The electroretinogram (ERG) has been a standard tool in clinical ophthalmology for decades, but its role in preclinical research has quietly expanded into territory well beyond its origins in retinal disease diagnosis. Four recent studies, spanning oncology drug safety, glaucoma pathophysiology, gene therapy validation, and antiepileptic drug toxicology, illustrate the breadth of contexts in which ERG now functions as a critical quantitative endpoint. Taken together, they make a strong argument for treating retinal electrophysiology not as a specialized ophthalmological add-on, but as a core component of preclinical functional assessment.
Catching Drug-Induced Retinal Toxicity Early, and Confirming It Reverses
One of the more consequential applications of preclinical ERG is in evaluating the safety of systemically administered drugs. The retina is metabolically demanding and selectively vulnerable, and drug-induced retinal toxicity can emerge as an unexpected liability late in development or, worse, after a drug has already reached patients.
A 2025 study in Translational Oncology (Hamm et al.) examined the retinal effects of camizestrant, a next-generation drug in development for breast cancer that works by breaking down estrogen receptors, in a rat model. ERG was the primary readout of retinal function, with recordings taken at baseline and at multiple timepoints during and after a seven-day dosing period. Those recordings revealed changes in retinal function that were both dose-dependent and, critically, reversed when treatment stopped. Without ERG as the primary readout, the distinction between a reversible functional change and progressive retinal damage would have been difficult to make. The reversibility finding matters clinically: it suggests the effect reflects how the drug is working in the body rather than structural damage to the retina, and it informs how any retinal signals observed during clinical monitoring should be interpreted.
A similar situation arises with vigabatrin, an anti-seizure drug with a well-documented association with visual field loss in patients. A 2020 study in Investigative Ophthalmology & Visual Science (Chan et al.) used ERG in a mouse model to characterize both the functional changes in the retina and the structural adaptations that the drug triggered in retinal nerve cells. The study identified extensive branching of rod bipolar, cone bipolar, and horizontal cells alongside ERG changes, providing insight into the biological mechanism behind vigabatrin’s retinal effects. That kind of mechanistic detail is directly relevant to understanding, and potentially preventing, this clinical side effect.
Disease Progression and the Limits of Structural Endpoints
In glaucoma research, the conventional focus on eye pressure and retinal nerve fiber thickness captures structural changes but can lag behind functional loss. A 2023 study in Documenta Ophthalmologica (Nork et al.) examined ERG responses in a nonhuman primate model of glaucoma in which the optic nerve was surgically severed in one eye to isolate the contribution of ganglion cell loss. Counterintuitively, ERG responses increased following the elevation of eye pressure, a finding the authors attribute to the pressure itself rather than to ganglion cell loss, pointing to involvement of photoreceptors, bipolar cells, and Muller cells in producing that heightened response.
This kind of result is precisely what makes functional endpoints valuable in disease models: they capture changes that structural measures do not predict and may not correlate with. For translational glaucoma research, understanding how ganglion cell loss relates to broader retinal circuit behavior has direct implications for how functional endpoints are interpreted in both preclinical studies and clinical trials.
Validating Gene Therapy: When ERG Is the Proof
Perhaps the most direct application of ERG as a therapeutic endpoint is in evaluating retinal gene therapies, where restoring photoreceptor function is the explicit goal and ERG provides the most immediate measure of whether that goal has been achieved.
A 2023 study in Molecular Therapy (Hanna et al.) reported the preclinical evaluation of ADVM-062, a gene therapy vector delivered by injection into the eye, designed to treat blue cone monochromacy. This is a rare inherited condition in which the light-sensitive proteins (opsins) responsible for color detection in cone photoreceptors are absent from birth, leading to severely impaired color vision, poor visual acuity, and light sensitivity. ERG was central to demonstrating that the therapy worked. Following delivery of the vector, treated animals showed dose-dependent electrical responses to long-wavelength (red) light that had not existed before treatment, providing direct functional evidence that ADVM-062 was successfully producing the missing opsin in cone photoreceptors.
This application underscores a point that applies across the studies reviewed here: the value of ERG as a preclinical endpoint is greatest when it is matched to the biology being investigated. In gene therapy for a photoreceptor disorder, ERG functions not as a stand-in measure but as a direct readout of the outcome of interest: restored sensitivity to the relevant wavelengths of light.
ERG as a Versatile Endpoint Platform
What emerges from these four studies is a picture of ERG not as a single technique but as a platform adaptable to a wide range of preclinical questions. Full-field ERG detects global retinal responses to drug treatment. Multifocal ERG maps regional changes in disease models across different areas of the retina. Pattern ERG and cortical VEPs extend the readout toward the inner retinal layers and beyond the eye into the brain’s visual processing pathways. The choice of approach is driven by the biology being studied, and increasingly, researchers are combining multiple ERG variants to build a more complete functional picture.
For drug developers, safety researchers, and disease model scientists alike, that flexibility makes retinal electrophysiology a tool worth building into study designs from the outset, not adding as an afterthought when an unexpected signal demands explanation.
References
Chan K, et al. Vigabatrin-induced retinal functional alterations and second-order neuron plasticity in C57BL/6J mice. Invest Ophthalmol Vis Sci. 2020;61(2):17. https://doi.org/10.1167/iovs.61.2.17
Hamm G, et al. Camizestrant causes reversible pharmacological effects on retinal responses in rats. Transl Oncol. 2025;62:102539. https://doi.org/10.1016/j.tranon.2025.102539
Hanna K, et al. Preclinical evaluation of ADVM-062, a novel intravitreal gene therapy vector for the treatment of blue cone monochromacy. Mol Ther. 2023;31(7):2014–2027. https://doi.org/10.1016/j.ymthe.2023.03.011
Nork TM, et al. Multifocal electroretinography increases following experimental glaucoma in nonhuman primates with retinal ganglion cell axotomy. Doc Ophthalmol. 2023;146(2):97–112. https://doi.org/10.1007/s10633-023-09922-1