Long-term and age-dependent restoration of visual function in a mouse model of CNGB3-associated achromatopsia following gene therapy

Abstract

Mutations in the CNGB3 gene account for >50% of all known cases of achromatopsia. Although of early onset, its stationary character and the potential for rapid assessment of restoration of retinal function following therapy renders achromatopsia a very attractive candidate for gene therapy. Here we tested the efficacy of an rAAV2/8 vector containing a human cone arrestin promoter and a human CNGB3 cDNA in CNGB3 deficient mice. Following subretinal delivery of the vector, CNGB3 was detected in both M- and S-cones and resulted in increased levels of CNGA3, increased cone density and survival, improved cone outer segment structure and normal subcellular compartmentalization of cone opsins. Therapy also resulted in long-term improvement of retinal function, with restoration of cone ERG amplitudes of up to 90% of wild-type and a significant improvement in visual acuity. Remarkably, successful restoration of cone function was observed even when treatment was initiated at 6 months of age; however, restoration of normal visual acuity was only possible in younger animals (e.g. 2–4 weeks old). This study represents achievement of the most substantial restoration of visual function reported to date in an animal model of achromatopsia using a human gene construct, which has the potential to be utilized in clinical trials.

AAV-Mediated Gene Therapy in the Guanylate Cyclase (RetGC1/RetGC2) Double Knockout Mouse Model of Leber Congenital Amaurosis

“…We restrict our focus to mouse cones because this photoreceptor subclass does not express GC2, and thus their function is not impaired by its absence (Lowe et al, 1995). Our findings of significant but incomplete cone rescue is in contrast to reports of other cone-targeted gene therapies in mouse models of retinal disease (Alexander et al, 2007;Carvalho et al, 2011). In two different models of achromatopsia, CNGB3…”

Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa

“…Some patients can show very limited or even normal rod function, and cone-targeting strategies must be developed for these subtypes. Proof-of-principle studies targeting cone diseases already have been successful in both mouse and dog models with mutations in cone phototransduction (46) or cyclic GMP gated channel (47)(48)(49) genes, allowing translation to the clinic to be expedited.…”

Absence of ocular malignant transformation after sub-retinal delivery of rAAV2/2 or integrating lentiviral vectors in p53-deficient mice

“…The clinical success of the RPE65 trials, combined with the increasing number of successful pre-clinical studies using rAAV [18][19][20][21] or lentiviruses, [22][23][24][25][26][27][28] suggest that more retinal gene therapy clinical trials are likely to start in the near future. It is, therefore, crucial to determine the oncogenic potential of these gene delivery vehicles in the context of the retina.…”