Restoring and sustaining human postmortem retinal light responses with scalable methods for testing degenerative disease therapies.

Neuro- and retinal degenerative diseases rob millions of aging individuals of their independence. Researching these diseases in human tissue has been hindered by the immediate loss of electric activity in neurons after the circulation ceases. Recent studies indicate that limited neuronal activity can be revived postmortem, even in the retina.

Closed-perfusion transretinal ERG setup for preclinical drug and nanostructure testing.

Objective: The isolated mammalian retina may serve as a sensitive biosensor for preclinical drug testing, including eye drugs and a broader range of pharmaceuticals. To facilitate testing with minimal amounts of drug molecules or nanostructures, we developed a closed-perfusion transretinal electroretinography (tERG) setup.

Methods: The major challenge with small amounts of circulating perfusate was maintaining retinal viability and stability during long experiments.

A p97/Valosin-Containing Protein Inhibitor Drug CB-5083 Has a Potent but Reversible Off-Target Effect on Phosphodiesterase-6.

CB-5083 is an inhibitor of p97/valosin-containing protein (VCP), for which phase I trials for cancer were terminated because of adverse effects on vision, such as photophobia and dyschromatopsia. Lower dose CB-5083 could combat inclusion body myopathy with early-onset Paget disease and frontotemporal dementia or multisystem proteinopathy caused by gain-of-function mutations in VCP. We hypothesized that the visual impairment in the cancer trial was due to CB-5083's inhibition of phosphodiesterase (PDE)-6, which mediates signal transduction in photoreceptors.