Andrea Sodi, Sandro Banfi, Michele Della Corte, Francesco Testa, Ilaria Passerini, Elisabetta Pelo, Settimio Rossi, and Francesca Simonelli | Orphanet Journal of Rare Diseases | Vol. 16 | Article 257 | 4 Jun 2021 |Â
Inherited retinal dystrophy caused by confirmed biallelic mutations in the RPE65 gene, which encodes all-trans retinyl ester isomerase, an enzyme critical to the visual cycle, is a serious and sight-threatening autosomal recessive genetic disorder that causes a severe form of rod-cone mediated IRD that eventually progresses to complete blindness.
Abstract
Background
This research aimed to establish recommendations on the clinical and genetic characteristics necessary to confirm patient eligibility for gene supplementation with voretigene neparvovec.
Methods
An expert steering committee comprising an interdisciplinary panel of Italian experts in the three fields of medical specialisation involved in the management of RPE65-associated inherited retinal disease (IRD) (medical retina, genetics, vitreoretinal surgery) proposed clinical questions necessary to determine the correct identification of patients with the disease, determine the fundamental clinical and genetics tests to reach the correct diagnosis and to evaluate the urgency to treat patients eligible to receive treatment with voretigene neparvovec. Supported by an extensive review of the literature, a series of statements were developed and refined to prepare precisely constructed questionnaires that were circulated among an external panel of experts comprising ophthalmologists (retina specialists, vitreoretinal surgeons) and geneticists with extensive experience in IRDs in Italy in a two-round Delphi process.
Results
The categories addressed in the questionnaires included clinical manifestations of RPE65-related IRD, IRD screening and diagnosis, gene testing and genotyping, ocular gene therapy for IRDs, patient eligibility and prioritisation and surgical issues. Response rates by the survey participants were over 90% for the majority of items in both Delphi rounds. The steering committee developed the key consensus recommendations on each category that came from the two Delphi rounds into a simple and linear diagnostic algorithm designed to illustrate the patient pathway leading from the patient’s referral centre to the retinal specialist centre.
Conclusions
Consensus guidelines were developed to guide paediatricians and general ophthalmologists to arrive at the correct diagnosis of RPE65-associated IRD and make informed clinical decisions regarding eligibility for a gene therapy approach to RPE65-associated IRD. The guidelines aim to ensure the best outcome for the patient, based on expert opinion, the published literature, and practical experience in the field of IRDs.
Background
Inherited retinal diseases (inherited retinal dystrophies; IRDs) are a heterogeneous group of ocular neurodegenerative disorders resulting from mutations in any one of over 250 causative genes [1]. They are mostly characterised by progressive retinal degeneration that leads to severe visual impairment and blindness [2,3,4,5,6]. Inherited retinal dystrophy caused by confirmed biallelic mutations in the RPE65 gene, which encodes all-trans retinyl ester isomerase, an enzyme critical to the visual cycle, is a serious and sight-threatening autosomal recessive genetic disorder that causes a severe form of rod-cone mediated IRD that eventually progresses to complete blindness [3,4,5]. The spectrum of RPE65-mediated IRD exhibits common clinical findings, initially characterised by nyctalopia (night blindness), present from early childhood and due to a primary effect on the rod photoreceptors [7, 8]. The visual function of individuals affected with IRD declines with age, with deteriorating visual acuity (VA) and progressive loss of retinal structure and function (retinal sensitivity) on visual field testing by Goldmann kinetic perimetry (GVF), often leading to blindness in young adulthood [8,9,10,11]. The disease course may include earlier or later onset, nystagmus, along with night blindness and loss of vision. Indeed, individuals with biallelic RPE65 mutations may be given one of a variety of clinical diagnoses. Depending on the time of disease onset, severity, rate of progression and presenting phenotype, the most common diagnoses are Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD) [5, 8]. These forms are thought to be responsible for approximately 5% of cases of severe IRDs [7]. However, a smaller proportion of patients exhibit a milder phenotype with a slower progression, possibly associated with hypomorphic alleles [11,12,13].
Initially considered incurable, as the understanding of the pathophysiological mechanisms underlying the subtypes of IRD has expanded, a number of therapeutic approaches to treating IRDs have been proposed, the most advanced of which is gene supplementation therapy [6]. Monogenic ocular diseases are good candidates for gene transfer therapy, as the eye has favourable anatomical and immunological characteristics, providing a contained physical space protected by the blood-ocular barrier that is particularly suited for local delivery [14]. Remarkably, RPE65-associated IRD represents a successful model for the development of ocular gene supplementation therapy applied to monogenic diseases.
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