Genetic Etiology and Clinical Consequences of Complete and Incomplete Achromatopsia

Thiadens, Alberta A H J; Slingerland, Niki W. R.; Roosing, Susanne; Schooneveld, Mary J. van; Lith-Verhoeven, Janneke J.C. van; Moll-Ramirez, Norka van; Born, L. Ingeborgh van den; Hoyng, Carel B.; Cremers, Frans P.M.; Klaver, Caroline C.W.

doi:10.1016/j.ophtha.2009.03.053

Cited by 106 publications

(102 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Three females (one in each group) also received additional topical atropine and tobramycin/ dexamethasone for 21-54 days. Two animals (one in the lower dose group and one in the higher dose group) received an intramuscular injection of analgesic (buprenorphine) on study day 5 and one animal in the higher dose group received intramuscular injections of a nonsteroidal antiinflammatory drug (flunixin meglumine on study days 5-7 and meloxicam on study days [8][9][10][11][12][13][14][15][16][17].…”

Section: Evaluation Of Raav2tyf-pr17-hcngb3 In Macaquesmentioning

confidence: 99%

“…Approximately 50% of cases in the United States and Europe are caused by mutations in the cone photoreceptorspecific cyclic nucleotide-gated channel b-subunit (CNGB3) gene 3 and 25% are caused by mutations in the cone-specific cyclic nucleotide-gated channel asubunit (CNGA3) gene, 4 and a small percentage are caused by mutations in other genes. [5][6][7][8][9] Most CNGB3 mutations result in a premature stop codon, and some missense mutations result in an abnormal CNGB3 protein that interacts with the a-subunit (CNGA3) protein to form channels with increased affinity for cGMP compared with wild-type channels. 10 As a result there is a loss of cone photoreceptor function in individuals with CNGB3 mutations and in animals with mutations in the homologous gene.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia

Budzynski

Sonnentag

et al. 2016

Human Gene Therapy Clinical Development

View full text Add to dashboard Cite

Section: Evaluation Of Raav2tyf-pr17-hcngb3 In Macaquesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia

Budzynski

Sonnentag

et al. 2016

Human Gene Therapy Clinical Development

View full text Add to dashboard Cite

“…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.…”

mentioning

confidence: 99%

Development of a Chromatic Pupillography Protocol for the First Gene Therapy Trial in Patients With CNGA3-Linked Achromatopsia

Lisowska

Lisowski

Kelbsch

et al. 2017

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

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 ...

show abstract

“…Mutations in five genes (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H) that encode proteins of the phototransduction pathway have been implicated in the pathogenesis of ACHM and result in clinically indistinguishable forms of the disease. [16][17][18] However, the cause of ACHM in 10-20% patients remains unresolved, implying further heterogeneity. A zebrafish model of human achromatopsia (pde6c w59 ) has been recently identified displaying rapid degeneration of cone photoreceptors caused by a mutation in the cone phosphodiesterase a-subunit gene (pde6c).…”

mentioning

confidence: 99%

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

et al. 2014

View full text Add to dashboard Cite

Achromatopsia is a progressive autosomal recessive retinal disease characterized by early loss of cone photoreceptors and later rod photoreceptor loss. In most cases, mutations have been identified in CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes. Owing to this genetic heterogeneity, mutation-independent therapeutic schemes aimed at preventing cone cell death are very attractive treatment strategies. In pde6c w59 mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death. In contrast, rod photoreceptor cells were alternatively immunopositive for caspase-3 indicating activation of caspase-dependent apoptosis in these cells. Morpholino gene knockdown of rip3 in pde6c w59 embryos rescued the dying cone photoreceptors by inhibiting the formation of reactive oxygen species and by inhibiting second-order neuron remodelling in the inner retina. In rip3 morphant larvae, visual function was restored in the cones by upregulation of the rod phosphodiesterase genes (pde6a and pde6b), compensating for the lack of cone pde6c suggesting that cones are able to adapt to their local environment. Furthermore, we demonstrated through pharmacological inhibition of RIP1 and RIP3 activity that cone cell death was also delayed.Collectively, these results demonstrate that the underlying mechanism of cone cell death in the pde6c w59 mutant retina is through necroptosis, whereas rod photoreceptor bystander death occurs through a caspase-dependent mechanism. This suggests that targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. As bystander cell death is an important feature of many retinal diseases, combinatorial approaches targeting different cell death pathways may evolve as an important general principle in treatment.

show abstract

Genetic Etiology and Clinical Consequences of Complete and Incomplete Achromatopsia

Cited by 106 publications

References 22 publications

Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia

Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia

Development of a Chromatic Pupillography Protocol for the First Gene Therapy Trial in Patients With CNGA3-Linked Achromatopsia

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

Contact Info

Product

Resources

About