October 2023
Volume 64, Issue 13
Open Access
Retina  |   October 2023
Retinal Dystrophy Associated With RLBP1 Retinitis Pigmentosa: A Five-Year Prospective Natural History Study
Author Affiliations & Notes
  • Marie Burstedt
    Clinical Sciences/Ophthalmology, University of Umeå, Umeå, Sweden
  • James H. Whelan
    Memorial University of Newfoundland, St John's, Newfoundland, Canada
  • Jane S. Green
    Memorial University of Newfoundland, St John's, Newfoundland, Canada
  • Karen Holopigian
    Novartis Institutes for BioMedical Research, East Hanover, New Jersey, United States
  • Claudio Spera
    Novartis Pharma AG, Basel, Switzerland
  • Erin Greco
    Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
  • Jean-Yves Deslandes
    Novartis Institutes for BioMedical Research, East Hanover, New Jersey, United States
  • Michael Wald
    Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
  • Cynthia Grosskreutz
    Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
  • Xiao Ni
    Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
  • Guillaume Normand
    Novartis Institutes for BioMedical Research, East Hanover, New Jersey, United States
  • Michael Maker
    Novartis Institutes for BioMedical Research, East Hanover, New Jersey, United States
  • Arnaud Charil
    Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
  • Michael Rosol
    Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
  • Yunsheng He
    Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
  • Kalliopi Stasi
    Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
  • Correspondence: Marie Burstedt, Clinical Sciences/Ophthalmology, Umeå University, Umeå 901 85, Sweden; marie.burstedt@umu.se
Investigative Ophthalmology & Visual Science October 2023, Vol.64, 42. doi:https://doi.org/10.1167/iovs.64.13.42
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      Marie Burstedt, James H. Whelan, Jane S. Green, Karen Holopigian, Claudio Spera, Erin Greco, Jean-Yves Deslandes, Michael Wald, Cynthia Grosskreutz, Xiao Ni, Guillaume Normand, Michael Maker, Arnaud Charil, Michael Rosol, Yunsheng He, Kalliopi Stasi; Retinal Dystrophy Associated With RLBP1 Retinitis Pigmentosa: A Five-Year Prospective Natural History Study. Invest. Ophthalmol. Vis. Sci. 2023;64(13):42. https://doi.org/10.1167/iovs.64.13.42.

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Abstract

Purpose: To assess the progression in functional and structural measures over a five-year period in patients with retinal dystrophy caused by RLBP1 gene mutation.

Methods: This prospective, noninterventional study included patients with biallelic RLBP1 mutations from two clinical sites in Sweden and Canada. Key assessments included ocular examinations, visual functional measures (best-corrected visual acuity [BCVA], contrast sensitivity [CS], dark-adaptation [DA] kinetics up to six hours for two wavelengths [450 and 632 nm], Humphrey visual fields [HVF], full-field flicker electroretinograms), and structural ocular assessments.

Results: Of the 45 patients enrolled, 38 completed the full five years of follow-up. At baseline, patients had BCVA ranging from −0.2 to 1.3 logMAR, poor CS, HVF defects, and prominent thinning in central foveal thickness. All patients had extremely prolonged DA rod recovery of approximately six hours at both wavelengths. The test-retest repeatability was high across all anatomic and functional endpoints. Cross-sectionally, poorer VA was associated with older age (right eye, correlation coefficient [CC]: 0.606; left eye, CC: −0.578; P < 0.001) and HVF MD values decreased with age (right eye, CC: −0.672, left eye, CC: −0.654; P < 0.001). However, no major changes in functional or structural measures were noted longitudinally over the five-year period.

Conclusions: This natural history study, which is the first study to monitor patients with RLBP1 RD for five years, showed that severely delayed DA sensitivity recovery, a characteristic feature of this disease, was observed in all patients across all age groups (17–69 years), making it a potentially suitable efficacy assessment for gene therapy treatment in this patient population.

