Essay Example on Vector administration The extension of the bleb of subretinal Vector

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Results Vector administration The extension of the bleb of subretinal vector included the fovea in all eyes except in participants 9 and 11 The absorption of subretinal vectors as indicated by findings on OCT took 24 to 48 hours Lacrimal fluid for vector DNA sequences was weakly positive at 1 day after surgery However it was not in participant 7 and 10 who were given the higher dose and in participant 4 who was given the lower dose of vector There was no detection of the vector DNA in the participant s saliva peripheral blood or semen which was analyzed in one participant Adverse events We observed ocular adverse events that included a transient or mild intraocular inflammation in three participants administered the higher dose A decline in visual acuity and macular thinning were evident after the administration of subfoveal vector We also observed systemic adverse events that are associated with the oral glucocorticoids Retinal sensitivity and vision guided ambulatory navigation The retinal sensitivity in the study eyes of six participants on the dark adapted perimetry 3 5 6 8 10 and 12 had improvements and five of the participants on microperimetry 3 5 6 8 and 12 After extended dark adaptation maximal improvement of rod function was evident for the first four months after vector administration on dark adapted perimetry

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There was a progressive improvement in the retinal sensitivity for up to four hours in dark adaptation Participants 3 5 6 8 and 10 reported advancements in night vision whereas participants 5 8 and 10 showed refinements in the navigation of vision guided ambulatory Participant 4 was the only subject who subjectively reported an improved night vision with no consistent measurement in retinal navigation and sensitivity Spectral sensitivity Participants 5 and 6 were confirmed to have substantial improvements in the measurement of spectral sensitivities in the superior retina at a fixed location following the administration of the higher dose This was 10 to 100 times as high in rod sensitivity that had a peak 12 months after treatment before declining subsequently Participant 6 had greater improvements that indicated recovery of rod function Participant 5 also had similar improvements of 500 nm and 600 nm that showed cone function improvement Visual acuity Participant 11 had an improvement in visual acuity with a similar improvement in the untreated contralateral eye Participants 3 and 7 experienced visual acuity decline by more than 15 letters on the ETDRS chart Participant 12 had a modest acuity but with a sustained decline in the study eye The decline in participants 7 and 12 was associated with a subjective deterioration of vision ERG The use of ERG at baseline were undetectable as measured by the rod photoreceptor mediated responses None of the participants had a significantly sustained rod in cone or rod responses Participants who retained the same function level has very low amplitude residual ERD findings Inflammatory and immune responses 



Five of the eight participants experienced intraocular inflammation or immune responses 5 and 12 but wasn't present in participants 1 through 4 who received the lower dose Participant 7 experienced an episode of mild anterior uveitis followed by focal pigmentary changes at the macula Participant 8 and 9 had posterior intraocular inflammation asymptomatic episodes in the study eye Dose response relations in RPE65 Deficient dogs We estimated the normal demand for ROE65 in each species to investigate the differences in responses to gene augmentation in humans and dogs with RPE65 deficiency We measured the endogenous expression of the protein while performing a dose response study in dogs of the RPE65 gene augmentation The human eye had the highest expression of RPE65 messenger RNA 2 5 times as high as that in the dog's eye Dogs that received the lower dose has a better vision compared to the untreated dogs with no significant improvement in the ERG response Discussion This trial had preliminary results that depicted an increased retinal sensitivity in one of the 3 participants following an administration of the intraocular rAAV2 2 hRPE65p hRPE65 We report here a 3 year outcome of 12 participants The absence of an improvement in the untreated contralateral eye and the improved sensitivity within the area that is treated provides evidence that such improvements are the consequence of the supplementation of RPE65 A greater proportion of participants who were administered high dose showed an improved retinal sensitivity compared to those administered lower doses The level of improvement in the retinal sensitivity at high dose widely differed among the participants

No magnitude improvement could be detected by means of ERG On the contrary there was a robust RPE65 deficiency in the responses after the same intervention in animal models Our results provided further evidence for the improved function of the rod photoreceptor in response to the AAV2 mediated RPE65 gene supplementation Substantial improvements in the retinal function in dogs were measurable by means of ERG Although they could offer protection against degeneration they were highly dose dependent The improvements in retinal sensitivity in humans were modest even in participants who had mild retinal degeneration and never had the protection against ongoing degeneration Therefore we can make the decision that gene therapy with a rAAV2 2 vector that carries RPE65 cDNA led to a temporary and incomplete restoration of retinal function in humans This partially reflects an unmet demand for RPE65 that is persistent Conclusions Retinal sensitivity was improved by the gene therapy rAAV2 2 RPE65 vector There is a species difference in the required amount of RPE65 that is required to drive the visual cycle in comparison with the obtained result in the dog model The RPE65 demand for affected persons wasn't met to the required extent for a durable and robust effect


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