Neuroglobin gene therapy prevents optic atrophy and preserves durably visual function in Harlequin mice.

Abstract

Neuroglobin (NGB) is considered as an endogenous neuroprotective molecule against stroke, since the protein alleviates the adverse effects of hypoxic and ischemic insults. We previously demonstrated the functional link between NGB and mitochondria since it is required for respiratory chain function. Thus, here, we evaluated the relevance of this effect in the Harlequin (Hq) mouse strain, which exhibits retinal ganglion cell (RGC) loss and optic atrophy due to a respiratory chain complex I (CI) defect. A twofold decrease of NGB amounts was observed in Hq retinas. We constructed a recombinant adeno-associated virus which combines to the mouse NGB open reading frame, its 5' and 3'UTR, for guarantying mRNA stability and translation capacity. The vector was administrated intravitreally to Hq mice and NGB expression was stable for up to 7 months without negative effect on retinal architecture or function. On the contrary, RGCs and their axons were substantially preserved from degeneration; consequently, CI activity in optic nerves was protected conferring improvements in vision. Hence, we established that NGB prevents respiratory chain impairment, therefore, protecting visual function otherwise compromised by mitochondrial energetic failure.

• Authors: Christophe Lechauve, Sébastien Augustin, Hélène Cwerman-Thibault, Élodie Reboussin, Delphine Roussel, René Lai-Kuen, Bruno Saubamea, José-Alain Sahel, Thomas Debeir, Marisol Corral-Debrinski
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 22 Issue 6 Pg. 1096-1109 (Jun 2014) ISSN: 1525-0024 [Electronic] United States
• PMID: 24622090 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nerve Tissue Proteins
• Neuroglobin
• Globins
• Electron Transport Complex I

Topics

• Animals
• Axons (metabolism, pathology)
• Dependovirus (genetics)
• Disease Models, Animal
• Electron Transport Complex I (deficiency)
• Genetic Therapy
• Genetic Vectors (administration & dosage)
• Gliosis (pathology, prevention & control)
• Globins (genetics, metabolism)
• Mice
• Nerve Tissue Proteins (genetics, metabolism)
• Neuroglobin
• Optic Atrophy (genetics, pathology, prevention & control, therapy)
• Retinal Ganglion Cells (metabolism, pathology)