Intravitreal AAV2 gene delivery to feline retinal ganglion cells.
Level 5 - mechanism / opinion, no new human data
Preclinical animal study
PubMed 39549467 · doi:10.1016/j.visres.2024.108519
What was done
Five adult normal cats received pre-retinal, posterior vitreal injections of AAV2/2-CMV-GFP directed over the area centralis, accompanied by perioperative oral prednisolone tapered over 6 to 10 weeks. In vivo monitoring included confocal scanning laser ophthalmoscopy (cSLO) and optical coherence tomography (OCT) at 1–2 week intervals for 6–10 weeks, as well as full-field electroretinograms (ERG) and visual evoked potentials (VEP). Retinas and visual pathway structures (optic nerve, optic tract, lateral geniculate nucleus) were evaluated post-mortem via histology and immunolabeling for RGC (RBPMS) and Müller cell/astrocyte (SOX9) markers.
What was found
GFP expression in retinal cells and RGC axons was detected by cSLO at 1–2 weeks post-injection. In vivo OCT showed no morphological changes, but 3/5 eyes exhibited mild retinal inflammation on histology. Retinal and optic nerve function (ERG and VEP) were preserved. Transduction was predominantly localized to RBPMS+ RGCs and SOX9+ Müller cells, with GFP fluorescence observed along the visual pathway to the LGN. Peak RGC transduction reached up to ~20% in localized high-expression regions, but overall RGC transduction across the whole retina was <1%.
Why it matters
This study provides proof-of-concept for intravitreal AAV2 gene delivery to feline retinal ganglion cells in an eye of comparable size and anatomy to humans. It establishes feasibility but underscores the need to overcome low whole-retina transduction efficiency and vector-related inflammation before therapeutic translation.
Limits
The sample size was very small (n = 5 cats) and tested only in normal animals rather than a glaucoma disease model. Whole-retina transduction was minimal (<1%), vector tropism was not exclusive to RGCs (transducing Müller cells), and mild histological inflammation occurred despite oral corticosteroid coverage.
Cited by
- supports Adeno-associated virus serotype 2 (AAV2) is used as a gene delivery vehicle to target nerve cells at the back of the retina.