Neonatal Estimation Of Brain Damage Risk And Identification of Neuroprotectants (NEOBRAIN)

Summary

NEOBRAIN brings together small and medium sized enterprises (SMEs), industry and academic groups devoted to the diagnosis, management, and neuroprotection in newborns with perinatal brain damage. The focus of NEOBRAIN is the prevention of brain damage mainly observed in preterm newborns.

The objectives of NEOBRAIN are

1. to generate marker profiles of damage in multiple animal models and in human preterm infants using genomic/genetic, proteomic, and metabolomic approaches, as well as imaging and electrophysiologic modalities;
2. to develop neuroprotective strategies by identifying candidate molecules for intervention in animals;
3. to implement a platform for an observational clinical epidemiologic study in human infants designed to contribute to objective #1 above, and to transfer from the animal to the human level insights gained in objectives #1 and #2;
4. to prepare for drug testing by using the project structure as a platform for initial steps in clinical testing of potential interventions discovered in NEOBRAIN.

We further envision developing the clinical platform in a fashion so it can serve as the basis for subsequent large scale pan-European perinatal neuroprotective research initiatives (Euro-Neo-Net, EURAIBI)

Problem

Prevention of perinatal brain damage is of major importance for public health and obviously for individual well being. Both white and grey brain matter are affected in perinatal brain damage observed in preterm infants. Longterm-consequences of extreme prematurity are devastating, and perinatal brain damage clearly plays a role in this scenario. The current pathogenetic paradigm of perinatal brain damage in preterm infants has multiple inter-related aspects and includes infection/inflammation, hypoxia-ischemia, excitotoxicity, and free radicals. It is likely that these mechanisms do not act alone, but in concert.
The absolute number of neurological handicap of perinatal origin is increasing in Western countries due to increasing survival of preterm infants. The major brain lesions associated with cerebral palsy (CP) and cognitive impairment are white matter damage (WMD) mostly occurring in very preterm infants (born below 32 weeks of gestation) and cortico-subcortical lesions mostly observed in term infants. For financial, technical, and ethical reasons, the pharmaceutical industry has difficulties in making substantial investments in this area, which has left perinatologists with a limited therapeutic arsenal. At the present time, despite major improvements in neonatal care, there are no established therapeutic regimens that are successful for the prevention or treatment of perinatal brain lesions. Nevertheless, epidemiological and experimental data have allowed identifying potential targets for neuroprotection. New animal models, such as those employed in NEOBRAIN, clearly show the pathophysiology involved in neurodegeneration and will help identify neuroprotective strategies in the newborn.

Aims

Objective #1: Generate marker profile(s)

To help reduce the enormous individual, familial, and societal burden that perinatal brain damage represents, it is our first objective to identify early damage markers and novel pathways for interventional neuroprotection. We will study in various established animal models, the mechanisms that lead to perinatal brain damage in order to identify genomic, proteomic, and metabolomic biomarkers to generate biomarker profiles. We will also establish biomarker profiles in human newborns (see objective #3, below) in an observational clinical study involving extremely preterm infants born before completion of 28 weeks gestation (normal pregnancy duration: 40 weeks).

Objective #2: Develop neuroprotective strategies

Once we have identified biomarkers of damage and potential avenues for neuroprotection, we can begin develop an intervention. Again, we will initially use multiple animal models to pursue this goal. Only the most promising strategies will be considered worthy of being translated from bench to bedside.

Objective #3: Implement clinical platform

We see the need to implement a clinical platform for two purposes. First, we want to design a biomarker profile of perinatal brain damage in experimental animals and in human newborns (see above). Thus, we will need to establish a functional network of institutions caring for newborns that can serve as the basis for such a clinical study designed to identify human biomarker profiles based on genetic and biochemical markers, electroencephalographic (EEG) patterns, and magnetic resonance imaging (MRI). Second, we use and expand this platform for clinical drug testing both within the 36 months of NEOBRAIN and thereafter.

Objective #4: Prepare for drug testing

After biomarker profiles of early brain damage are established in animals and newborns, and neuroprotective strategies have been identified, NEOBRAIN is going to pave the way for clinical drug development. In essence, it is our 4th objective to design our clinical platform in a fashion that allows for quick expansion (i.e., recruitment of further centers), so that bench-to-bedside translational steps (i.e., a clinical trial) can be taken quickly after NEOBRAIN is finished. Indeed, we will prepare for the possibility that this might be the case even within the three years of NEOBRAIN.

Potential applications

Societal impact

The most obvious potential impact of NEOBRAIN is its potential to help reduce mortality and “stamp out” developmental disabilities associated with perinatal brain damage. The most important source of societal suffering from perinatal brain damage is on the individual and family level. Four out of five preterm infants are limited in their everyday activities. Moreover, brain-damage-associated cognitive and learning difficulties represent a potentially preventable source of suffering. It is NEOBRAIN’s goal to contribute to an improvement of this situation for future generations.

Economic impact

Economic burden of prematurity: The economic burden of prematurity is immense. It is estimated that in 2005 a cumulative cost of hospital inpatient admissions during the first 10 years of life of about 20,000 UK pounds for children born at <28 weeks gestation incurred. This estimate does not include non-hospital inpatient health care cost, such as cost incurred through family practitioners, educational, and social services. An average total 2-yr healthcare cost of 104,635 Euros was estimated based on surviving infants with a birthweight <1000g from a regional cohort of Helsinki university catchment area, Finland.
Approximately 60.000 infants are born each year in the EU who sustain some sort of brain injury. Improved capabilities to protect or even intervene in this scenario are much desired. Especially the high risk group of preterm infants ranges from 4-6% to up to 10% of all newborns in developed Western countries. Annually, approximately 4 million live births occur in the EU. Thus, approximately 200.000 infants will be preterm, and about 15-20.000 will be extremely preterm (<28 weeks gestation). In the USA, approximately 4 million live births occur annually. Among these are 499.000 (12.3%) preterm infants, 30.000 being <28weeks gestation 4. Thus, the potential market for any diagnostic modality and neuroprotective intervention in preterm infants is very large.
Economic burden of prematurity-associated brain damage: Moreover, the potential savings to the EU and worldwide are worth mention. Almost half of all cerebral palsy is due to prematurity (41%). The estimated total life-time cost for one case of cerebral palsy in the United States in 1992 US-Dollar is 500,000. About 80% of extremely low gestational age newborns will be disabled in such a fashion that will incur more than annually about € 6-7billion of newly incurring prospective healthcare cost in the EU, which could be saved if neurodisability only among extremely preterm infants could be prevented.

Potential market

The close cooperation and integration of enterprises and academic centers offers the unique chance to exploite new business areas and to position the participating companies as market leaders not only in Europe, but also in the USA, Australia and Asia.
New multi-parametric biomarker measurement tools will be developed based on metabolomic and proteomic techniques. These tools, in turn, will help improve the clinical diagnostics with regard to perinatal brain injury. This will contribute to better capabilities among neonatologists to consult with parents and amongst their therapeutic teams with regard to the individual child’s prognosis. As such, we consider the growing medical subdiscipline of “neonatology” one potential market for tools to be developed in NEOBRAIN.
Another potential market among sick and preterm newborns is called “Theranostics“, the individualized surveillance of therapy efficacy and results. NEOBRAIN will contribute to this field by offering improved strategies of biomarker measurements, including imaging and electroencephalographic markers of infant well-being.