A Systematic Review and Meta-Analyses of Interventional Clinical Trial Studies for Gene Therapies for the Inherited Retinal Degenerations (IRDs)

Abstract

IRDs are one of the leading causes of visual loss in children and young adults. Mutations in over 271 genes lead to retinal dysfunction, degeneration and sight loss. Though no cure exists, gene augmentation therapy has brought hope to the field. This systematic review sought to assess the efficacy of available gene therapy treatments for IRDs. Databases and public resources were searched for randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs). Standard methodological procedures were used, including a risk-of-bias assessment. One RCT and five NRSIs were assessed, all for adeno-associated virus two (AAV2)-mediated treatment of RPE-specific 65 kDa (RPE65)-associated LCA (Leber congenital amaurosis). Five outcomes were reported for meta-analyses. Modest improvements in visual acuity, ambulatory navigation/mobility testing or central retinal thickness was observed. There was significant improvement in red and blue light full-field stimulus testing (FST) (red light risk ratio of 1.89, treated v control, p = 0.04; and blue light risk ratio of 2.01, treated v control, p = 0.001). Study design assessment using a ROBIN-I tool (Cochrane Library) showed risk-of-bias judgement to be “low/moderate”, whilst there were “some concerns” for the RCT using a RoB-2 tool (Cochrane Library). Although comparison by meta-analysis is compromised by, amongst other issues, a variable amount of vector delivered in each trial, FST improvements demonstrate a proof-of-principle for treating IRDs with gene therapy.

1. Introduction

The IRDs are a heterogenous group of overwhelmingly monogenic eye conditions that cause premature sight loss [1]. Currently, 271 causal genes have been identified (last updated 8 April 2021 [2]) which have roles in various aspects of photoreceptor and/or retinal pigment epithelium (RPE) function. Dominant, recessive, X-linked, digenic and mitochondrial modes of inheritance have all been described [3,4,5,6,7,8,9,10,11,12,13,14]. IRDs cause progressive retinal degeneration, which results in a variety of progressive symptoms including night blindness (nyctalopia), visual field constriction, central visual loss, dark adaptation problems, photophobia, nystagmus and pupillary abnormalities [14].

There is considerable phenotypic variability between IRDs and historically they have been grouped into several different disease patterns, including retinitis pigmentosa (RP), cone dystrophies, cone-rod dystrophies and Leber congenital amaurosis (LCA) [15]. Further, many attempts have been made at genotype-phenotype correlation. However, in reality, there is both considerable inter-allelic disease overlap and marked intra-allelic disease variability. Thus, the progress made in genetic diagnosis of IRDs has been invaluable.

LCA is a severe congenital or early infant-onset IRD characterised by vision loss, nystagmus, an absence of a normal pupil response and an almost non-recordable ERG [16,17,18,19]. Known genes associated with LCA includes GUCY2D (estimated 10–20% patients), CEP290 (15–20%), CRB (10%), AIPL1 (4–8%) and NMNAT1 (uncertain). Following the original description of the infantile disorder, a subsequent milder form of disease, considered to be on the LCA spectrum, was described that presents in the 6th or 7th year of life and leads to blindness by the age of 30 [20]. Whilst this later-onset disease has been referred to by several different names [21,22,23,24,25], there is considerable overlap with LCA in both genotype and phenotype, with causal genes including RPE65 (5–10%), LRAT (<1%) and RDH12 (4–5%) [18].

Mutations in RPE65 are estimated to account for approximately 5–10% of LCA and approximately 1–2% of retinitis pigmentosa [26]. RPE65 is localized to chromosome 1p31, comprising 14 exons and encoding a 65-Kd protein [23]. RPE65 is a key component of the retinoid visual cycle. It is expressed in the retinal pigment epithelium (RPE) which, together with LRAT, is involved in continuous regeneration of the visual chromophore [24]. LCA-mediated IRDs have a prevalence of between 1 in 33,000 [25] and 1 in 81,000 [27]. In Ireland, there are an estimated ~130 LCA patients [28], while NICE has reported there may be 86 LCA2 patients potentially eligible for EMA-approved gene augmentation therapy [29] in England [30].

Gene augmentation therapy is a novel therapeutic approach for genetic disease that seeks to replace null or loss-of-function protein by expressing wild-type copies of the gene of interest, typically through delivery via a viral capsid [31]. The approach is most applicable to recessive traits, and decades-long efforts have demonstrated the approach efficient at rescuing visual loss in animal models of achromatopsia, X-linked and recessive RP, LCA and Stargardt’ disease, amongst others [32,33].

