Genetics and Disease Expression in the CNGA3 Form of Achromatopsia

Zelinger, Lina; Cideciyan, Artur V.; Kohl, Susanne; Schwartz, Sharon; Rosenmann, Ada; Eli, Dalia; Sumaroka, Alexander; Román, Alejandro J.; Luo, Xunda; Brown, Cassondra; Rosin, Boris; Blumenfeld, Anat; Wissinger, Bernd; Jacobson, Samuel G.; Banin, Eyal; Sharon, Dror

doi:10.1016/j.ophtha.2014.11.025

Cited by 62 publications

(64 citation statements)

References 54 publications

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“…' The subjective responses used in this form of LDT testing lead to variation in the data, and a more objective method of measurement, such as electromyography 31 or lid-fissure measurement, 32 may be preferable in future studies. Although the variability inherent in such a subjective test precludes detailed analysis, a couple of general conclusions can be made: thresholds for the patients in our sample were in the normal range or above and thresholds were lower for short-wavelength stimuli than for long-wavelength stimuli.…”

Section: Light Discomfort Thresholdsmentioning

confidence: 99%

Full-Field Pupillary Light Responses, Luminance Thresholds, and Light Discomfort Thresholds inCEP290Leber Congenital Amaurosis Patients

Collison¹,

Park

Fishman

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To investigate visual function in patients with CEP290 Leber congenital amaurosis (LCA-CEP290), using three full-field tests that can be performed by patients with poor fixation. METHODS.Six patients (age range, 9-39 years) with LCA-CEP290 participated in the study. Stimuli for all three tests (full-field stimulus test [FST], pupillometry, and light discomfort threshold [LDT] testing) were generated by the Diagnosys ColorDome ganzfeld, by using achromatic stimuli as well as long-and short-wavelength stimuli to target rod and cone photoreceptors with all three tests and, in the latter two tests, melanopsin photoreceptors.RESULTS. Dark-adapted FST thresholds in LCA-CEP290 patients were cone mediated and elevated between 4.8 and 6.2 log units above the normal achromatic threshold. The FST threshold was not measurable in one patient. The rod-mediated transient pupillary light reflex (PLR) was absent in all but the youngest patient, where unreliable responses precluded PLR quantification. Cone-mediated transient PLRs were subnormal in five patients, and absent in another. Sustained melanopsin-mediated PLRs were measurable in all patients. Full-field LDT thresholds were elevated compared to normal controls, and were lower for short-wavelengh than for long-wavelength stimuli.CONCLUSIONS. The FST thresholds and transient PLRs were cone mediated in our cohort LCA-CEP290 patients. Rod-mediated PLRs were undetectable, whereas melanopsin-mediated sustained responses were detected in all patients, suggesting a relative preservation of innerretina function. The LDT elevations for the patients are somewhat paradoxical, given their subjective perception of photoaversion. Relative aversion to short-wavelength light suggests influence from melanopsin on LDTs in these patients.

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Section: Light Discomfort Thresholdsmentioning

confidence: 99%

Full-Field Pupillary Light Responses, Luminance Thresholds, and Light Discomfort Thresholds inCEP290Leber Congenital Amaurosis Patients

Collison¹,

Park

Fishman

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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“…2,3 In other populations, CNGA3-associated ACHM seems to be more prevalent. 4,5 CNGA3 and CNGB3 mutations result in a loss of cone photoreceptor function in humans and in animals with mutations in the homologous genes. [6][7][8] Studies in mouse, sheep, and dog models of achromatopsia caused by mutations in the CNGA3 and CNGB3 genes indicate that gene augmentation therapy using a recombinant adeno-associated virus (AAV) vector expressing a normal CNGA3 or CNGB3 gene can produce the functional CNGA3 or CNGB3 proteins and restore cone photoreceptor function.…”

Section: Introductionmentioning

confidence: 99%

Safety and Efficacy Evaluation of rAAV2tYF-PR1.7-hCNGA3 Vector Delivered by Subretinal Injection in CNGA3 Mutant Achromatopsia Sheep