The retinaldehyde-binding protein 1 (RLBP1) gene encodes the cellular RLB protein (CRALBP), a key visual cycle protein that provides 11-cis-retinal photosensitive chromophore to both rods and cones. In Müller cells, CRALBP supports a cone-specific visual pathway that permits cells to quickly adapt to a wide range of light intensities. Dysfunction in the CRALBP results in extremely prolonged dark adaptation, reduced light sensitivity, and progressive loss of vision.1 
Biallelic mutations in the RLBP1 gene have been associated with autosomal recessive forms of retinal dystrophies (RD) that include retinitis pigmentosa (RP), retinitis punctata albescens, Bothnia-type dystrophy, Newfoundland rod-cone dystrophy, and fundus albipunctatus.26 RLBP1 RD is characterized by night blindness and slow dark adaptation from early childhood, followed by progressive loss of visual fields, visual acuity, and color vision.46 With disease progression, central retinal function is also affected, leading to central visual loss and eventually legal blindness.7 
RLBP1-RD is a rare disease, and limited literature is available on patients. Approximately 160 cases of RLBP1-RD have been reported in the literature, with most published reports based on cases in Sweden and Canada.26,825 In both countries, the cases are clustered in specific geographic areas: Västerbotten County in Sweden and Newfoundland in Canada.2123 
The visual prognosis for individuals with biallelic RLBP1 mutations remains poor, with no therapeutic intervention to either slow the disease progression or restore vision.25 Moreover, disease progression is not well understood because no prospective natural history study has been conducted in these patients. As per guidance from the Food and Drug Administration, the conduct of natural history studies of rare diseases will help to design and conduct adequate and well- controlled clinical trials, with adequate duration and clinically meaningful endpoints, to support marketing applications for new drugs.26 This study details the progression of the visual dysfunction and retinal structure abnormalities of RD patients with biallelic RLBP1 mutations over five years. 
Methods
Study Design
This was a noninterventional, prospective, observational study, conducted in two locations: Västerbotten County in Sweden and Newfoundland in Canada from September 2013–June 2019. The primary objective of the study was to obtain longitudinal measurements of visual functional and structural endpoints in patients with biallelic RLBP1 mutations. Secondary objectives were to obtain test-retest variability and progression rate of a number of outcome measures to aid in selection of the appropriate measurements for any potential therapeutic intervention and to identify patients who could reliably perform visual function tests as good candidates for future therapeutic clinical trials such as CPK850 trial (NCT03374657). 
Each patient in the study was observed for up to 60 months (five years). Patients visited the site every six months for four years and had their final fifth-year assessment after 60 months. Patients had a dedicated additional visit to assess the test-retest variability of visual function, performed one to 28 days after either the six-month or 12-month visit based on the investigator's discretion. 
Eligibility
Patients aged eight to 70 years with documented biallelic mutations in the RLBP1 gene associated with a phenotype of retinitis punctata albescens or RP were eligible. Historical genotyping data were acceptable for enrollment; in addition, a confirmatory blood test for genotyping was collected at screening. The complete exclusion criteria are provided in Supplementary Appendix A1
Written informed consent was obtained from all patients. The study followed the International Conference on Harmonization Tripartite Good Clinical Practice Guidelines, applicable local regulations, and ethical principles laid down in the Declaration of Helsinki. 
Assessments
Visual Function Assessments
Visual function assessments (measured at baseline and at all study visits) included the followig: (1) Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) expressed as a logarithm of the minimum angle of resolution (logMAR) scale; (2) low-luminance (LL) BCVA measured with a 2.0 log unit neutral density filter; (3) contrast sensitivity (CS) measured using Pelli-Robson charts (highest score = 2.25; lowest = 0); (4) dark adaptation (DA) tested with Espion Ganzfeld Profile (Diagnosys, Lowell, MA, USA) and ColorDome LED stimulator under full-field stimulation; (5) Humphrey visual fields (HVF), measured using the Swedish Interactive Threshold Algorithm standard 30-2 program with foveal thresholds turned on; (6) color vision under illuminant C-equivalent testing conditions, conducted using either the Lanthony Desaturated D-15 test or Farnsworth D-15 dichotomous color test; (7) full-field light-adapted 30 Hz flicker electroretinograms (ERGs) measured using the International Society for the Clinical Electrophysiology of Vision (ISCEV) standard (Supplementary Appendix A2).27 The ERG assessment was only performed in the Canadian cohort; all other functional assessments were performed in both cohorts. Per study protocol, visual field perimetry could be performed on both eyes using either automated static perimetry HVF or kinetic perimetry (e.g., Goldmann visual fields); however, all patients were tested using the Humphrey perimeter at all visits per the site's preference. 