Subsequently, gene augmentation therapy has begun to be translated in clinical trials. ClinicalTrials.gov have estimated 250 listed studies focused on IRDs, including patient registry studies, natural histories, observational and interventional trials [34]. One of the first genes to be targeted was RPE65-LCA, so chosen because of the relative delay in the development of retinal degeneration despite early-onset visual loss, thus offering a wide treatment window. Gene augmentation therapy (voretigene neparvovec-rzyl/Luxturna [35]) has now received FDA approval in the USA (2017) and EMA approval in Europe (2018) for adult and paediatric disease. This first-in-class treatment gives the field hope that a new class of drugs may arise for IRDs [36,37].

Gene augmentation therapies used to date to treat IRDs are based around similar basic adeno-associated virus (AAV) vectors and their capsids, with a variety of promoters chosen by different research groups and companies. To rigorously determine the efficacies of these new therapies it is critical to assess how results show benefit. This requires that methodology, study design and outcome measures provide a clear and reasonable conclusion for the impact on the patient. To this end, we performed a systematic review and meta-analyses of clinical trials for RP patients undergoing gene therapy.

2. Materials and Methods

2.1. Criteria for Considering Studies for This Review

2.1.1. Types of Studies

Articles eligible for inclusion in this systematic review were interventional clinical trials, either randomized or non-randomized, for gene therapy treatments for IRD patients, published in English searched in the relevant databases from <1946 to 2020 Week 5>.

2.1.2. Types of Participants

All patients who have been diagnosed with IRDs, either non-syndromic or syndromic, were included with no restrictions of age, gender or ethnicity. Clinical trials were excluded from patients with ocular comorbidities, or excluded from patients with complications known to influence visual function. Women who were pregnant or lactating or any participants unwilling to use effective contraception were also ineligible.

2.1.3. Types of Interventions

Studies included any investigational gene therapy interventions for IRDs. There were no comparators available for any approved interventions for IRD patients.

2.2. Types of Outcome Measures

2.2.1. Primary Outcomes

The primary outcome of intervention was a mean change from baseline best corrected visual acuity (BCVA) at one year, as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) chart and measured by logMAR (standard logarithm of the minimum angle of resolution) [38,39,40,41].

Ambulatory navigation/mobility mazes have been developed by a number of research groups and were included as a primary outcome. However, several methodologies exist. To allow comparison between trials, reporting of these assays used a mean difference, i.e., comparing the proportion of improved performances post-operatively, between groups (a risk ratio [RR]).

2.2.2. Secondary Outcomes

Secondary outcomes included full-field light sensitivity threshold (FST) [42], visual field, visual perception, electroretinogram (ERG), Goldmann visual fields, fundus photography, nystagmus testing, central retinal thickness (as measured by optical coherence tomography (OCT)), pupillary light reflex response (PLR) and diagnostic ophthalmic techniques [38,43,44].

2.2.3. Adverse Events

Adverse events were not searched for vector administration, due to a considerable volume of literature for AAV safety outcomes from several authors [45,46,47,48,49].

2.3. Search Methods for Identification of Studies

2.3.1. Electronic Searches

The literature search used the Cochrane Handbook for Systematic Reviews of Interventions [50], using the Ovid database for MEDLINE and EMBASE.

We used a PICOS strategy to identify a systematic review of interventional clinical trials (the study design) for gene therapies (the intervention) for IRD patients (the population), for the purpose of improving the disorder (the outcomes), given there were no treatments available (the comparison). The PICOS search terms and search strings included 36 words and phrases using MeSH terms and Boolean operators, identified in Table S1 (Supplemental).

Structuring and collection of the relevant studies used the PRISMA checklist process [51]. We used the ROBINS-I risk of bias in non-randomised studies of interventions tool [52,53] and the RoB-2 tool for the Cochrane Collaboration’s process for assessing risk of bias in randomised trials [54].

2.3.2. Searching Other Resources

We searched FDA and clinicaltrials.gov databases, including the Biologics License Application resource (BLA) at FDA.

2.4. Data Collection and Analysis

2.4.1. Selection of Studies

Following database searching, each article was assessed as being definitely relevant, possibly relevant or definitively not relevant. Duplicates were removed and all articles assessed for exclusion and inclusion. All included articles were evaluated for study design and reports and final studies reviewed in depth.

