Author: Gearoid Tuohy (Ireland)
Co-authors: Roly Megaw, n/a n/a
Purpose
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 the field hope. This systematic review sought to assess the effectiveness 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 (AAV)-mediated treatment of RPE-specific 65kDa (RPE65)-associated LCA. 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 showed risk-of-bias judgement to be “low/moderate”, whilst there were “some concerns” for the RCT using a RoB-2 tool (Cochrane Library). FST improvements demonstrate a proof-of-principle for treating IRDs with gene therapy and there remains scope for improvement.
Setting/Venue
IRDs include Retinitis pigmentosa (RP) which comprise a group of disorders causing the deterioration of rod and cone photoreceptor cells in the retina leading to visual impairment or blindness. There is currently no cure for RP. Leber Congenital Amaurosis (LCA), a juvenile form of RP, shows an early infant-onset form of the disease characterised by severe retinal dystrophy, vision loss, nystagmus and an almost non-recordable ERG. Gene therapy is a potential treatment for LCA with previously published trials aimed at addressing several clinical outcomes, including visual acuity, mobility, visual field testing and retinal thickness, amongst others.
Methods
Search methods Ovid databases for MEDLINE (from Jan. 1946 to Jun. 2020) and EMBASE (Jan. 1980 to Jun. 2020) were searched for IRDs, methodology, gene therapy and outcomes, including other terms. Additional public resources were searched in the FDA, the EMA, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and international patient organisations. Selection criteria Randomised controlled trials (RCTs) and non-randomised studies of the effects of interventions (NRSIs) with any gene therapy treatment for any human patients diagnosed with any syndromic or non-syndromic RP. Data collection and analysis Standard methodological procedures of the Cochrane Collaboration for screening, data abstraction, and study assessment. A structured PICOS search strategy used screened records and abstracted data following with a review and assessment of risk-of-bias tools with included studies (with two independent authors). 115 records were found, 7 articles were duplicated and removed, 108 publications were screened, 87 were excluded and 21 articles were accessed for eligibility; of these, 15 articles were excluded: one (1) was not applicable (choroideremia), five (5) were follow-up studies and nine (9) articles included duplicate data. A final six (6) primary articles were conducted for review and meta-analyses, summarised in a PRISMA flowchart.
Results
Six (6) clinical trial studies reported one (1) RCT and five (5) NRSIs, including a sample of n=84 LCA2 (RPE65) patients across three countries (UK, France and the USA). A gene therapy augmentation treatment for recombinant AAV-RPE65 was sub-retinally transfected for a range of subjects spanning ages from 4-44 years. Twelve meta-analyses were reported but only one (1) assay, visual acuity (VA), was common to all six (6) papers. ETDRS logMAR results found a summary weighted mean difference (MD) of -0.06 logMAR improvement over treated vs. untreated eyes (95% CI -0.14, 0.02), p=0.16, including six (6) studies with a I2 heterogeneity of 65%. An ambulatory navigation / mobility test across a light-intensity level of 4 lux showed an RR (risk ratio) improvement of 1.03, over treated vs. untreated eyes (95% CI 0.75, 1.42), p=0.84, including four studies with a I2 heterogeneity of 0%. A summary weighted mean difference (MD) of FST (full-field stimulus testing) (red) showed 0.89 log10(cd.s/m2) over treated vs. untreated eyes (95% CI -0.06, 1.84), p=0.07, and; a summary weighted mean difference (MD) of FST (blue) showed 1.69 log10(cd.s/m2) over treated vs. untreated eyes (95% CI 1.21, 2.16), p=0.00001.
Conlusions
Results of this overall systematic review and meta-analyses showed no clinically meaningful benefit and no statistical significance with the six (6) trials combined. One RCT found a clinically meaningful benefit for an assessment for a primary endpoint for mobility, a MD of 1.6 (95% CI 0.72-2.41), p=0.0013. All other studies however, showed variable and modest benefits. A significant loss of outcome data showed a considerable amount of under-reporting across all of the trials. While gene therapy is an extremely positive field capable to deliver an enormous new medical opportunity, there are clear weaknesses to be addressed to ensure that patients can be benefitted at the earliest opportunity.
Financial Disclosure
No conflicts.
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