TreatOPON

OPA1-linked Optic Neuropathies (OPONs) represent a group of inherited neurodegenerative disorders including isolated optic atrophy (adOA) as well as syndromic disease such as adOAplus or Behr syndrome with a variety of additional extraocular symptoms. OPONs are caused by mutations in OPA1, a nuclear encoded mitochondrial large GTPase of the dynamin family that plays a central role in mitochondrial dynamics and cristae junction maintenance. Progressive visual loss is the most common symptom in these patients resulting from a dysfunction and eventually loss of retinal ganglion cells and their axons forming the optic nerve. Since haploinsufficiency is the predominant disease mechanisms in OPONs we here propose to further develop and validate several innovative therapeutic approaches which either generally elevate OPA1 expression (artificial transcription factors and AONs blocking upstream µORF translation) or specifically rescue mutant OPA1 alleles or transcripts (trans-splicing, U1/U6-based splice correction, and gRNA/dCas9-mediated cryptic exon elimination). These therapeutic approaches are based on preliminary work and overcome current limitations of supplementation gene therapy for OPA1. A central objective of this project is the use of a common resource of established in vitro and in vivo models, the definition and implementation of common outcome measures applied in all teams and a pilot study on a direct comparison of the efficacy of different therapeutic approaches in the mouse model.