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Clinical Perspectives on Gene Therapy for Retinal and Eye Diseases
Published in Yashwant Pathak, Gene Delivery, 2022
Devika S. Joshi, Gaurav M. Karve, Shrikant D. Joshi
This disorder leads to loss of colour vision, nystagmus, photophobia, and poor visual acuity. About 70 to75% of mutations for this autosomal recessive disease are seen in the CNGA3 (25%) and CNGB3 genes (40 to 50%).
Gene therapy for inherited retinal diseases: progress and possibilities
Published in Clinical and Experimental Optometry, 2021
Monica L Hu, Thomas L Edwards, Fleur O’Hare, Doron G Hickey, Jiang-Hui Wang, Zhengyang Liu, Lauren N Ayton
Mutations in CNGB3 and CNGA3, which encode subunits of a cone photoreceptor cGMP-gated channel, account for the majority of achromatopsia cases.10 Gene augmentation studies using AAV vectors carrying either of the two genes, and targeting cone photoreceptors, have progressed from showing proof-of-concept in murine,70 ovine71 and canine72 models. An open-label dose-escalation trial conducted in Germany demonstrated the safety and efficacy of an AAV8 vector carrying the CNGA3 gene in nine achromatopsia patients.73 During 12 months of follow-up, there were no substantial safety problems, and all treated eyes showed improvement in cone photoreceptor function, including an increased mean visual acuity of 2.9 letters (p = 0.006) and increased mean contrast sensitivity of 0.33 log (p = 0.003). Other phase 1/2 clinical trials are underway across the USA, UK, and Israel (Table 1).
Interocular Symmetry of Foveal Cone Topography in Congenital Achromatopsia
Published in Current Eye Research, 2020
Katie M. Litts, Michalis Georgiou, Christopher S. Langlo, Emily J. Patterson, Rebecca R. Mastey, Angelos Kalitzeos, Rachel E. Linderman, Byron L. Lam, Gerald A. Fishman, Mark E. Pennesi, Christine N. Kay, William W. Hauswirth, Michel Michaelides, Joseph Carroll
In addition to structural symmetry, there is functional symmetry (e.g., visual acuity, contrast sensitivity, and microperimetry) in patients with ACHM. Consistent with our result in a population of mostly patients with CNGB3-associated ACHM, no significant interocular difference in BCVA in patients with CNGA3-associated ACHM has been reported.10,33 Matet et al.31 also showed a strong correlation between visual acuity from the right and left eyes in patients with ACHM (r = 0.82, p = .001). In addition, Zobor et al.33 demonstrated a lack of significant interocular difference in functional results, including contrast sensitivity and microperimetry in patients with ACHM and Aboshiha et al.34 found no significant interocular difference in dark adaptation thresholds in patients with ACHM. Together with our findings of structural symmetry in AOSLO, these data suggest that both eyes of a given subject may have similar therapeutic potential.
CNGB3 mutations cause severe rod dysfunction
Published in Ophthalmic Genetics, 2018
J. Maguire, M. McKibbin, K. Khan, S. Kohl, M. Ali, D. McKeefry
Complete achromatopsia (ACHM), also known as rod monochromacy, is a rare autosomal recessive congenital condition with a prevalence of 1:30,000, characterized by complete or partial loss of cone function (1). Clinically, patients present with photophobia, nystagmus, severely reduced visual acuity (20/200), and severe color vision deficits (2). Currently, six genes have been implicated in the generation of this disease, all of which encode crucial steps in the cone photo-transduction cycle. Two genes encoding for the cyclic nucleotide gated (CNG) channels alpha (α) and beta (β) (CNGA3, CNGB3) account for approximately 25% and 60% of the all mutations, respectively, with the rarer mutations found in the GNAT2, PDE6C, PDE6H, ATF6 genes (1,3). Over 140 mutations have been discovered in the CNGA3 and CNGB3 genes, most of which result in a failure to produce α or β subunits. In the normal functioning retina, the CNG channels, located in the plasma membrane of the outer segment, are held open in darkness by cyclic guanosine monophosphate (cGMP), creating an inward positive current. When light causes hydrolysis of cGMP, the channels are closed causing a hyperpolarization of the cell; without functional subunits, CNG channels remain constantly closed, preventing cone hyperpolarization. In adults this can frequently result in the degeneration of cone photoreceptors. However, evidence of foveal disruption and hypoplasia has also been shown in young children (4–7). In a few cases, some residual cones may remain, although they too may later progressively decline (7–9).