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Development of a Chromatic Pupillography Protocol for the First Gene Therapy Trial in Patients With CNGA3-Linked
Jolanta Lisowska1, Lukasz Lisowski1, Carina Kelbsch2
1Pupil Research Group at the Centre for Ophthalmology, University of Tübingen, Tübingen, Germany 2Medical University of Bialystok, Bialystok, Poland.
Purpose:
To establish a feasible and sensitive pupillographic protocol to assess outer and inner retinal function for the first gene therapy trial in achromatopsia patients (ACHM) with mutations in CNGA3.
Methods:
Twenty-seven CNGA3-ACHM patients and 22 age-matched control subjects were tested using chromatic pupillography. Three different protocols were established to assess the pupillary light reflex parameters and to create the final protocol. In the individual protocols, various stimulus parameters (i.e., intensity, duration, wavelength, adaptation states) were applied to evaluate the impact of these stimuli on the pupillary response in untreated ACHM patients.
Results:
In the light-adapted conditions, CNGA3-ACHM patients showed significantly reduced maximal amplitudes compared with the control group when using a 1-second high intensity (28-lux corneal illumination) blue or red stimulus (P < 0.005). In the dark-adapted conditions, CNGA3-ACHM patients unexpectedly revealed significantly increased maximal amplitudes when stimulating with red (1 second) or blue (4 ms and 1 second) stimuli of low intensity (0.01-lux corneal illumination; P < 0.05). Pupil responses of CNGA3-ACHM patients after high intensity (28 lux) red and blue 1-second stimuli were within the normal range.
Conclusions:
Chromatic pupillography demonstrated significant reduced pupil responses to stimuli addressing primarily cone function, an increased sensitivity to rod-favoring stimuli and evidence for disinhibition of intrinsically photosensitive retinal ganglion cells in CNGA3-ACHM patients. A final protocol was established based on these findings. These conclusions may be useful for the objective assessment of efficacy gained by gene therapy or other innovative interventions in this hereditary retinal disorder.
Insights
A new pupillography protocol helps assess retinal function in achromatopsia (ACHM) patients. CNGA3-ACHM patients show reduced cone responses and increased rod sensitivity, aiding gene therapy evaluation.
Area of Science:
- Ophthalmology
- Genetics
- Neuroscience
Background:
- Achromatopsia (ACHM) is a hereditary retinal disorder.
- Mutations in CNGA3 cause a significant form of ACHM.
- Gene therapy offers a potential treatment for ACHM.
Purpose of the Study:
- To develop a sensitive pupillographic protocol for assessing retinal function in CNGA3-ACHM patients.
- To evaluate outer and inner retinal function for a gene therapy trial.
- To establish a baseline for measuring treatment efficacy.
Main Methods:
- Chromatic pupillography was used to test 27 CNGA3-ACHM patients and 22 controls.
- Three protocols were tested, varying stimulus intensity, duration, wavelength, and adaptation states.
- The final protocol was established based on stimulus impact on pupillary response.
Main Results:
- CNGA3-ACHM patients had reduced pupil responses to high-intensity blue/red light (cone function).
- Patients showed increased pupil responses to low-intensity stimuli (rod function).
- Pupil responses to high-intensity stimuli were within normal ranges.
Conclusions:
- Chromatic pupillography effectively differentiates retinal function in CNGA3-ACHM patients.
- Findings indicate reduced cone function, enhanced rod sensitivity, and disinhibition of retinal ganglion cells.
- The developed protocol can objectively assess gene therapy efficacy in ACHM.
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