Advancing the pathologic phenotype of giant axonal neuropathy

Early involvement of the ocular lens

Diane Armao, Thomas W. Bouldin, Rachel M. Bailey, Jody Hooper, Diana X. Bharucha, Steven J. Gray

Research output: Contribution to journalArticle

Abstract

Giant axonal neuropathy (GAN; ORPHA: 643; OMIM# 256850) is a rare, hereditary, pediatric neurodegenerative disorder associated with intracellular accumulations of intermediate filaments (IFs). GAN knockout (KO) mouse models mirror the IF dysregulation and widespread nervous system pathology seen in human GAN. Validation of therapeutic efficacy and viral vector delivery systems with these GAN KO models has provided the springboard for the development of a viral vector being delivered intrathecally in an ongoing Phase I gene therapy clinical trial for the treatment of children with GAN (https://clinicaltrials.gov/ct2/show/NCT02362438). During the course of a comprehensive pathologic characterization of the GAN KO mouse, we discovered the very early and unexpected involvement of the ocular lens. Light microscopy revealed the presence of intracytoplasmic inclusion bodies within lens epithelial cells. The inclusion bodies showed strong immunohistochemical positivity for glial fibrillary acidic protein (GFAP). We confirmed that intracytoplasmic inclusion bodies are also present within lens epithelial cells in human GAN. These IF inclusion bodies in lens epithelial cells are unique to GAN. Similar IF inclusion bodies in lens epithelial cells have not been reported previously in experimental animal models or human diseases. Since current paradigms in drug discovery and drug repurposing for IF-associated disorders are often hindered by lack of validated targets, our findings suggest that lens epithelial cells in the GAN KO mouse may provide a potential target, in vivo and in vitro, for evaluating drug efficacy and alternative therapeutic approaches in promoting the clearance of IF inclusions in GAN and other diseases characterized by intracellular IF accumulations.

Original languageEnglish (US)
Article number27
JournalOrphanet Journal of Rare Diseases
Volume14
Issue number1
DOIs
StatePublished - Feb 1 2019

Fingerprint

Giant Axonal Neuropathy
Crystalline Lens
Intermediate Filaments
Inclusion Bodies
Phenotype
Lenses
Epithelial Cells
Knockout Mice
Drug Repositioning
Genetic Databases
Glial Fibrillary Acidic Protein
Drug Discovery
Neurodegenerative Diseases
Genetic Therapy
Nervous System
Microscopy
Therapeutics
Animal Models
Clinical Trials
Pediatrics

Keywords

  • GAN KO mouse model
  • Giant axonal neuropathy (GAN)
  • Gigaxonin
  • Human GAN
  • IF accumulations
  • Intermediate filaments (IF)
  • Lens epithelium

ASJC Scopus subject areas

  • Genetics(clinical)
  • Pharmacology (medical)

Cite this

Advancing the pathologic phenotype of giant axonal neuropathy : Early involvement of the ocular lens. / Armao, Diane; Bouldin, Thomas W.; Bailey, Rachel M.; Hooper, Jody; Bharucha, Diana X.; Gray, Steven J.

In: Orphanet Journal of Rare Diseases, Vol. 14, No. 1, 27, 01.02.2019.

Research output: Contribution to journalArticle

Armao, Diane ; Bouldin, Thomas W. ; Bailey, Rachel M. ; Hooper, Jody ; Bharucha, Diana X. ; Gray, Steven J. / Advancing the pathologic phenotype of giant axonal neuropathy : Early involvement of the ocular lens. In: Orphanet Journal of Rare Diseases. 2019 ; Vol. 14, No. 1.
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