Antibody-based gene-agnostic treatment for inherited retinal degeneration

PROJECT SUMMARY Retinitis Pigmentosa (RP), or Rod-Cone Dystrophy, is the most common inherited retinal degeneration (IRD) and represents the leading cause of visual impairment and blindness in individuals under 60 years of age. RP is associated with mutations in approximately 80 genes that are critical for retinal function, leading to the progressive primary death of rod photoreceptors, followed by secondary death of cone photoreceptors. With the human retina containing approximately 100 million individual rod cells, each packed with large amounts of membrane around individual outer segment discs, rod cell death represents a significant debris burden. Toxic byproducts from this debris lead to secondary damage of surrounding photoreceptors and underlying retinal pigment epithelium (RPE), disrupting the cellular communication and mechanisms essential for vision. The current therapeutic pipeline in RP, however, does not directly address this upstream problem of cytotoxic photoreceptor debris and thus significant visual improvement may be limited. Moreover, these approaches are limited to select populations of RP patients that fit a gene specific mutation or represent end stage disease. To address these significant drawbacks, Piximune Inc. has developed a unique class of therapeutic antibodies to treat RP in a gene-agnostic and cell type-agnostic manner. Furthermore, these antibodies can be administered early in the disease process when only rods are dying, or in the intermediate and late phases when cones are impacted. The mechanism of action centers on augmentation of natural mechanisms that eliminate debris from dead and dying photoreceptors, thereby ensuring that surrounding functional cells are sufficiently shielded. Uniquely, this approach offers protection against secondary damage of all photoreceptors (rods and cones) and RPE cells independent of the causal gene mutation, allowing broad treatment of RP. Piximune Inc. has demonstrated pharmacological augmentation of this natural mechanism for photoreceptor debris clearance successfully mitigates secondary damage in photoreceptor degenerative disease models in mice, identifying an important drug target that is conserved in humans. To date, Piximune Inc. has identified 21-human specific antibodies, which will be further tested for augmentation, stability and efficacy of retinal cell health and protection in this Phase I SBIR proposal. This work represents a critical step towards IND-enabling studies and clinical development.