Retinal ganglion cell surface receptors (AAV204-binding) (RGC-AAV204 receptors)

AAV204 (also known as 4D-R100) is a synthetic, highly optimized adeno-associated virus (AAV) capsid discovered through directed evolution by 4D Molecular Therapeutics (4DMT, 2024). It is specifically engineered for intravitreal delivery, a route that typically faces significant barriers such as the inner limiting membrane (ILM) and neutralizing antibodies in the vitreous (Grishanin et al., 2019). The interaction between the AAV204 capsid and surface receptors on retinal ganglion cells (RGCs) facilitates efficient viral entry and transduction across the retinal layers, including the RGCs, bipolar cells, and photoreceptors. While the specific molecular targets on the RGC surface include the universal Adeno-associated virus receptor (AAVR, encoded by KIAA0319L) (Pillay et al., 2016) and potentially Heparan Sulfate Proteoglycans (HSPG), the AAV204 capsid's unique surface architecture provides superior penetration and cell-type specificity compared to naturally occurring serotypes like AAV2. This interaction is the foundational mechanism for several clinical-stage gene therapies, such as 4D-150 for wet age-related macular degeneration (NCT05197270) and 4D-125 for X-linked retinitis pigmentosa, which aim to turn retinal cells into bio-factories for therapeutic proteins.

Other names

4D-R100 receptorsAAV204 binding partnersRetinal ganglion cell entry receptorsAAV204-RGC interaction complex

The AAV204 capsid binds to specific receptors on the retinal ganglion cell surface, enabling the vector to bypass the inner limiting membrane and undergo receptor-mediated endocytosis for the delivery of genetic material to the nucleus.