AAV Tropism for Ocular and Retinal Cells

In the eye, AAV tropism is highly dependent on the route of administration. Because the eye is a “compartmentalized” organ, a virus injected into the vitreous (front/middle) will struggle to reach the photoreceptors at the very back (the retina) due to physical barriers like the Inner Limiting Membrane (ILM).

The following table details how natural and common engineered serotypes target specific ocular tissues.

Serotype	Target Tissue/Cells	Optimal Route	Notes
AAV2	RGCs, Müller Glia, RPE	Intravitreal / Subretinal	The most established; used in Luxturna. Primarily targets Retinal Ganglion Cells (RGCs) when injected intravitreally.
AAV1	RPE, Photoreceptors	Subretinal	High efficiency for the Outer Nuclear Layer (ONL).
AAV4	RPE Only	Subretinal	Highly specific to Retinal Pigment Epithelium; very little “leakage” into the neural retina.
AAV5	Photoreceptors, RPE	Subretinal	One of the most efficient for targeting rods and cones in the outer retina.
AAV8	Photoreceptors, RPE	Subretinal	Known for rapid onset and deep penetration into the outer retina; better than AAV2 for photoreceptors.
AAV9	RGCs, Photoreceptors	Intravitreal / Subretinal	Broad tropism; can reach the outer retina more effectively than AAV2 from the vitreous.
AAV7m8	Pan-retinal (all layers)	Intravitreal	An engineered variant of AAV2 designed to bypass the ILM and reach photoreceptors without subretinal surgery.
AAV8 (Y733F)	Photoreceptors	Subretinal	A “tyrosine-mutant” synthetic variant that avoids degradation, leading to much higher expression levels than natural AAV8.

Understanding the Delivery Routes

The “where” is just as important as the “what” in ocular gene therapy:

• Intravitreal (IVT): The virus is injected into the jelly-like vitreous. This is a simple, safe office procedure but mostly targets the inner retina (RGCs) because the virus gets trapped by the ILM barrier.
• Subretinal (SR): The virus is injected between the RPE and the photoreceptors. This requires surgery but is the only way for most natural serotypes to reach the light-sensing cells (rods and cones).
• Suprachoroidal: A newer, less invasive route between the sclera and choroid. It provides a wider “spread” of the virus across the back of the eye compared to a localized subretinal bleb.

Selecting the Right Promoter

To ensure the gene only turns on in the correct eye cells, researchers use specific promoters:

• GRK1 or Rhodopsin: Restricts expression to Photoreceptors.
• Best1: Restricts expression to the RPE.
• SNCG: Restricts expression to Retinal Ganglion Cells.