AAV Delivery of Wild-Type Rhodopsin Preserves Retinal Function in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa

Abstract

Autosomal dominant retinitis pigmentosa (ADRP) is frequently caused by mutations in RHO, the gene for rod photoreceptor opsin. Earlier, a study on mice carrying mutated rhodopsin transgenes on either RHO þ / þ or RHO þ /-backgrounds suggested that the amount of wild-type rhodopsin affected survival of photoreceptors. Therefore, we treated P23H RHO transgenic mice with adeno-associated virus serotype 5 (AAV5) expressing a cDNA clone of the rhodopsin gene (RHO301) that expressed normal opsin from the mouse opsin promoter. Analysis of the electroretinogram (ERG) demonstrated that increased expression of RHO301 slowed the rate of retinal degeneration in P23H mice: at 6 months, a-wave amplitudes were increased by 100% and b-wave amplitudes by 79%. In contrast, nontransgenic mice injected with AAV5 RHO301 demonstrated a decrease in the ERG, confirming the damaging effect of rhodopsin overproduction in normal photoreceptors. In P23H mice, the increase in the ERG amplitudes was correlated with improvement of retinal structure: the thickness of the outer nuclear layer in RHO301-treated eyes was increased by 80% compared with control eyes. These findings suggest that the wild-type RHO gene can be delivered to rescue retinal degeneration in mice carrying a RHO mutation and that increased production of normal rhodopsin can suppress the effect of the mutated protein. These findings make it possible to treat ADRP caused by different mutations of RHO with the expression of wild-type RHO.

Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

“…For example, the thoroughly studied P23H mutation in rhodopsin (a single amino acid substitution of proline at position 23 for histidine), frequently encountered in retinitis pigmentosa patients (2,3), was shown to cause rhodopsin misfolding and endoplasmic reticulum (ER) accumulation (4,5), ultimately resulting in an unfolded protein response and cell death (6,7). Protein misfolding is considered a therapeutic target in the ongoing clinical trial in which patients with retinitis pigmentosa are treated with valproic acid (http:// clinicaltrials.gov/ct2/show/study/NCT01233609), the substance suggested to act as a pharmacological chaperone for unfolded proteins (8,9).…”

Leber Congenital Amaurosis Caused by Mutations in GUCY2D

“…The notable retinal preservation reported by Jacobson et al (2013) suggests that LCA1 patients are good candidates for subretinal injection. The AAV serotypes used in proof-of-concept LCA1 studies, AAV5 and AAV8, have proven utility following subretinal injection in various mouse and dog models of photoreceptor-mediated disease (Min et al 2005;Alexander et al 2007;Boye et al 2010Boye et al , 2013Gorbatyuk et al 2010;Komaromy et al 2010;Mao et al 2011;Pang et al 2011Pang et al , 2012Yao et al 2011;Beltran et al 2012). Because transduction can vary across species, it is essential to evaluate vectors in a species as closely related to man as possible.…”

Gene-based therapies for dominantly inherited retinopathies

“…48 In situations where at least some of the disease phenotype results from reduced levels of wild-type protein, delivery of the wild-type gene in the absence of suppression of the mutant allele may potentially provide benefit. In this regard, Mao et al 49 have delivered the wildtype RHO gene to P23H Rho+/+ mice and obtained some histological and electroretinographic benefit at 6 months post-injection benefit. The thickness of the outer nuclear layer of treated eyes was 80% greater than of control eyes and A-and B-wave amplitudes were increased by 100% and 79%, respectively.…”