Targeting Müller cells for complement modulating gene addition therapy in a mouse model for Stargardt disease type 1

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Although the retina is immune privileged, retinal cells express components of the complement system (CS), a pathway of the innate immune system. Retinal complement activation and neuro-destructive parainflammation induced by lipofuscin accumulation is a hallmark in Stargardt disease type 1 (STGD1). This inherited retinal dystrophy (IRD) of young adults is caused by mutations in the ATP binding cassette subfamily A member 4 (ABCA4) gene. We showed that the main inhibitory complement regulator, complement factor H (CFH), was mainly expressed in retinal pigment epithelium, microglia and vascular cells, while the only known positive regulator, properdin (CFP), was primarily detected in Müller cells, microglia and neurons. In the ABCA4-/- STGD1 mouse model, we found an increased expression of complement factors in various retinal cell populations compared to controls. Cell type-specific rebalancing of CS activity could be a promising, gene-independent therapeutic strategy for IRD such as STGD1 with complicated or unknown genetics (about 25% STGD and ~40-50% of all IRD patients). Indeed, overshooting CS has recently also been associated with disease progression, e.g., in retinitis pigmentosa. Clinical trials investigating the therapeutic potential of repetitive intravitreal injections of recombinant proteins and therapeutic antibodies targeting key factors of the CS already gave positive results supporting our hypothesis. We now aim to develop a long-term efficient gene addition therapy modulating the retinal CS by expression of mini-FH (truncated CFH) or an antibody fragment blocking CFP. Expression of exogenous protein could stress the highly specialized retinal neurons like photoreceptors. Accordingly, we consider Müller cells as ideal targets for a gene addition approach as they (i) have an intrinsically high secretory activity, (ii) are huge contacting every retinal cell type and, thus, proteins secreted by them reach every retinal subcompartment, (iii) given their distinct morphology they can be addressed by comparably safe intravitreal injections and (iv) they themselves are a major source of activators of the CS and, thus, could actively shape the retinal complement homeostasis. After generating adeno-associated viral vectors driving Müller cell-specific expression of our therapeutic proteins, we will treat ABCA4-/- mice to determine whether this can dampen complement activity, thereby halt disease progression and positively affect Müller cell physiology.The in-depth characterization of effects of complement modulatory tools in STGD1 at cell type-specific level identifying the local source of complement factors and regulation thereof is highly innovative and probably will lead to a rethinking of current therapeutic approaches already tested in clinical trials. In the end, especially those STGD (and IRD) patients not suited for gene correction strategies will benefit from the therapeutic tools we hope to develop.