2.4.2. Data Extraction and Management

All relevant data (intervention characteristics, study design, primary and secondary outcomes) were extracted and collected in Excel prior to analysis [55] of all available data with Review Manager (RevMan) 5.4 software [56].

2.4.3. Assessment of Risk of Bias in Included Studies

Selected studies were independently assessed for sources of systematic bias according to the guidelines in the relevant sections for the Cochrane Handbook for the Systematic Reviews of Interventions [50] using ROBINS-I and Rob-2 tools.

2.4.4. Measures of Treatment Effect

Primary and secondary outcome data was assessed in accordance with the methods within each selected study. Number of BCVA letters/logMAR at one year (or more) was used to collect the mean difference (MD), standard deviations [SD] and corresponding 95% confidence intervals (CI), comparing mean change from baseline between groups. Continuous data was additionally recorded for improvements (with 95% CIs) for full-field stimulus testing data (red and blue wavelengths) and retinal thickness. Risk ratios (RRs) (with 95% CIs) for dichotomous outcomes were reported, including the proportion of participants with improved/worsening mobility/ambulatory navigation. A random-effects model in RevMan 5.4 meta-analysis [57] was used for meta-analysis.

2.4.5. Unit of Analysis Issues

For most studies, the unit of analysis was the individual participant (one study eye per participant). Five of six studies used a design with one treated eye compared to an untreated control eye. One study (Russell, 2017 [58]), used a crossover design where both eyes received interventions one year apart.

2.4.6. Missing Data

Missing data was not imputed for the purpose of the analysis while only one study (Russell, 2017 [58]) used both an intent-to-treat (ITT) and a modified intent-to-treat (mITT) model.

2.4.7. Heterogeneity

Heterogeneity was tested between the studies using chi-square analysis with significant heterogeneity (p < 0.05) precluding meta-analysis. An I² value of greater than 50% indicated a substantial statistical heterogeneity.

2.4.8. Assessment of Reporting Biases

ROBIN-I and ROB tools were used to assess risk of bias in the five NSRIs and one RCT respectively. Assessments were made by 2 independent examiners.

3. Results

3.1. Systematic-Review of Search Results

Following the structured search approach (Appendix A.1), 115 peer-reviewed research articles were screened and assessed (Figure 1; Appendix A.2), seven articles were removed due to duplication, leaving one hundred and eight articles to be screened. Eighty-seven records were excluded that did not include relevant information. Twenty-one articles were accessed for eligibility; fifteen articles were excluded: one was not applicable for meta-analysis (a study on gene therapy for choroideremia), five were follow-up studies and nine articles included duplicate data. This left six final articles (Appendix A.3) for review and meta-analysis:

3.2. Outcomes

In total, 23 different assays were reported and analysed across the six studies in Figure 2 and Table 1 (including Figure S1a–c, Appendix A.4 and Table A1). Safety data was not collected on specific AAV2 vectors, having been examined in other independent studies on interventional clinical studies in the retina [37,59,60,61,62]. Only one assay, visual acuity (VA), was common to all six papers. Of the 23 assays reviewed, only five outcomes were reported for meta-analysis—VA (logMAR), mobility, red light full-field stimulus (FST) testing (log10(cd.s/m²)), blue light full-field stimulus (FST) testing (log10(cd.s/m²)) and central retinal thickness (CRT).

All continuous and dichotomous data was reported. If either continuous and dichotomous data were available, then analysis was used to compare and contrast the models. However, continuous data was preferred from a statistical perspective as some information risked being lost in categorical data.

3.3. Visual Acuity Measured by logMAR

A 0.30 logMAR (3 line) mean post-operative change of VA was accepted as being a “clinically meaningful” improvement [43]. VA results were reported in Figure 3. Overall, outcomes showed a benefit of treatment compared to control eyes, but did not meet statistical significance.

There was a mean [SD] improvement of −0.142[0.181] logMAR letters in treated eyes (n = 73), compared to −0.079[0.103] logMAR letters in untreated (n = 62), showing a difference of logMAR −0.063 (including Table S2 (Supplemental)). RevMan 5.4 analysis showed a statistical difference of −0.06 logMAR (95% CI [−0.14, 0.02], p = 0.16) above. Individually, only one study (Testa, 2013), reported a clinically meaningful improvement in VA, with a mean [SD] improvement of −0.49 [0.04] logMAR letters in the treated eye, compared to a mean [SD] improvement of −0.26 [0.13] logMAR in the untreated eye.

