Gene Therapy in Hereditary Retinal Dystrophies: The Usefulness of Diagnostic Tools in Candidate Patient Selections
Authors: Malvasi Mariaelena , Casillo Lorenzo , Avogaro Filippo , Abbouda Alessandro , Vingolo Enzo Maria 
Published: September 2023

Purpose: Gene therapy actually seems to have promising results in the treatment of Leber Congenital Amaurosis and some different inherited retinal diseases (IRDs); the primary goal of this strategy is to change gene defects with a wild-type gene without defects in a DNA sequence to achieve partial recovery of the photoreceptor function and, consequently, partially restore lost retinal functions. This approach led to the introduction of a new drug (voretigene neparvovec-rzyl) for replacement of the RPE65 gene in patients affected by Leber Congenital Amaurosis (LCA); however, the treatment results are inconstant and with variable long-lasting effects due to a lack of correctly evaluating the anatomical and functional conditions of residual photoreceptors. These variabilities may also be related to host immunoreactive reactions towards the Adenovirus-associated vector. A broad spectrum of retinal dystrophies frequently generates doubt as to whether the disease or the patient is a good candidate for a successful gene treatment, because, very often, different diseases share similar genetic characteristics, causing an inconstant genotype/phenotype correlation between clinical characteristics also within the same family. For example, mutations on the RPE65 gene cause Leber Congenital Amaurosis (LCA) but also some forms of Retinitis Pigmentosa (RP), Bardet Biedl Syndrome (BBS), Congenital Stationary Night Blindness (CSNB) and Usher syndrome (USH), with a very wide spectrum of clinical manifestations. These confusing elements are due to the different pathways in which the product protein (retinoid isomer-hydrolase) is involved and, consequently, the overlapping metabolism in retinal function. Considering this point and the cost of the drug (over USD one hundred thousand), it would be mandatory to follow guidelines or algorithms to assess the best-fitting disease and candidate patients to maximize the output. Unfortunately, at the moment, there are no suggestions regarding who to treat with gene therapy. Moreover, gene therapy might be helpful in other forms of inherited retinal dystrophies, with more frequent incidence of the disease and better functional conditions (actually, gene therapy is proposed only for patients with poor vision, considering possible side effects due to the treatment procedures), in which this approach leads to better function and, hopefully, visual restoration. But, in this view, who might be a disease candidate or patient to undergo gene therapy, in relationship to the onset of clinical trials for several different forms of IRD? Further, what is the gold standard for tests able to correctly select the patient? Our work aims to evaluate clinical considerations on instrumental morphofunctional tests to assess candidate subjects for treatment and correlate them with clinical and genetic defect analysis that, often, is not correspondent. We try to define which parameters are an essential and indispensable part of the clinical rationale to select patients with IRDs for gene therapy. This review will describe a series of models used to characterize retinal morphology and function from tests, such as optical coherence tomography (OCT) and electrophysiological evaluation (ERG), and its evaluation as a primary outcome in clinical trials. A secondary aim is to propose an ancillary clinical classification of IRDs and their accessibility based on gene therapy’s current state of the art. Material and Methods: OCT, ERG, and visual field examinations were performed in different forms of IRDs, classified based on clinical and retinal conditions; compared to the gene defect classification, we utilized a diagnostic algorithm for the clinical classification based on morphofunctional information of the retina of patients, which could significantly improve diagnostic accuracy and, consequently, help the ophthalmologist to make a correct diagnosis to achieve optimal clinical results. These considerations are very helpful in selecting IRD patients who might respond to gene therapy with possible therapeutic success and filter out those in which treatment has a lower chance or no chance of positive results due to bad retinal conditions, avoiding time-consuming patient management with unsatisfactory results.