Dataset Information

Restoration of cone vision in the CNGA3-/- mouse model of congenital complete lack of cone photoreceptor function.

ABSTRACT: Congenital absence of cone photoreceptor function is associated with strongly impaired daylight vision and loss of color discrimination in human achromatopsia. Here, we introduce viral gene replacement therapy as a potential treatment for this disease in the CNGA3(-/-) mouse model. We show that such therapy can restore cone-specific visual processing in the central nervous system even if cone photoreceptors had been nonfunctional from birth. The restoration of cone vision was assessed at different stages along the visual pathway. Treated CNGA3(-/-) mice were able to generate cone photoreceptor responses and to transfer these signals to bipolar cells. In support, we found morphologically that treated cones expressed regular cyclic nucleotide-gated (CNG) channel complexes and opsins in outer segments, which previously they did not. Moreover, expression of CNGA3 normalized cyclic guanosine monophosphate (cGMP) levels in cones, delayed cone cell death and reduced the inflammatory response of Müller glia cells that is typical of retinal degenerations. Furthermore, ganglion cells from treated, but not from untreated, CNGA3(-/-) mice displayed cone-driven, light-evoked, spiking activity, indicating that signals generated in the outer retina are transmitted to the brain. Finally, we demonstrate that this newly acquired sensory information was translated into cone-mediated, vision-guided behavior.

SUBMITTER: Michalakis S

PROVIDER: S-EPMC2997579 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Restoration of cone vision in the CNGA3-/- mouse model of congenital complete lack of cone photoreceptor function.

Michalakis Stylianos S Mühlfriedel Regine R Tanimoto Naoyuki N Krishnamoorthy Vidhyasankar V Koch Susanne S Fischer M Dominik MD Becirovic Elvir E Bai Lin L Huber Gesine G Beck Susanne C SC Fahl Edda E Büning Hildegard H Paquet-Durand François F Zong Xiangang X Gollisch Tim T Biel Martin M Seeliger Mathias W MW

Molecular therapy : the journal of the American Society of Gene Therapy 20100713 12

Congenital absence of cone photoreceptor function is associated with strongly impaired daylight vision and loss of color discrimination in human achromatopsia. Here, we introduce viral gene replacement therapy as a potential treatment for this disease in the CNGA3(-/-) mouse model. We show that such therapy can restore cone-specific visual processing in the central nervous system even if cone photoreceptors had been nonfunctional from birth. The restoration of cone vision was assessed at differe ...[more]

PMID: 20628362

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Project description:PurposeTo understand consequences of reconstituting cone photoreceptor function in congenital binocular blindness resulting from mutations in the centrosomal protein 290 (CEP290) gene.DesignPhase 1b/2 open-label, multicenter, multiple-dose, dose-escalation trial.ParticipantsA homogeneous subgroup of 5 participants with light perception (LP) vision at the time of enrollment (age range, 15-41 years) selected for detailed analyses. Medical histories of 4 participants were consistent with congenital binocular blindness, whereas 1 participant showed evidence of spatial vision in early life that was later lost.InterventionParticipants received a single intravitreal injection of sepofarsen (160 or 320 μg) into the study eye.Main outcome measuresFull-field stimulus testing (FST), visual acuity (VA), and transient pupillary light reflex (TPLR) were measured at baseline and for 3 months after the injection.ResultsAll 5 participants with LP vision demonstrated severely abnormal FST and TPLR findings. At baseline, FST threshold estimates were 0.81 and 1.0 log cd/m2 for control and study eyes, respectively. At 3 months, study eyes showed a large mean improvement of -1.75 log versus baseline (P < 0.001), whereas untreated control eyes were comparable with baseline. Blue minus red FST values were not different than 0 (P = 0.59), compatible with cone mediation of remnant vision. At baseline, TPLR response amplitude and latency estimates were 0.39 mm and 0.72 seconds, respectively, for control eyes, and 0.28 mm and 0.78 seconds, respectively, for study eyes. At 3 months, study eyes showed a mean improvement of 0.44 mm in amplitude and a mean acceleration of 0.29 seconds in latency versus baseline (P < 0.001), whereas control eyes showed no significant change versus baseline. Specialized tests performed in 1 participant confirmed and extended the standardized results from all 5 participants.ConclusionsBy subjective and objective evidence, intravitreal sepofarsen provides improvement of light sensitivity for individuals with LP vision. However, translation of increased light sensitivity to improved spatial vision may occur preferentially in those with a history of visual experience during early neurodevelopment. Interventions for congenital lack of spatial vision in CEP290-associated Leber congenital amaurosis may lead to better results if performed before visual cortex maturity.

Dataset Information

Restoration of cone vision in the CNGA3-/- mouse model of congenital complete lack of cone photoreceptor function.

Publications

Restoration of cone vision in the CNGA3-/- mouse model of congenital complete lack of cone photoreceptor function.

Similar Datasets

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