Researchers at the Moorfields Eye Hospital and UCL Institute of Ophthalmology, University College London, UK, have reported the natural history of a retinopathy associated with IQCB1 variants in children and adults. Mutations of the IQCB1 gene (IQ calmodulin-binding motif-containing protein-1; also known as NPHP5) may cause a rare autosomal recessive condition with pathologic variants associated with Senior-Loken syndrome (SLS), involving renal dysfunction and LCA/EOSRD (Leber Congenital Amaurosis / Early Onset Severe Retinal Dystrophy). Evaluating the natural history, clinical and genetic characterisation and demography data are key steps required to treat the disorder.
The research study at Moorfields and UCL, led by Prof. Michel Michaelides, recruited 19 patients with disease-causing variants in IQCB1 collecting population data, clinical presentations, BCVA, fundus appearance, optical coherence tomography (OCT) and autofluorescence features, electroretinography (ERG) and genotyping. The research showed that IQCB1-retinopathy was a severe early-onset cone-rod dystrophy. Ten patients had BCVA better than 1.0 LogMAR, seven patients had a vision of hand movements or worse in at least one eye; there was no correlation found between age of onset and severity of vision loss. Nine patients (47.4%) had a diagnosis of end-stage renal failure at presentation and the other 10 patients (52.6%) had a diagnosis of non-syndromic IQCB1-retinopathy. OCT showed ellipsoid zone (EZ) disruption with foveal sparing in 8/13 patients. Full-field ERGs in four adults revealed a severe cone-rod dystrophy and three children had extinguished ERGs. Following analysis of the results, the UK researchers concluded that, “[t]he dissociation between severely decreased retinal function and relative preservation of retinal structure over a wide age window makes the disease a candidate for gene therapy”.
[Open Access: This figure is an open access article distributed under the terms of the CC-BY License version 4.0 (Creative Commons) © 2024; Sen, Sagnik et al., J Ophthalmol. 2024 Mar 22: S0002-9394(24)00115-6. doi: 10.1016/j.ajo.2024.03.009.].
Figure 1 – IQCB1 gene and variants identified in the current cohort. The schematic shows a representation of the location of variants in the IQCB1 gene along with their relation to the binding domains of the gene. It also shows known interactions of the different regions of the protein with BBSome and CEP290. All 17 variants were truncating variants predicted to show loss-of-function.
Natural history is a key step to clearly understand the travel of direction for patients, for this and any long-term pathology, and then how to consider treating the disease. In due course, the UK research team may apply this data to consider a gene therapy treatment for IQCB1-retinopathy. IQCB1 gene augmentation therapy in a canine model has now been shown “to improve photoreceptor morphology and visual function in the form of recovery of rod and cone-mediated ERG responses”. The safety, efficacy, and different doses of gene therapy vectors with dog or human IQCB1 transgenes are now to be explored. Their research commented that an “anatomical window for intervention appears relatively wide, with preservation of retinal structure till late in life. Phase 1/2 trial duration for short term results will likely need to be in the range of 1-2 years, to explore safety and efficacy signals, since effectiveness could be focused on functional improvement rather than halting/slowing the degeneration”. Patient—reported outcomes will also be required, not only to “treat”, but also to “manage” the disorder. Over recent years, engagement between independent clinicians, patients and regulators are important to measure real-world outcomes relevant to both patients and their families.