A DA test of retinal sensitivity was specifically designed for this study28 and differed from the usual full-field sensitivity measure29 typically acquired with this equipment (Supplementary Appendix A2). Retinal sensitivity was measured after the eye was dark adapted overnight using an eye patch to protect the eye before testing. After pupil dilation, retinal sensitivity was assessed at the following time points: before exposure to a bleaching light (prebleach), immediately after exposure to the bleaching light (0 minutes), and at 15 and 30 minutes and one, two, three, and six hours after exposure to the bleaching light. Retinal sensitivity was measured in one eye at two wavelengths: 450 nm (short wavelength, blue) and 632 nm (long wavelength, red) using triplicate measurements of the minimal detected light intensity for each time point for which the median intensity was used (see Supplementary Appendix A2 for more details). Subjects kept the study eye covered and remained in a dimly lit room throughout the six-hour testing period. The details of weighted visual function scores and other assessments are included in Supplementary Appendix A2
Structural/Anatomic Assessments
Structural/anatomic assessments included (1) dilated fundus examination, (2) color fundus photography (CFP) (3D-OCT 2000, Topcon only performed in the Swedish cohort; Topcon, GB Ltd., Newbury, Berkshire, UK), and (3) optical coherence tomography (OCT) of the macula through 512 × 128 macular cubes [3DOCT 2000; Topcon, GB Ltd. [Swedish cohort], and Cirrus, Carl Zeiss Meditec, Dublin, CA, USA [Canadian cohort]). Total retinal thickness was reported for each of the nine ETDRS subfields within the proprietary software after manually centering the grid to the foveal center. Central retinal thickness (CRT) represented the average of all points within the inner circle of 1-mm radius. The central foveal point thickness (CPT) represented the point thickness at the foveola.30 All scans were processed using automated single retinal layer analysis (OCT Explorer). Finally, two trained graders evaluated the OCT and CFP for retinal abnormalities. 
Endpoint Analysis
An endpoint sensitivity analysis was performed for each visual function measure to estimate its sensitivity in detecting disease progression. 
Safety Analysis
Adverse events (AE) were recorded despite no interventional therapy in these natural history study patients. 
Potential Candidates for Future Trials
Patients, who met the predefined criteria of BCVA <2.3 (better than hand motion), had identifiable photoreceptor and retinal pigment epithelium layers in OCT, and had reduced DA after viewing a bleaching light by a factor of 10 were identified as potential candidates for future trials. 
Statistical Analysis
All data were analyzed descriptively (N, mean, standard deviation [SD], median, range, 95% confidence intervals [CIs]). For functional assessments, disease progression was estimated as slope using a random effect linear growth model. Clinically meaningful change was based on test-retest analysis performed at visits at month 6 + one to 28 days or at month 12 + one to 28 days during the study. For structural/anatomic assessments, annual progression was estimated as change from baseline. Individual profile plots were created for each eye and by site. Annual progression for retinal sublayers was based on the mean difference between one and two years, and one and five years. DA sensitivity recovery kinetic curves averaged across patients were created with standard error of the mean. 
Test-retest variability (reproducibility) was assessed using the intraclass correlation coefficient (ICC), coefficient of variation (CV%), and Bland-Altman plots, by patient eye, for each ocular endpoint. The ICC was estimated using the ratio of between-patient variability to the total variability obtained from a one-way random effect analysis of variance, using data from the test (at every six months) and retest visits (one to 28 days after the test). Correlations between endpoints and between eyes were assessed using Pearson's correlation coefficient and scatter plots. For all correlation analyses, a correlation coefficient of the magnitude of ≥0.6 with an associated P value <0.05 was considered as a strong correlation. All analyses were performed overall and by site. All analyses included all enrolled patients without protocol deviations. 
Results
Demographic and RLBP1 Genotype Profile
In total, 45 patients (Sweden n = 30 and Canada n = 15) were enrolled, and 44 patients completed at least one year of follow-up (one patient was excluded because the RLBP1 mutations could not be confirmed). Of these 44 patients, 42 and 38 patients completed the four- and five-year follow-up visits, respectively. All assessments except the ERG and CFP were performed at both sites. The patients tolerated the procedures well and had minimal missed visits. 
The mean (SD) age of the patients was 45.2 years (15.3); the majority of patients were female (65.9%). In total, seven different RLBP1 mutations (in eight allelic combinations) were identified in the patients. The most common mutations were homozygous p.R234W in 83% of the Swedish, and c.141G>A/c.141+2T>C in 53% of the Canadian patients (Table 1). 
Table 1.
 