Finally, an analysis of dichotomous data on visual outcomes post treatment (better or worse) was performed. Five studies provided individual patient data to allow this analysis (n = 58 treated eyes; n = 47 untreated eyes). The line of no effect showed an RR of 1.13 (95% CI 0.83, 1.53), indicating an improvement with treatment that did not reached clinical significance (p = 0.44) (Figure S2 (Supplemental)).

3.4. Mobility

Given the disparity between the four different mobility methods used in the studies in terms of size, light intensity, scoring and reporting, no direct comparison was possible. Instead, a meta-analysis of dichotomous data (better/worse post-treatment) was performed, To do so, four sub-groups were defined, according to light intensity used to illuminate the mobility mazes: (a): mobility under a single light of intensity of 4 lux; (b): mobility under a “low” ambient light level (0.2, 0.6, 1, 2 or 4 lux), broadly scotopic light; (c): mobility under a “high” ambient light level (10, 15, 50, 100 or 125 lux), broadly photopic light vision function; (d): mobility under all ambient light levels ranging from 0.2 to 100 lux. Results are summarised in Figure 4 (and in Table S3 (Supplemental)).

Under a light intensity of 4 lux (Figure 4, “Lux 4”), analysis of 4 studies showed an RR of 1.03 (95% CI 0.75, 1.42), indicating an improvement with treatment that did not reach clinical significance (p = 0.84). Under low ambient light (“Low Lux 0.2 to 4”), analysis of 4 studies showed an RR of 1.35 (95% CI 0.78, 2.35), indicating an improvement with treatment that did not reach clinical significance (p = 0.29). Under high ambient light (“High Lux 10 to 100”), analysis of 4 studies showed an RR of 0.42 (95% CI 0.12, 1.50), indicating a worsening with treatment that did not reach clinical significance (p = 0.18). Analysis of all ambient light levels (“All lux levels 0.2 to 100”) of 4 studies showed an RR of 1.15 (95% CI 0.84, 1.58), indicating an improvement with treatment that did not reach clinical significance (p = 0.39).

3.5. Full-Field Stimulus (FST) Testing for Red and Blue Wavelength

Only two studies used FST testing that allowed for a meta-analysis. Both continuous and dichotomous (better/worse) data was analysed (Figure 5a–d).

Under red light FST results, analysis of continuous data, showed a mean difference [MD] of 0.89 log10(cd.s/m²) (95% CI −0.06, 1.84) in treated eyes compared to control, indicating an improvement with treatment that did not reach clinical significance (p = 0.07). Analysis of dichotomous data (better/worse) for red light FST showed a RR of 1.89 (95% CI 1.04, 3.41), indicating an improvement with treatment that reached clinical significance (p = 0.04).

Under blue light FST results, analysis of continuous data, showed a difference of 1.69 log10(cd.s/m²) (95% CI 1.21, 2.16) in treated eyes compared to control, indicating an improvement with treatment that reached clinical significance (p = 0.00001). Analysis of dichotomous data (better/worse) showed a RR of 2.01 (95% CI 1.32, 3.06), indicating an improvement with treatment that reached clinical significance (p = 0.001).

3.6. Central Retinal Thickness (CRT)

Three studies reported CRT outcomes as measured by optical coherence tomography (OCT), but only two included quantitative data that allowed for meta-analysis. Analysis of dichotomous data (thinner/thicker) at 1 year post treatment, showed a RR of 1.15 (95% CI 0.45, 3.00), indicating an increase of CRT with treatment that did not reach clinical significance (p = 0.77) (Figure 6a). Analysis of dichotomous data for a long term timepoint (3 years), showed a RR of 1.29 (95% CI 0.33, 5.10), indicating an increase of CRT with treatment that did not reach clinical significance (p = 0.72) (Figure 6b).

3.7. Risk of Bias Tools within Studies

Cochrane risk-of-bias tools were used to assess study reliability; ROBIN-I methods [52], for non-randomised study designs, and RoB-2 methods [63], for randomised clinical trials. Overall, a risk-of-bias judgement was reported “low/moderate”, with a predicted direction of bias “towards null/unpredictable” for the 5 NRSIs, and a report with “some concerns” and a predicted direction of bias with “favours experimental” for the RCT (Table 2; Appendix A.5, Table A2. and Appendix A.6, Table A3).

