Effective gene therapy of Stargardt disease with PEG-ECO/ nanoparticles.

Stargardt disease (STGD) is the most common form of inherited retinal genetic disorders and is often caused by mutations in . Gene therapy has the promise to effectively treat monogenic retinal disorders. However, clinically approved adeno-associated virus (AAV) vectors do not have a loading capacity for large genes, such as . Self-assembly nanoparticles composed of (1-aminoethyl)iminobis[N-(oleoylcysteinyl-1-amino-ethyl)propionamide (ECO; a multifunctional pH-sensitive/ionizable amino lipid) and plasmid DNA produce gene transfection comparable with or better than the AAV2 capsid. Stable PEG-ECO nanoparticles produce specific and prolonged expression of ABCA4 in the photoreceptors of mice and significantly inhibit accumulation of toxic A2E in the eye. Multiple subretinal injections enhance gene expression and therapeutic efficacy with an approximately 69% reduction in A2E accumulation in mice after 3 doses. Very mild inflammation was observed after multiple injections of the nanoparticles. PEG-ECO/ nanoparticles are a promising non-viral mediated gene therapy modality for STGD type 1 (STGD1).