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Targeting unfolding protein response to prevent neurodevelopmental disorders

Country of Origin: Belgium
Reference Number: TOBE20190508001
Publication Date: 8 May 2019

Summary

Neurodevelopmental disorders may impair motricity, behavior, language or cognitive capacity. A Belgian university research group develop models of cerebral cortex development. The group used this comprehensive set of models to demonstrate that inhibitors of unfolded protein response activation pathway stand as potential therapeutics to treat or prevent neurodevelopmental disorders, and is seeking for research collaboration with companies in the field.

Description

The Belgian university research group  aims at identifying fundamental mechanisms that regulate cerebral neurogenesis.

Based on its expertise in cortical development and Unfolded Protein Response (UPR), the group showed that the Zika virus (ZIKV) infects cortical neuronal progenitors during development. This infection dramatically decreases the total neuronal outcome leading to a microcephalic cerebral cortex. The group investigated ZIKV-induced impairments in infected postmortem human fetal brains as well as in cultures of infected human neural stem cells. By intracerebral and intraplacental inoculation of ZIKV in mouse embryos they revealed that ZIKV triggers endoplasmic reticulum stress in cerebral cortex precursor cells in vivo. This perturbs a physiological unfolded protein response within cortical progenitors that control neurogenesis. Thus, ZIKV-infected progenitors have an imbalanced neurogenesis that finally leads to a decrease in the production of projection neurons, the main constituents of the cerebral cortex. Moreover, the sustained endoplasmic reticulum stress in the neurons leads to apoptosis at late stages of cortical development, and this further depletes the number of neurons in infected cortices. Interestingly, administration of pharmacological inhibitors of unfolded protein response counteracts the pathological mechanisms and prevents microcephaly in ZIKV-infected mouse embryos.

Moreover, the identification of new molecular pathways that promote the formation of the cortex is critical to interpret the pathological mechanisms that contribute to the onset and the progression of neurological disorders.
It is also expected that it will contribute to unravel the mechanisms of neurodegeneration involved in pathologies such as Alzheimer or Parkinson diseases. As these neurodegenerative disorders are age-dependent, they are becoming increasingly prevalent and should rise dramatically in the forthcoming years, increasing their societal and economic burden. Interestingly, the mechanisms identified in these studies can be applied to degenerative pathologies of other tissues such as age related macular degeneration (AMD)
The researchers are looking for research collaboration with companies developing therapies/vaccines related to neurodevelopmental disorders, cortex pathologies, ZIKV infection.

Advantages and Innovations

The researchers demonstrated that inhibitors of the UPR activation pathway stand as potential therapeutic molecules to treat or prevent neurodevelopmental disorders
They did the set up and validation of an integrated set of biological models to study cerebral cortex development or neurodegeneration in mouse , iPSC , human brain and cell cultures.

Stage Of Development

Under development/lab tested

Requested partner

Types of partners: 
• Companies developing therapies/vaccines related to neurodevelopmental disorders
• Companies developing therapies/vaccines related to cortex pathologies
• Companies developing therapies/vaccines linked to ZIKV infection

Role of the parners:
Research collaboration in:
• mode of administration of UPR inhibitors for treating/preventing neurodevelopmental disorders
• validation of the relevance of UPR targeting in neurodegenerative diseases
• validation of the relevance of UPR targeting in other virus-dependant congenital microcephaly

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