Finally, Table 3 provided a summary of 12 meta-analyses reported for each of the outcomes, a PRISMA summary of a structured abstract in Appendix A.7, and a PRISMA checklist in Appendix A.8 (Table A4).

4. Discussion

Inherited retinal dystrophies (IRDs) are a leading cause of visual loss in children and adults of working age. Formerly untreatable, the emergence of gene augmentation therapy represents a real paradigm shift in patient care. We thus performed a systematic review and meta-analysis of interventional clinical trials to assess the efficacy of gene therapies for IRDs, thus delivering useful information for both clinicians and patients. The purpose of this systematic review is also based on a “fair test” [64], grounded in evidence-based medicine [65,66] (and Figure S1). To test such new therapies, it is critical to assess how transparent results show clear benefit for the patient. This requires that methodology, study design and outcome measures have to provide a clear and reasonable conclusion for the impact on the patient. A systematic review and meta-analysis of IRD patient outcomes for gene therapy is critical in order to support the field [67].

A search of peer-reviewed literature found that only gene therapies to treat Leber congenital amaurosis (LCA) met the criteria for addressing the original question (Appendix A.1). LCA is a rare disorder and gene therapy is an expensive treatment, which led to studies with small patient numbers. Further, the particularly severe phenotype of the disease, with low visual acuity from birth, led to difficulties in assessing the effect of treatment.

Of the 6 studies analysed, a significant drawback to the meta-analysis performed here is the variability in vector design and concentration of virus injected sub-retinally. All studies analysed used an AAV2 serotype, with most using an AAV2/2 capsid. However, one study used an AAV2/4 capsid. Further, some studies used a hybrid chicken β-actin promoter with a cytomegalovirus enhancer, whilst some used the human RPE65 promoter. Treatment doses ranged from 10⁸ to 10¹² vg, in volumes from 0.15 to 1.0 mL. This spans a number of logarithmic steps in each dose, potentially compromising the comparison of the results within the 6 studies. Despite all this, in our view, the similarities in products compared in the meta-analyses outweigh the differences. All contain the same recombinant human RPE65 gene, all are packaged in a similar AAV2 vector and all use a similar sub-retinal surgical procedure for delivery. All were used to treat the same trial population (RPE65-LCA2 patients). Further, there were similar criteria for controls and there was considerable overlap in trial duration and endpoints. Finally, we felt the comparison appropriate as pre-clinical work has shown good photoreceptor transduction and expression efficiency. As such, despite the analyses’ obvious limitations, we felt it appropriate in order to increase numbers of this rare disease and thus improve statistical power. Given the differences outlined, it is extremely encouraging to note the significant improvements in full-field stimulus (FST) testing that are seen following meta-analysis.

With gene augmentation in its infancy, it is perhaps unsurprising that there were variabilities in the biomarkers used to determine treatment efficacy. In total, 23 outcome assays were used. Visual acuity was the only outcome used in all six studies analysed. Five studies used Goldmann perimetry, four used ambulatory navigation/mobility and three used electroretinography. A further nineteen assays were used in two or less studies. Many of the assays were not comparable for several reasons. Five studies assessed visual fields using Goldmann perimetry, although different studies presented different isopters with variable follow up time. Further, a lack of quantitative data in some studies meant overall meta-analysis was not possible. Three studies used electroretinography as an assay, but two provided no data. Other assays used in two or more studies were unsuitable for meta-analysis due to a lack of quantitative data or irreconcilable differences in the way data was presented. As the field evolves, it is hoped agreed standards for methods and reporting will be established, allowing for easier meta-analyses of trials.

Visual acuity is the gold standard assay by which retinal disease treatments are assessed. Though our meta-analysis showed only modest improvement with gene therapy (in terms of clinical or statistical significance), the result is perhaps not surprising given the low-vision phenotype of LCA patients. Two studies (Bainbridge and Testa) did not provide raw visual acuity data and instead patient vision was determined from results presented in study graphs. This was undertaken by two independent researchers, with a mean of the two readings being used, but an element of uncertainty remains with the overall result due the unavailability of raw data within the actual papers. It should be noted that an I² value 65% indicates substantial statistical heterogeneity within the VA assays (Figure 3). As such, little weight can be placed upon the outcome of our VA analyses.

The study designs often dictated that the eye with the worse vision was treated, with control eyes having a better baseline vision. Although logMAR vision charts determine a linear improvement in vision with each letter or line gained, if treatment and control arms have different baseline values, bias is introduced and outcomes may be influenced as a result. Without adjustment, it may be unclear what impact arises from the treatment effect, as opposed to the treated eye being worse at baseline. Even adjusted data may not be robust enough to eliminate this confounding factor. Emerging gene therapy trials, where both eyes are treated and compared for one year to a deferred treatment group, should address this issue.