Baseline Demographic and Clinical Characteristics of Patients With RLBP1 RD
Table 1.
 
Baseline Demographic and Clinical Characteristics of Patients With RLBP1 RD
Ocular, Functional, and Structural Assessments
Ocular Examinations
At baseline, CFP and dilated fundus examination of both eyes revealed the presence of optic disc pallor (commonly known as waxy pallor), white dots or pigment, and atrophy of the retina (Supplementary Tables S1, S2). Results from the dilated fundus examination and CFP grading at month 60 versus baseline were comparable. 
Visual Functions
Approximately 25% of the patients were legally blind at baseline with a BCVA score ≥1.0 logMAR in both eyes, and a wide range of scores of 2.6 to −0.2 logMAR was observed among all patients (Fig. 1A). The mean value of BCVA scores remained relatively stable during the study period, with a range of 0.9–1.0 logMAR in both eyes (Table 2). 
Figure 1.
 
(A) Weighted visual acuity (BCVA) of all patients with RLBP1 RD throughout the duration of this study as a function of age. Each shape in respective color represents each patient. (B) Weighted contrast sensitivity of all patients with RLBP1 RD throughout the duration of this study as a function of age. Each shape in respective color represents each patient. (C) Weighted HVF MD of all patients with RLBP1 RD throughout the duration of this study as a function of age. Each shape in respective color represents each patient.
Figure 1.
 
(A) Weighted visual acuity (BCVA) of all patients with RLBP1 RD throughout the duration of this study as a function of age. Each shape in respective color represents each patient. (B) Weighted contrast sensitivity of all patients with RLBP1 RD throughout the duration of this study as a function of age. Each shape in respective color represents each patient. (C) Weighted HVF MD of all patients with RLBP1 RD throughout the duration of this study as a function of age. Each shape in respective color represents each patient.
Table 2.
 
Mean Visual Functional and Structural Measurements, Between-Eye Correlations, and Disease Progression Over Five Years
Table 2.
 
Mean Visual Functional and Structural Measurements, Between-Eye Correlations, and Disease Progression Over Five Years
The LL BCVA testing performed at month 36 (the baseline visit for this test), showed mean (SD) BCVA logMAR scores of 0.93 (0.840) and 0.94 (0.90) in the right and left eye, respectively. LL BCVA scores remained relatively stable, similar to the standard BCVA during the study period with logMAR scores ranging between 0.92 and 1.01 at month 60 (Supplementary Fig. S1A). 
CS scores showed that approximately 15% of the patients had nonmeasurable CS at baseline (Fig. 1B). The mean (SD) CS scores of the patients with RLBP1 RD were 0.94 (0.674) and 0.86 (0.70) at baseline, and 0.81 (0.615) and 0.85 (0.650) at month 60, in the right and left eye, respectively (Table 2). 
At baseline, one third of the patients had severe VF loss with an average HVF mean deviation (MD) of approximately −23 dB. The mean [SD] change in HVF MD from baseline at month 60 was minimal (right eye: −2.5 [8.03] dB, left eye: −1.5 [3.09] dB) (Table 2). 
During the study period, overall, no change in mean BCVA (Supplementary Fig. S1B), LL BCVA (Supplementary Fig. S1A), CS scores (Supplementary Fig. S1C), HVF MD (Supplementary Fig. S1D), and total color difference scores (Supplementary Fig. S1E) was observed, although a few patients showed a worsening over time (Table 2). Moreover, the weighted BCVA (logMAR), CS scores and HVF MD stratified by age, showed that few patients had a gradual decline in all age groups (Figs. 1A–C). 
All patients showed severely delayed DA, with minimal or no retinal sensitivity recovery at 30 minutes or one hour postbleach, which reflect the times by which healthy volunteers (normative data; Diagnosys LLC) showed complete retinal sensitivity recovery (Fig. 2A). After one hour in the dark, a difference of ≥2.0 log-units in DA sensitivity recovery scores between short and long wavelengths was observed (Fig. 3) across the patients with RLBP1 mutation. DA profiles from selected patients are shown in Supplementary Figure S2. The difference in DA sensitivity recovery scores between short and long wavelengths (assessed within one hour postbleaching), ranged between approximately 1.0 and 1.5 log units (Table 3Fig. 2B). Overall, no trend of change in DA retinal sensitivity recovery was observed up to month 60. 
Figure 2.
 
(A) Mean DA sensitivity during six hours in patients with RLBP1 RD in comparison with healthy volunteers. (B) DA kinetic curves (mean ± SEM) at short (blue 450 nm) and long (red 632 nm) wavelengths in patients with RLBP1 RD. BAS, baseline.
Figure 2.
 
(A) Mean DA sensitivity during six hours in patients with RLBP1 RD in comparison with healthy volunteers. (B) DA kinetic curves (mean ± SEM) at short (blue 450 nm) and long (red 632 nm) wavelengths in patients with RLBP1 RD. BAS, baseline.
Figure 3.
 
Difference between short (blue 450 nm) and long (red 632 nm) wavelength DA sensitivity: A difference of ≥2.0 log-units in DA sensitivity recovery scores between short and long wavelengths after one hour in the dark explains the role of rods in recovering sensitivity at one-hour after bleaching. BAS, baseline.
Figure 3.
 
