ESR 12 - Grigorios Kyriatzis

Hosted at AMU

ESR11 round

The main objective of my research in the context of the ECMED project is to investigate how a vectorised neuropeptide with seizure modulatory effect acts as well to generate conjugates of our peptide vectors with novel AEDs developed by the consortium.

Coming from Greece, I obtained my M.Sc. at Uppsala University in Sweden, with a major in Molecular Medicine. What interests me most is the understanding of the pathogenesis of neurodegenerative diseases and novel therapeutic approaches against them. During my Master's thesis, I validated in vivo a number of candidate drug compounds, targeting tumor-initiating cells in glioblastoma multiform. 


Development of vector molecules for CNS delivery of ECM drug and imaging candidates developed by partners



Background

Some of the candidate anti-epileptic drugs (AEDs) and radiotracers to be developed within the project will be biomolecules, notably peptides. Peptides were generally considered to be bad drug candidates because of their poor pharmacokinetics. New synthetic strategies to improve productivity and reduce metabolism of peptides, along with alternative routes of administration have been developed in recent years, and a large number of peptide-based drugs are now being marketed. However, while biomolecules, including peptides can be developed as efficient drug candidates, this class of molecules crosses poorly the blood brain barrier (BBB). Hence, BBB technology is paramount to efficient CNS delivery of bio-molecules. Among the different options to deliver drugs to the CNS are vector molecules that can transport a cargo from blood to brain using specific BBB receptors involved in “receptor mediated transport/transcytosis (RMT). This technology has been successfully applied by the host laboratory and its industrial partner Vect-Horus for the delivery of bioactive peptides. One of these conjugated peptides has neuroprotective properties in status epilepticus and excitotoxic neuronal death.

Objectives

  • to further characterize the vector-drug conjugate generated and patented by AMU and Vect-Horus that has anti-convulsive/anti inflammatory and neuroprotective properties in an animal model of epilepsy
  • to conjugate the AED drug candidates and peptide-based radiotracers generated within the project that cross poorly the BBB, to peptide vectors in order to enhance their delivery into the brain

Approach

In the first objective, AMU and Vect-Horus will provide the conjugates it has developed to assess their anticonvulsive properties in vitro on primary neurons and cortico-hippocampal slices and in vivo in different animal models besides the kainate model that was already tested. 

In the second objective, AMU and Vect-Horus will use peptide synthesis and chemistry to generate conjugates between its lead peptide vectors and radiotracers generated by UA, and the AEDs such as the LGI1 interaction reagents developed by Iproteos/DZNE or the MMP-9 inhibitors developed by Iproteos. Different linkers will be evaluated (amino acid- or PEG-based) to be inserted between the peptide vectors and the AEDs or radiotracers. Conjugates will be tested in vitro to confirm that they still target the receptor involved in RMT across the BBB. They will also be tested on in vitro BBB models (primary rat and/or mice endothelial cells co-cultured with astrocytes). The conjugates will then be assessed by the Partner that generated the AEDs or the radiotracers to confirm that they retain their properties in the appropriate tests. Linker strategies with acid-labile or cleavable linkers will be assessed if required.  

Collaborations

On the one hand, the available vector-neuropeptide conjugate with anticonvulsive properties will be studied in collaboration with UCL, DZNE, IIT and UEF with their expertise, electrical activity in primary neurons and cortico-hippocampal slices, different animal models of epilepsy (post traumatic for instance) and the potential to monitor EEG continuously. On the other hand, AMU and Vect-Horus will collaborate with Iproteos, DZNE and UAntwerpen to evaluate the benefits of enhanced CNS delivery of the AEDs and radiotracers using peptide vectors.

ESR11

Page last modified on 24 jul 17 15:55