II and Bayley Scales of Infant Development (2nd edition) \< 85, cerebral palsy, or severe visual or hearing impairment.

To investigate this outcomes and the mechanisms by which extracellular vesicles (EVs) might effect we will analyze the biomarkers of perinatal brain injury (S-100, NSE, EPO) and mRNA.

Key secondary outcomes are incidences of short term outcomes: individual components of the composite primary outcome, survival with and without major neonatal morbidity including severe retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC).

Safety analyses will assess the injures or damages of the nasal mucosa, allergic reaction to EVs and any adverse events after intranasal administration of EVs.

The results of this trial may help to improve the quality of life of ELBW infants and reduce long-term health care costs.

• Rate of death [Срок оценки: From enrollment until discharge or 40 weeks corrected gestational age (whichever occurs first)]
• Occurrence of Other Severe Complications of Prematurity [Срок оценки: From enrollment until discharge or 40 weeks corrected gestational age (whichever occurs first)]
• Need for Ventilatory Support [Срок оценки: From enrollment until discharge, 40 weeks corrected gestational age, or death (whichever occurs first)]
• Changes in Hemodynamics [Срок оценки: Time Frame: At enrollment, 48 hours following intranasal administration of EVs, 28 days of life, and 36 weeks corrected gestational age]
• Feasibility: Administration [Срок оценки: Day of life 1-10]
• Feasibility: Recruitment Efficiency [Срок оценки: Day of life 1-10]
• Feasibility: Recruitment Timing [Срок оценки: Day of life 1-10]
• Feasibility: Participant Retainment [Срок оценки: From enrollment until follow-up at 18-36 months-of-age]
• Griffiths-II and Bayley Scales of Infant Development (2nd edition) [Срок оценки: 18-36 months-of-age]
• Long-term Safety Follow-Up [Срок оценки: 3 years following follow-up visit]