Difference between short (blue 450 nm) and long (red 632 nm) wavelength DA sensitivity: A difference of ≥2.0 log-units in DA sensitivity recovery scores between short and long wavelengths after one hour in the dark explains the role of rods in recovering sensitivity at one-hour after bleaching. BAS, baseline.
Table 3.
 
DA Sensitivity Thresholds (Mean ± SD) and Progression Over Five Years
Table 3.
 
DA Sensitivity Thresholds (Mean ± SD) and Progression Over Five Years
Patients aged 20–50 years showed prebleach sensitivity thresholds similar to those of healthy volunteers for both wavelengths. However, for patients >50 years, the prebleach sensitivity thresholds were less sensitive, with a wide range of ∼5 log units (100,000 times change) for both the short and long wavelengths. During the five-year follow-up, prebleach sensitivity in most of the patients was relatively stable, but in several patients, especially those >50 years, sensitivity showed a gradual decline for both wavelengths (Fig. 4). 
Figure 4.
 
DA prebleach sensitivity of all patients with RLBP1 RD throughout the duration of this study as a function of age. Each shape in respective color represents each patient.
Figure 4.
 
DA prebleach sensitivity of all patients with RLBP1 RD throughout the duration of this study as a function of age. Each shape in respective color represents each patient.
Structural Characteristics
CPT showed remarkable reduction from baseline, whereas CRT showed minimal reduction at month 60 (Table 2). The details of further structural characteristics are provided in Supplementary Appendix A3
Ocular and Functional Endpoints Across Sites and Eyes
Overall, the mean visual functions except for ERG (Canadian cohort only) were comparable for patients enrolled in Sweden and Canada. The mean CRT across visits was greater in the Canadian cohort than in the Swedish cohort. Moreover, changes in structural measurements and visual functions from baseline to year 5 were similar in both eyes (Table 2). 
Disease Progression
The disease progression analysis over the five years of follow-up showed no clinically meaningful disease progression for most of the mean values of the assessments except for CPT (Table 2). However, based on the random effect linear growth model, the average rate of change (across all patients) in the measurement per year over five years for CPT, BCVA, CS, and HVF MD (only in the left eye) was considered statistically significant. For BCVA, loss of VA by one or two letters per year was predicted, which was not considered clinically meaningful, although the average rate of change showed statistical significance. The results for most ocular assessments in these patients were relatively stable, although some patients showed progressive decline. For DA sensitivity, the slope estimate at 0 minutes (immediately after bleaching light) was statistically significant for both wavelengths; however, the magnitude of these changes was not clinically meaningful. No significant disease progression was observed based on the slope and 95% CI for DA sensitivity recovery over the study duration. The prebleach sensitivity for both short and long wavelengths showed a progressive decline at >45 and >50 years, respectively. 
Correlation Analysis
Strong correlations were observed among the visual function assessments, namely BCVA, CS, HVF MD, color vision score, and flicker ERG (amplitude and implicit time). However, OCT CRT did not show any strong correlation with any of the visual function outcomes (Supplementary Table S3A). The correlation between age and individual measures at baseline is shown in Supplementary Table S3B. With increase in age, BCVA scores worsened (CC: 0.606 [right eye]; 0.578 [left eye], P < 0.001) and HVF MD declined (CC: −0.672, [right eye]; −0.654 [left eye], P < 0.001). Strong association of DA retinal sensitivity was observed with BCVA and HVF MD, as shown in Supplementary Figure S5
Sensitivity Analysis and Test-Retest Repeatability
The highest signal-to-noise ratio for two years were observed for HVF MD and OCT CPT (Fig. 5A), whereas BCVA, HVF MD and CS were the most sensitive over five years (Fig. 5B). The CPT (only left eye) with increased sensitivity at two years may explain the lack of confidence (Fig. 5A). These results indicate that BCVA, HVF MD, and CS can be sensitive assessments to detect disease progression. 
Figure 5.
 
(A) Endpoints sensitive to disease progression at two years. (B) Endpoints sensitive to disease progression at 5 years. **For these measures higher value indicates worse result; therefore the SNR sign was reversed to compare across all measures. SNR, signal-to-noise ratio.
Figure 5.
 
(A) Endpoints sensitive to disease progression at two years. (B) Endpoints sensitive to disease progression at 5 years. **For these measures higher value indicates worse result; therefore the SNR sign was reversed to compare across all measures. SNR, signal-to-noise ratio.
High ICC values were observed for both eyes across all functional endpoints except ERG and OCT IR (inner retinal layer) indicating a remarkably high degree of repeatability (Table 4A; Fig. 6). The same was observed for DA assessments (Table 4B). Owing to the wide variations in disease characteristics among patients, the variance was higher for between-patient estimates than for the within-patient measures across all endpoints (Tables 4A, 4B). Results of further analysis are provided in Supplementary Appendix A3
Figure 6.
 
