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Related Concept Videos

Brain Imaging01:14

Brain Imaging

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Brain imaging technologies provide critical insights into both the structure and function of the human brain, enabling medical professionals and researchers to diagnose, study, and treat neurological disorders or psychiatric disorders more effectively.
These technologies include computerized axial tomography (CAT or CT scans), positron-emission tomography (PET scans),  magnetic resonance imaging (MRI),  functional magnetic resonance imaging (fMRI), and Transcranial Magnetic...
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Exploring ITM2A as a new potential target for brain delivery.

Céline Cegarra1, C Chaves2, C Déon3

  • 1Rare and Neurologic Diseases Research Therapeutic Area, Sanofi, Chilly Mazarin, France. celine.cegarra@sanofi.com.

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Integral membrane protein 2A (ITM2A) shows promise for brain drug delivery, but challenges remain. Further research is needed to confirm ITM2A as a viable target for crossing the blood-brain barrier.

Keywords:
AntibodiesBlood brain barrierITM2ATranscytosis

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Area of Science:

  • Neuroscience
  • Biochemistry
  • Pharmacology

Background:

  • Integral membrane protein 2A (ITM2A) is a transmembrane protein with largely unknown functions, especially in the brain.
  • ITM2A is highly expressed in the human brain compared to peripheral endothelial cells, as indicated by transcriptomic and proteomic data.
  • This study investigates ITM2A as a potential target for facilitating drug delivery across the blood-brain barrier (BBB).

Purpose of the Study:

  • To explore the potential of ITM2A as a target for mediating transcytosis across the BBB.
  • To identify and characterize tools, including antibodies, for studying ITM2A.
  • To assess the feasibility of using ITM2A for brain drug delivery.

Main Methods:

  • Generated ITM2A constructs, cell lines, and specific anti-ITM2A antibodies.
  • Performed binding and internalization studies in ITM2A-overexpressing HEK293 cells and primary brain microvascular endothelial cells (mouse and non-human primate).
  • Evaluated the best ITM2A antibody in an in vitro human BBB model and an in vivo mouse pharmacokinetic study.

Main Results:

  • Antibodies targeting extracellular ITM2A demonstrated selective binding and uptake in ITM2A-overexpressing cells.
  • ITM2A protein levels decreased rapidly in cultured endothelial cells, hindering in vitro transcytosis assessment.
  • In vivo studies in mice to demonstrate ITM2A transcytosis were inconclusive.

Conclusions:

  • Antibodies against ITM2A are internalized in ITM2A-overexpressing cells, and ITM2A is present in brain microvessels.
  • The rapid downregulation of ITM2A in cultured endothelial cells presents a significant challenge for in vitro studies.
  • Further investigation is required to validate ITM2A as a potential target for brain drug delivery, despite initial challenges.