Abstract
Purpose :
To assess the safety and efficacy of sub-retinal injections of AAV8-RLBP1 gene therapy in patients with Bothnia Dystrophy.
Methods :
In an open-label, dose escalating Ph1/2 clinical trial, 12 patients were treated with sub-retinal AAV8-RLBP1 of increasing doses (5x109 to 1 x1011 vg/eye). In addition to ocular and systemic safety assessments, efficacy assessments included dark adaptation (DA) kinetics as well as other measures of light- and dark-adapted visual functions. DA kinetics was chosen as the primary efficacy endpoint due to the very delayed dark adaptation in these patients and was assessed with short and long-wavelength stimuli using a protocol developed from a 5-year natural history study in the same patient population (Burstedt et al 2023). Following overnight dark adaptation, recovery to full-field stimuli was assessed over a period of 6 hours. For DA recovery, a responder was defined as having sensitivity fall outside their pretreatment variability ranges at a minimum of two consecutive follow up visits.
Results :
The primary endpoint of DA recovery for the short wavelength stimuli (450 nm) was improved beyond the pre-defined variability in multiple patients; there were 8 responders at 1 hour, 11 at 2 hours and 9 at 3 hours post bleach and for the long wavelength stimuli (632 nm), there were 4 responders at 1 hour, 9 at 2 hours and 9 at 3 hours post bleach. These improvements were sustained up to the latest follow-up. In addition, in three patients who presented with punctata albescens (‘white dots’) at baseline, these punctata showed a rapid reduction in prevalence that correlated with the improvement in DA parameters in the treated eyes only. In patients treated with higher doses, intraocular inflammation and localized hyperpigmentation with secondary atrophy of the retinal pigment epithelium were observed at 2 to 4 year follow up. This inflammation responded to steroids.
Conclusions :
Sub-retinal administration of AAV8-RLBP1 was overall safe and well tolerated in Bothnia dystrophy patients. Treatment with AAV8-RLBP1 showed long-lasting improvement in dark adaptation kinetics and anatomical phenotypes in these patients. This improvement was also reflected as patient-reported functional benefits in activities of their daily living.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.