Bland-Altman plot for the test-retest repeatability across endpoints. EZ, ellipsoid zone; IR, inner retinal layer; ONL, outer nuclear layer; PR, photoreceptor.
Figure 6.
 
Bland-Altman plot for the test-retest repeatability across endpoints. EZ, ellipsoid zone; IR, inner retinal layer; ONL, outer nuclear layer; PR, photoreceptor.
Table 4A.
 
Test-Retest Variability Across Both Eyes for Functional and Structural Measures
Table 4A.
 
Test-Retest Variability Across Both Eyes for Functional and Structural Measures
Table 4B.
 
Test-Retest Variability Assessments for DA
Table 4B.
 
Test-Retest Variability Assessments for DA
Safety Analysis
The majority (81.8%) of the patients experienced at least one AE during the study. The most frequently reported ocular AE was cataract (22.7%). Serious AEs are reported in four patients (9.1%); none were related to the study procedure (Table 5). 
Table 5.
 
Incidence of Ocular AEs
Table 5.
 
Incidence of Ocular AEs
Potential Candidates for Future Trials
Of the 44 patients, 29 patients across all age groups from 17 to 70 years old were identified as potential candidates for future clinical trials. Notably, elderly patients (51–70 years) were identified as potential candidates, making them available for future treatment, although they represented a smaller proportion of the patients (seven of 29 patients) (Table 6). 
Table 6.
 
Number (Percent) of Patients Identified as Potential Candidates For Future Trials
Table 6.
 
