Mitochondrial-Targeted HDAP2 Preserves Retinal Ganglion Cells and Increases Pressure Tolerance in DBA/2J Mice

Area of Science:

• Ophthalmology
• Neuroscience
• Mitochondrial Biology

Background:

• Glaucoma causes retinal ganglion cell (RGC) loss, often persisting despite intraocular pressure (IOP) reduction.
• Mitochondrial dysfunction is a critical factor linking elevated IOP to RGC degeneration.

Purpose of the Study:

• To investigate the neuroprotective potential of HDAP2, a novel peptide stabilizing mitochondrial membranes, against RGC loss in the DBA/2J mouse model of glaucoma.

Main Methods:

• DBA/2J mice received intraperitoneal injections of HDAP2 (3 mg/kg) every other day for 8 months.
• IOP was monitored monthly. RGC survival was quantified by counting RBPMS-stained cells in retinal wholemounts.
• Optic nerve axon preservation was assessed in semithin toludine blue-stained sections.

Main Results:

• HDAP2 treatment resulted in approximately 49% more RGCs compared to untreated controls at similar IOP levels.
• HDAP2 significantly increased RGC survival under both mild (58% increase) and high (180% increase) IOP exposures.
• Kaplan-Meier analysis showed HDAP2 raised the threshold for severe RGC loss by 29 mmHg and reduced the risk of severe degeneration by 4.6-fold.

Conclusions:

• HDAP2 demonstrated significant neuroprotection for RGCs and optic nerve axons in a pressure-dependent manner.
• HDAP2 enhanced tolerance to IOP, suggesting its potential as an adjunctive therapy for various forms of glaucoma, including normal-tension and treatment-refractory cases.