More than 3000 mutations in 70 different genes causing RP have been identified, showing variations in age of onset, rate of progression, and clinical outcomes. Mutations in the rhodopsin (RHO) gene are the most common cause of autosomal dominant RP (adRP). Dominant RHO mutations resulting in protein misfolding lead to protein deposits and proteotoxic stress and progressively impair photoreceptor survival. Ueffing’s research team has identified the ATP-driven chaperone valosin-containing protein (VCP) as a potential new treatment target for adRP. The inhibition of VCP, a major modular quality control unit for protein misfolding, can rescue photoreceptors from degeneration. Yet, the delivery of exogenous molecules (e.g., VCP inhibitors) to the retina is significantly limited and remains a pending problem.
As part of an international collaboration funded by the European Horizon 2020 – Framework Programme for Research and Innovation (2016-2020) titled "Educational Network in Ocular Drug Delivery and Therapeutics" (OcuTher), scientists in Tübingen, Padova, and Kuopio have now developed nanoformulations to deliver VCP inhibitors to the retina. OcuTher Early Stage Researcher Merve Sen conducted the study under the supervision of Prof. Marius Ueffing and Dr. Blanca Arango-Gonzalez (Institute for Ophthalmic Research, at Tübingen University, Germany), publishing the results in the Journal of Controlled Release, a top-ranked journal in Pharmacology and Pharmacy.
The researchers generated self-assembling nanoparticles based on mPEG5kDa-cholane that provide increased drug solubility and slow-release combined with excellent ocular tolerability. Using this system to deliver the VCP inhibitor ML240 resulted in prolonged neuroretinal protection due to its increased bioavailability. As such, the controlled release of a VCP inhibitor from self-assembled nanoparticles can serve as a pre-clinical proof of concept for future drug delivery to halt retinal degeneration.
Furthermore, the cover photo of the publication was selected for the back page of the JCR November issue.
Original Publication
Retinal neuroprotection by controlled release of a VCP inhibitor from self-assembled nanoparticles
Sen, M.; Al-Amin, M.; Kicková, E.; Sadeghi, A.; Puranen, J.; Urtti, A.; Caliceti, P.; Salmaso, S.; Arango-Gonzalez, B.; Ueffing, M. Retinal neuroprotection by controlled release of a VCP inhibitor from self-assembled nanoparticles. J. Control. Release 2021, 339, 307–320