Number (Percent) of Patients Identified as Potential Candidates For Future Trials
Discussion
To our knowledge, this is the first prospective study to provide longitudinal data for functional and structural retinal changes over five years in patients with RLBP1 RD. The study highlights the progressive nature of the disease with age and the challenge to identify decline in visual function assessment in this RD phenotype. 
The baseline structural and visual function assessments of the patients with RLBP1 RD were consistent with previously published reports, where decreased visual acuity, visual field defects, severely delayed DA, and decrease in retinal thickness were observed.31 The phenotype was symmetric between the right and left eyes similar to the previous reports in patients with RP (mutations in RPGR).32 Variabilities were seen for various retinal and visual function outcomes among these patients. However, delayed DA was similarly affected in all patients across all age groups, making it a highly specific phenotype for this patient population, consistent with a prior study.33 
Strong correlations were observed among the visual function assessments indicating that patients experience decline in multiple visual function assessments. The OCT CRT did not show strong correlations with any visual function assessments. The age of the patients showed strong correlations with VA (BCVA) and HVF MD but not with the OCT CRT at baseline visit. Central and peripheral vision showed the most dependency on the age of the patients. 
The CRT was reduced in patients with RLBP1 mutation as compared to healthy subjects (data from published normative database)34 by approximately 20% to 36% over the study period from month 6 to 60. Although there are no previous reports of OCT CRT assessment in patients with RLBP1 RD, the CRT reduction observed in this study is consistent with that in the previous studies with RP patients where reduction in CRT of approximately 34% was noted compared with healthy volunteers.35 
Dark adaptation was severely prolonged in all the patients, even in young patients with good visual acuity. In most of the patients, the prebleach sensitivity was relatively stable, but in some patients aged >50 years, sensitivity showed a gradual decline for both wavelengths. These results are in agreement with prior reports where the DA mixed rod cone responses were obtained using white light and stimuli localized to the periphery in patients with RLBP1 RD. The DA final threshold recovery was prolonged, reaching the final threshold value after 10 to 12 hours.36 
Based on these results, delayed DA can be evaluated in clinical trials using the same methodology for the initial detection of treatment benefit, whereas further information about different shorter duration tests and their sensitivity in this patent population can be explored. Moreover, patients in this study tolerated the DA test generally well. 
Patients across all age groups were identified as potential candidates. However, patients aged 51 to 70 years represented a small proportion of these patients. The results of this longitudinal study suggest that any future gene therapies may be more beneficial in a younger overall cohort. 
About 25% to 33% of the patients, mostly >50 years old, had values at the “floor” for many of the functional assessments at baseline making it difficult to demonstrate any worsening. The disease progression analysis over the five-year follow-up based on the averaged values of all patients participating in this study showed no meaningful disease progression for most of these assessments, except for central foveal point thickness. The lack of meaningful progression as a group could be partially explained by the presence of a considerable proportion of patients with end-stage disease with minimal expected decline in functional performance (“floor effect”). The same was observed for most ocular assessments, which were relatively stable, although some individual patients showed progressive decline across five years. 
A limitation of the current study is that the ETDRS chart that was used for measuring BCVA does not measure below 20/800, and BCVA below this level was estimated using techniques such as counting fingers and hand motion and then transformed into the approximate logMAR values using the conversion scale of Lange et al.37 In future studies, methods for direct measurement of low vision acuities, such as the Freiburg Vision Test (FrACT)38,39 should be used to allow accurate evaluation of BCVA in patients with low vision. The method for calculation of weighted visual acuity and visual fields may have limitations in regards of estimating these parameters in patients ranging from very low to very good visual function, but it has the advantage that it is very similar to the way of accessing visual disability for visual acuity and visual fields for calculation of disability in real world situations.40 
Further examination of results for individual patients for weighted VA, CS, DA retina sensitivity (prebleach), and HVF MD revealed that most of the patients showed stability in functional assessments, some at the lowest possible values, although several individual patients showed steady decline consistent with disease progression. The results in this study involving patients with a mean age of 45.2 years are in agreement with prior reports of patients with RLBP1 RD who showed decreased central and peripheral vision function at middle age indicating slow progression of the disease.4,17,41 
Several RLBP1 mutations have been reported to show geographic clustering.35,16,21 In line with these reports, patients from Sweden and Canada in this study had distinct RLBP1 mutations. 
A majority of the patients were able to successfully complete the four- and five-year study visits and perform many of the visual assessments. BCVA, CS and HVF MD were among the most sensitive variables to assess disease progression over five years, whereas HVF MD and OCT CPT were the most sensitive for two years. These outcomes look promising as sensitive endpoints and could be considered for further evaluation of this disease. Moreover, the test-retest repeatability and progression rate reported for various measures provide valuable information for the design of future clinical trials. 
Because only a few patients were available for the full-field flicker ERG and CPT final assessments, the results should be confirmed in further studies. The HVF MD (only left eye) correlation with disease progression, despite a high symmetry observed between the two eyes, is an observation to be explored further. The mean CRT was greater in the Canadian cohort than in the Swedish cohort, which might be due to the different devices of OCT used at each site.42 Although the CRT data cannot be interchangeable, the structure-function correlation were comparable when each device was compared against the standard automated perimetry.43 
Compared to the RPE65 retinal dystrophies, patients with RLBP1 retinal dystrophy in general showed a wider therapeutic window for intervention because of preservation of retina photoreceptors to much more advanced age. Similar to RPE retinal dystrophies, in RLBP1 retinal dystrophy patients, BCVA does not seem like a sensitive endpoint, whereas delayed dark adaptation and visual field may be more promising endpoints to show potential improvements after therapeutic intervention, such as with gene replacement therapy. In conclusion, this five-year follow-up study confirmed that RLBP1 RD is a slowly progressive disease, in which most patients >50 years of age show severely affected retina function. Reduced DA occurs early in life and was present in all patients independent of age in this cohort; therefore a treatment that improves DA would be beneficial to all patients. The current study implies that any future intervention involving gene therapy may be more meaningful to patients with RLBP1 RD who are assessed for visual function including DA at a young age. 
Acknowledgments
The authors thank the patients who participated in the study. Medical writing and editorial support for this manuscript was provided by Shivani Vadapalli, Saraladevi Selvam and Shaswati Khan of Novartis Healthcare Private Limited, India, which was funded by Novartis Pharma in accordance with Good Publication Practice (GPP3) guidelines. 
Funded by Novartis Institutes for Biomedical Research. 
Disclosure: M. Burstedt, Novartis (F, R); J.H. Whelan, Novartis (F, R), Bayer (R), Alcon (R), Sentrex (R), Roche (C); J.S. Green, Novartis (C) Memorial University, Newfoundland, Canada (R); K. Holopigian, Novartis (E); C. Spera, Novartis (E); E. Greco, Novartis (E), PHASTAR (E); J.-Y. Deslandes, Novartis (E), Blue Companion (E); M. Wald, Novartis (E), Biogen (F), Novartis (F), Biogen, Inc. (E); C. Grosskreutz, Novartis (E); X. Ni, Novartis (E), Sarepta Therapeutics (E); G. Normand, Novartis (E); M. Maker, Novartis (E), Invicro, LLC (E); A. Charil, Novartis (E), Eisai Inc. (E); M. Rosol, Novartis (E); Y. He, Novartis (E); K. Stasi, Novartis (E), Adverum Biotechnologies, Inc. (E) 
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Figure 1.
 
