Development of Methodology and Study Protocol: Safety and Efficacy of a Single Subretinal Injection of rAAV.hCNGA3 in Patients withCNGA3-Linked Achromatopsia Investigated in an Exploratory Dose-Escalation Trial

Abstract

Achromatopsia is an autosomal recessively inherited congenital defect characterized by a lack of cone photoreceptor function, leading to severely impaired vision. In this clinical study, achromatopsia patients were treated with a single subretinal injection of rAAV.hCNGA3 to restore cone function. The focus of this trial was on the safety of the treatment. After surgery, patients were monitored in eight extensive visits during the first year, followed by a 4-year follow-up period with annual visits. For essential complementation of the standard ophthalmological and systemic examinations, disease-specific methods were developed to assess the safety, efficacy, and patient-reported outcomes in this trial.

Safety and Vision Outcomes of Subretinal Gene Therapy Targeting Cone Photoreceptors in Achromatopsia

“…Best-corrected visual acuity (to rule out loss of ≥15 letters in visual acuity at 1 m) and clinical examinations of the eye (to rule out severe, vector-induced intraocular inflammation unresponsive to treatment) were performed to examine the primary end point (safety). 19 Systemic safety parameters included vital signs, clinical chemical analyses (eg, C-reactive protein level, IgG titer, IgM titer, and differential blood cell counts), quantitative polymerase chain reaction-based analysis of vector shedding and biodistribution, an enzyme-linked immunosorbent assay quantifying antibody titers against AAV8 capsid proteins, and lymphocyte transformation tests and supernatant cytokine assays to monitor cellular immune reactivity against AAV8. 11,20 Details are given in eTables 1 through 6 in Supplement 2.…”

“…To explore the efficacy of AAV8.CNGA3 gene therapy, a number of functional tests centered around cone photoreceptor function were performed by an assessor masked to the treatment. 19 These tests included assessments of visual acuity and contrast sensitivity, color vision, flicker fusion frequency, full-field stimulus threshold, pupillography, microperimetry, and questionnairebased measures of patient-reported outcome measures at baseline and during follow-up for 1 year. Details are given in eTables 9 through 11 in Supplement 2.…”

Nr2e3 is a genetic modifier that rescues retinal degeneration and promotes homeostasis in multiple models of retinitis pigmentosa

“…The most widely accepted success of adeno-associated virus (AAV) vector-mediated ocular gene replacement is for treatment of Leber's congenital amaurosis 2 (LCA2), a rare retinal disease due to mutations in the RPE65 gene [8,9]. Currently, there are several ongoing clinical gene augmentation trials for other rare inherited retinal diseases [10][11][12][13]. However, several factors such as gene size, gene function, and the large number (~40%) of retinitis pigmentosa (RP) patients that cannot be genetically diagnosed present challenges for developing individual gene replacement/augmentation-based therapies.…”

Molecular Genetic Cause of Achromatopsia in Two Patients of Czech Origin

“…Pokud jsou známé kauzální mutace, mají rodiče postiženého dítěte v případě další gravidity možnost preimplantační genetické diagnostiky [10,35]. V současnosti také probíhají klinické zkoušky genové terapie u pacientů s mutacemi v genech CNGA3 a CNGB3 [6,7,12]. Jejich možný efekt byl podpořen v preklinických studiích na zvířecích modelech, které prokázaly zlepšení elektroretinografických nálezů i zrakové ostrosti [4,20,24].…”