Intravitreal Therapy Against the Complement Factor C5 Prevents Retinal Degeneration in an Experimental Autoimmune Glaucoma Model
Authors: Sabrina Reinehr
H Burkhard Dick
M Ali Asaad
Sara C Gomes
Marc Schargus
Gesa Stute
Caroline J Gassel
Stephanie C Joachim
Journal: Frontiers in Pharmacology (2019)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: complement; complement inhibition; glaucoma; membrane attack complex; optical coherence tomography.
Affiliations: Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, Bochum, Germany.

Abstract:  In glaucoma, studies revealed an involvement of the complement system. In an experimental autoimmune glaucoma model, immunization with an optic nerve homogenate antigen (ONA) led to retinal ganglion cell (RGC) loss, while intraocular pressure (IOP) remained unchanged. Here, we investigated the therapeutic effect of a complement system inhibition in this model. Hence, rats were immunized with ONA and compared to controls. In one eye of the ONA animals, an antibody against complement factor C5 was intravitreally injected (15 Œºmol: ONA+C5-I or 25 Œºmol: ONA+C5-II) before immunization and then every two weeks. IOP was measured weekly. After 6 weeks, spectral-domain optical coherence tomographies (SD-OCT), electroretinograms (ERG), immunohistochemistry, and quantitative real-time PCR analyses were performed. IOP and retinal thickness remained unchanged within all groups. The a-wave amplitudes were not altered in the ONA and ONA+C5-I groups, whereas a decrease was noted in ONA+C5-II animals (p &lt; 0.05). ONA immunization provoked a significant decrease of the b-wave amplitude (p &lt; 0.05), which could be preserved in ONA+C5-I, but not in ONA+C5-II animals. ONA animals showed a loss of RGCs (p = 0.001), while ONA+C5-I and ONA+C5-II retinae had similar cell counts as controls. A significant downregulation of apoptotic Bax/Bcl2 mRNA was noted in ONA+C5-I retinae (p = 0.02). Significantly more C3+ and MAC+ cells were observed in ONA animals (p &lt; 0.001). The amount of C3+ cells in both treatment groups was significantly increased (p &lt; 0.01), while the number of MAC+ cells in the treated retinas did not differ from controls. The number of activated microglia cells remained unchanged in ONA animals, but was increased in the treatment groups (p &lt; 0.05). Recoverin+ cells were diminished in ONA animals (p = 0.049), but not in treated ones. Rho mRNA was downregulated in ONA and in ONA+C5-II retinas (both p = 0.014). Less opsin+ cones were observed in ONA animals (p = 0.009), but not in the treated groups. Our results indicate that the C5 antibody inhibits activation of the complement system, preventing the loss of retinal function as well as RGC, cone bipolar, and photoreceptor loss. Therefore, this approach might be a suitable new treatment for glaucoma patients, in which immune dysregulation plays an important factor for the development and progression of glaucoma. 

Retracted: No

PubPeer comments:
 Serious issue with the design of this study: BB5.1 antibody used here does not work in rats, though the entire study was done in rats. BB5.1 inhibits C5 only in mouse models and this can be easily found in BLA documents (Eculizumab). Second, how come strong conclusions are made, such as  Our results indicate that the C5 antibody inhibits activation of the complement system, preventing the loss of retinal function , however, most of the data presented are not statistically significant? ,