Gootwine

Ofri

Banin

et al. 2017

Human Gene Therapy Clinical Development

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{These authors contributed equally to this work.Applied Genetic Technologies Corporation (AGTC) is developing a recombinant adeno-associated virus (rAAV) vector expressing the human CNGA3 gene designated AGTC-402 (rAAV2tYF-PR1.7-hCNGA3) for the treatment of achromatopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity, and absence of color discrimination. The results are herein reported of a study evaluating safety and efficacy of AGTC-402 in CNGA3-deficient sheep. Thirteen day-blind sheep divided into three groups of four or five animals each received a subretinal injection of an AAV vector expressing a CNGA3 gene in a volume of 500 lL in the right eye. Two groups (n = 9) received either a lower or higher dose of the AGTC-402 vector, and one efficacy control group (n = 4) received a vector similar in design to one previously shown to rescue cone photoreceptor responses in the day-blind sheep model (rAAV5-PR2.1-hCNGA3). The left eye of each animal received a subretinal injection of 500 lL of vehicle (n = 4) or was untreated (n = 9). Subretinal injections were generally well tolerated and not associated with systemic toxicity. Most animals had mild to moderate conjunctival hyperemia, chemosis, and subconjunctival hemorrhage immediately after surgery that generally resolved by postoperative day 7. Two animals treated with the higher dose of AGTC-402 and three of the efficacy control group animals had microscopic findings of outer retinal atrophy with or without inflammatory cells in the retina and choroid that were procedural and/or test-article related. All vector-treated eyes showed improved cone-mediated electroretinography responses with no change in rod-mediated electroretinography responses. Behavioral maze testing under photopic conditions showed significantly improved navigation times and reduced numbers of obstacle collisions in all vector-treated eyes compared to their contralateral control eyes or predose results in the treated eyes. These results support the use of AGTC-402 in clinical studies in patients with achromatopsia caused by CNGA3 mutations, with careful evaluation for possible inflammatory and/ or toxic effects.

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“…These measures have become increasingly used as indicators of visual function beyond early processing in primary visual cortex. With the advance of new treatments for rod and cone dystrophies, such as gene therapy (Bainbridge et al, 2015;Cideciyan et al, 2008;Jacobson et al, 2012;Komáromy et al, 2010;Sundaram et al, 2014;Zelinger et al, 2015) it is becoming increasingly important to understand how different aspects of visual function, including higher cortical visual functions, are influenced by rod and cone loss. Gaining an understanding of visual function in observers with healthy vision under light conditions designed to activate rods and/or cones will provide important baseline information for comparison with retinal dystrophy patients before and after treatment with new therapies.…”

Section: Introductionmentioning

confidence: 99%

Cortical processing of global form, motion and biological motion under low light levels

et al. 2016

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'Cortical processing of global form, motion and biological motion under low light levels.', Vision research., 121. pp. 39-49. Further information on publisher's website: Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. however, global form thresholds were relatively more impaired than those for global motion or biological motion. VEP responses to coherent global form and motion were reduced in low light, and motion responses showed a shift in topography from the midline to more lateral locations. Contrast sensitivity measures confirmed that basic visual processing was also affected by low light. However, comparison with CSF reductions achieved by optical blur indicated that these were insufficient to explain the pattern of results, although the temporal properties of the rod system may also play a role.Overall, mid-level processing in extra-striate areas is differentially affected by light level, in ways that cannot be explained in terms of low-level spatiotemporal sensitivity. A topographical shift in scotopic motion VEP responses may reflect either changes to inhibitory feedback mechanisms between V1 and extra-striate regions or a reduction of input to the visual cortex. These results provide insight into how higher-level cortical vision is normally organised in absence of cone input, and provide a basis for comparison with patients with cone dystrophies, before and after treatments aiming to restore cone function.

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Genetics and Disease Expression in the CNGA3 Form of Achromatopsia

Cited by 62 publications

References 54 publications

Full-Field Pupillary Light Responses, Luminance Thresholds, and Light Discomfort Thresholds inCEP290Leber Congenital Amaurosis Patients

Full-Field Pupillary Light Responses, Luminance Thresholds, and Light Discomfort Thresholds inCEP290Leber Congenital Amaurosis Patients

Safety and Efficacy Evaluation of rAAV2tYF-PR1.7-hCNGA3 Vector Delivered by Subretinal Injection in CNGA3 Mutant Achromatopsia Sheep

Cortical processing of global form, motion and biological motion under low light levels

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