Four studies reported mobility testing as a key outcome. Mobility testing for the MLMT assay (Russell et al.) received criticism by an independent commentator [68] and reviewers in the FDA regarding uneven luminance levels [29]. In addition, we note that the MLMT assay results were indirect. A “passing level” of the assay compared baselines between 1-year timepoints however, the original data for measuring speed, time, accuracy (and further components) for assessment, were not included in the paper or the Biologicals License Application (BLA). Further, the MLMT assay used a logarithmic scale, based on light intensity (lux), which was then subsequently converted to an ordinal scale (ranging from −1 to 6), such that a two-point change in the ordinal scale may have a different interpretation depending on the baseline score (Table S4 (Supplemental)) [68].

Due to disparate methodologies (maze size and design, measurement, quantification and reporting), only analysis of dichotomous data (better/worse post treatment) was possible. This risks overestimating the benefit in certain studies. For example, Russell et al. reasoned that results in their maze required at least 2 levels of improvement on their assessment scale to accept the result as showing therapeutic benefit, whereas we defined even a 1 level gain post-operatively as performing ‘better’.

Some studies had datapoints missing, while quantitative data was missing from others, and required interpretation from results presented in study graphs (Jacobson et al.). Though RevMan analysis of dichotomous data suggested overall improvement in mobility, statistical significance was not reached. At present, there is no better test available for assessing the impact of gene therapy on visual function and so, as the field develops, it would be advantageous if some standardisation of the test could be agreed upon, recently supported by other literature [69,70,71].

The use of full-field stimulus (FST) testing (white, red and blue wavelength) is highly relevant because few research tools can quantify changes in visual perception if sight loss is as severe as it is in an RPE65/LCA2 population. Thus, the FST data carries extra significance. FST results presented in the studies was at times confusing. One study (Russell et al.) alternately presented white light FST results in log10(cd.s/m²) units and −log10(cd.s/m²) units, whilst not commenting on their red and blue light FST results (Russell et al.). A further study only described results in terms of “log10” units, which we interpreted as log10(cd.s/m²) units (Jacobson et al.), thus allowing for meta-analysis. Although the FDA, as part of the Biologics Licence Application (BLA) review for Luxturna [29], stated ‘the direct clinical benefit of FST is not clear’, it is apparent from meta-analysis of these two studies that retinal sensitivity improves with AAV-mediated gene augmentation therapy for RPE65-mediated LCA2. The significance of this cannot be underestimated. It is proof of principle that visual improvement is achievable with this technology and gives us hope that similar benefit could be achieved when other alleles are targeted.

The first attempt to use gene augmentation therapy for retinal disease has led to an FDA and EMA approved product (voretigene neparvovec-rzyl [Luxturna]). Improvements in surgical technique and improved knowledge of treatment technicalities (e.g., virus concentration) could mean subsequent iterations of these therapies show improved efficacy. Further, the more novel outcomes for mobility may drive innovative end-points. Though some concerns were raised by our Cochrane risk of bias analysis, further treatments targeting more common disease-causing genes [37] will mean increased patient numbers in trials and may allow for blinded evaluations, resulting in more robust studies.

As of April 2021, there are > 40 interventional gene therapy trials for IRDs reported at clinicaltrials.gov, from both academic and commercial institutions targeting several different IRD genes [72,73,74,75,76]. This meta-analysis highlights the need for consistency of trial design to allow comparison of gene products, but also shows the potential this technology has for addressing a leading cause of blindness in children and adults of working age.

5. Conclusions

The objective of this work was to conduct a systematic review of interventional clinical trial studies for IRDs and to assess and compare the effectiveness of available gene therapy treatments. Following the search, review and analysis of the relevant studies, the systematic review concluded that a meta-analysis for AAV-RPE65 gene therapy for LCA2 reported a modest improvement for visual acuity, mobility and full-field stimulus testing (FST), with FST improvements reaching statistical significance. In terms of a recommendation to support the IRD patient communities and researchers, we propose that full and open-access data is key. If the field is to be progressed and improved, then objective and transparent results need to be shared in order to improve outcomes, analysis, reporting and interpretation.

Competing interests

Conflicts of InterestThe authors declare no conflict of interest.

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