No abstract

Pupillographic campimetry allows measuring the visual field objectively by analyzing the pupil response to perimetric stimuli. One of the drawbacks of this technique, similar to static perimetry, is the need of reliable fixation of the subject. By using stimulus sizes comparable to static perimetry and applying gaze tracking, we enable a retinotopic visual field examination regardless of fixation problems and with an increased stability and improved spatial resolution. Here, we present the results of applying the method in eight normal sighted subjects as well as in three patients suffering from diseases usually diagnosed by perimetry. The results in normal sighted subjects show a reduction in the amplitude of the pupil response with increasing eccentricity as expected. We also demonstrate that gaze-controlled campimetry is able to detect organic visual field defects objectively in a patient group and classify the visual field defects without an organic background. Moreover, we show that our method is able to evaluate the visual field sensitivity loss beyond classical perimetry in patients with late-stage retinitis pigmentosa. Thus, gaze-controlled pupil campimetry can be used in addition to classical perimetry, allowing for an objective monitoring of disease progression, rendering it as a biomarker for novel treatments.

PurposeTo evaluate the safety and tolerability of intravitreal ISTH0036, an antisense oligonucleotide selectively targeting transforming growth factor beta 2 (TGF-β2), in patients with primary open angle glaucoma (POAG) undergoing trabeculectomy (TE; glaucoma filtration surgery).MethodsIn this prospective phase I trial glaucoma patients scheduled for TE with mitomycin C (MMC) received a single intravitreal injection of ISTH0036 at the end of surgery in escalating total doses of 6.75 μg, 22.5 μg, 67.5 μg or 225 μg, resulting in calculated intraocular ISTH0036 concentrations in the vitreous humor of approximately 0.3 μM, 1 μM, 3 μM or 10 μM after injection, respectively. Outcomes assessed included: type and frequency of adverse events (AEs), intraocular pressure (IOP), numbers of interventions post trabeculectomy, bleb survival, visual acuity, visual field, electroretinogram (ERG), slit lamp biomicroscopy and optic disc assessment.ResultsIn total, 12 patients were treated in the 4 dose groups. Main ocular AEs observed were corneal erosion, corneal epithelium defect, or too high or too low IOP, among others. No AE was reported to be related to ISTH0036. All other safety-related analyses did not reveal any toxicities of concern, either. The mean medicated preoperative IOP at decision time-point for surgery was 27.3 mmHg +/- 12.6 mmHg (SD). Mean IOP (±SD) for dose levels 1, 2, 3, and 4 were at Day 43 9.8 mmHg ± 1.0 mmHg, 11.3 mmHg ± 6.7 mmHg, 5.5 mmHg ± 3.0 mmHg and 7.5 mmHg ± 2.3 mmHg SD; and at Day 85 9.7 mmHg ± 3.3 mmHg, 14.2 mmHg ± 6.5 mmHg, 5.8 mmHg ± 1.8 mmHg and 7.8 mmHg ± 0.6 mmHg, respectively. In contrast to IOP values for dose levels 1 and 2, IOP values for dose levels 3 and 4 persistently remained below 10 mmHg throughout the observation period.ConclusionThis first-in-human trial demonstrates that intravitreal injection of ISTH0036 at the end of TE is safe. Regarding IOP control, single-dose ISTH0036 administration of 67.5 μg or 225 μg at the time of TE resulted in IOP values persistently < 10 mmHg over the three month postoperative observation period.

Citation: Lisowska J, Lisowski L, Kelbsch C, et al. Development of a chromatic pupillography protocol for the first gene therapy trial in patients with CNGA3-linked achromatopsia. Invest Ophthalmol Vis Sci. 2017;58:127458: -128258: . DOI:10.1167 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.Keywords: chromatic pupillography, achromatopsia, CNGA3, ipRGC A chromatopsia (ACHM) is an inherited autosomal recessive congenital retinal disease, with a prevalence of one in 30,000.1 The most characteristic symptom is the inability to discriminate colors due to the loss of cone photoreceptor function. Achromatopsia patients also suffer from severely reduced visual acuity, nystagmus, and photophobia. 2 Rarely, individuals have incomplete ACHM, in which one or more cone types may be partially functioning. 3 The clinical findings of incomplete ACHM are similar to the complete form, but milder. Fundus examination is usually normal, and electrophysiological testing demonstrates absent cone responses and normal or near-normal rod function. [2][3][4][5] To date, mutations in six genes have been shown to be associated with ACHM: CNGA3 and CNGB3 encode the a and b subunits of the cGMP-gated cation channel, 6 GNAT2 the a subunit of the cone-specific G-protein transducing, 7 PDE6C and PDE6H code for the ...

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