Neuroglobin gene therapy for use in the treatment or prevention of a mitochondrial ophthalmic disease associated with respiratory chain complex

Mitochondrial dysfunction is responsible for hereditary optic neuropathies. We wished to determine whether preserving mitochondrial bioenergetics could prevent optic neuropathy in a reliable model of glaucoma. DBA/2J mice exhibit elevated intraocular pressure, progressive degeneration of their retinal ganglion cells, and optic neuropathy that resembles glaucoma. The inventors established that glaucoma in these mice is directly associated with mitochondrial dysfunction: respiratory chain activity was compromised in optic nerves 5 months before neuronal loss began, and the amounts of some mitochondrial proteins were reduced in retinas of glaucomatous mice. One of these proteins is neuroglobin, thus the inventors investigated whether gene therapy aimed at restoring neuroglobin levels in the retina via ocular administration of an adeno-associated viral vector could reduce neuronal degeneration. The approach of treating 2-month-old mice impeded glaucoma development: few neurons died and respiratory chain activity and visual cortex activity were comparable to those in young, asymptomatic mice. When the treatment was performed in 8-month-old mice, the surviving neurons acquired new morphologic and functional properties, leading to the preservation of visual cortex activity and respiratory chain activity. The beneficial effects of neuroglobin in DBA/2J retinas confirm this protein to be a promising candidate for treating glaucoma.

Keywords: Ophthalmology - Gene Therapy - Neuroglobine - Mitochondrial Diseases
Patent Application number: PCT/IB2013/002461
Mol Ther. 2014 Jun;22(6):1096-1109. doi: 10.1038/mt.2014.44. Epub 2014 Mar 13. Mol Ther Methods Clin Dev. 2017 Apr 27;5:200-220. doi: 10.1016/j.omtm.2017.04.008. eCollection 2017 Jun 16

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