(A) Weighted visual acuity (BCVA) of all patients with RLBP1 RD throughout the duration of this study as a function of age. Each shape in respective color represents each patient. (B) Weighted contrast sensitivity of all patients with RLBP1 RD throughout the duration of this study as a function of age. Each shape in respective color represents each patient. (C) Weighted HVF MD of all patients with RLBP1 RD throughout the duration of this study as a function of age. Each shape in respective color represents each patient.
Figure 1.
 
(A) Weighted visual acuity (BCVA) of all patients with RLBP1 RD throughout the duration of this study as a function of age. Each shape in respective color represents each patient. (B) Weighted contrast sensitivity of all patients with RLBP1 RD throughout the duration of this study as a function of age. Each shape in respective color represents each patient. (C) Weighted HVF MD of all patients with RLBP1 RD throughout the duration of this study as a function of age. Each shape in respective color represents each patient.
Figure 2.
 
(A) Mean DA sensitivity during six hours in patients with RLBP1 RD in comparison with healthy volunteers. (B) DA kinetic curves (mean ± SEM) at short (blue 450 nm) and long (red 632 nm) wavelengths in patients with RLBP1 RD. BAS, baseline.
Figure 2.
 
(A) Mean DA sensitivity during six hours in patients with RLBP1 RD in comparison with healthy volunteers. (B) DA kinetic curves (mean ± SEM) at short (blue 450 nm) and long (red 632 nm) wavelengths in patients with RLBP1 RD. BAS, baseline.
Figure 3.
 
Difference between short (blue 450 nm) and long (red 632 nm) wavelength DA sensitivity: A difference of ≥2.0 log-units in DA sensitivity recovery scores between short and long wavelengths after one hour in the dark explains the role of rods in recovering sensitivity at one-hour after bleaching. BAS, baseline.
Figure 3.
 
Difference between short (blue 450 nm) and long (red 632 nm) wavelength DA sensitivity: A difference of ≥2.0 log-units in DA sensitivity recovery scores between short and long wavelengths after one hour in the dark explains the role of rods in recovering sensitivity at one-hour after bleaching. BAS, baseline.
Figure 4.
 
DA prebleach sensitivity of all patients with RLBP1 RD throughout the duration of this study as a function of age. Each shape in respective color represents each patient.
Figure 4.
 
DA prebleach sensitivity of all patients with RLBP1 RD throughout the duration of this study as a function of age. Each shape in respective color represents each patient.
Figure 5.
 
(A) Endpoints sensitive to disease progression at two years. (B) Endpoints sensitive to disease progression at 5 years. **For these measures higher value indicates worse result; therefore the SNR sign was reversed to compare across all measures. SNR, signal-to-noise ratio.
Figure 5.
 
(A) Endpoints sensitive to disease progression at two years. (B) Endpoints sensitive to disease progression at 5 years. **For these measures higher value indicates worse result; therefore the SNR sign was reversed to compare across all measures. SNR, signal-to-noise ratio.
Figure 6.
 
Bland-Altman plot for the test-retest repeatability across endpoints. EZ, ellipsoid zone; IR, inner retinal layer; ONL, outer nuclear layer; PR, photoreceptor.
Figure 6.
 
Bland-Altman plot for the test-retest repeatability across endpoints. EZ, ellipsoid zone; IR, inner retinal layer; ONL, outer nuclear layer; PR, photoreceptor.
Table 1.
 
Baseline Demographic and Clinical Characteristics of Patients With RLBP1 RD
Table 1.
 
Baseline Demographic and Clinical Characteristics of Patients With RLBP1 RD
Table 2.
 
Mean Visual Functional and Structural Measurements, Between-Eye Correlations, and Disease Progression Over Five Years
Table 2.
 
Mean Visual Functional and Structural Measurements, Between-Eye Correlations, and Disease Progression Over Five Years
Table 3.
 
DA Sensitivity Thresholds (Mean ± SD) and Progression Over Five Years
Table 3.
 
DA Sensitivity Thresholds (Mean ± SD) and Progression Over Five Years
Table 4A.
 
Test-Retest Variability Across Both Eyes for Functional and Structural Measures
Table 4A.
 
Test-Retest Variability Across Both Eyes for Functional and Structural Measures
Table 4B.
 
Test-Retest Variability Assessments for DA
Table 4B.
 
Test-Retest Variability Assessments for DA
Table 5.
 
Incidence of Ocular AEs
Table 5.
 
Incidence of Ocular AEs
Table 6.
 
Number (Percent) of Patients Identified as Potential Candidates For Future Trials
Table 6.
 
Number (Percent) of Patients Identified as Potential Candidates For Future Trials
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