Principal investigators Dr. Aaron Nagiel, MD, PhD, at Children’s Hospital of Los Angeles, and Dr. Lesley Everett, MD, PhD, MPhil, at the Oregon Health Sciences University, Portland, have reported that the first patient has been dosed in the phase 1/2 “LIGHTHOUSE” clinical trial. The experimental treatment (“ASTN-201”) uses an investigational adeno-associated virus (AAV) gene therapy for the treatment of X-linked retinoschisis (XLRS) associated with mutations in the RS1 gene. The Clinicaltrials.gov site have reported the official title as: “A Phase 1/2, Open-Label, Dose Escalation and Dose Expansion Study to Evaluate the Safety and Tolerability of ATSN-201 Gene Therapy in Male Subjects With RS1-Associated X-linked Retinoschisis” and the randomized and interventional study is scheduled to primary completion in October 2025.
X-linked retinoschisis (XLRS) is a monogenic X-linked disease that leads to schisis (or splitting) of the neural retina leading to reduced visual acuity in approximately 12,000 males in the US. The disorder affects visual acuity from an early age, typically with visual limitations in their daily function, including difficulty with reading, and obtaining a driver’s license. According to the researchers, XLRS manifests haplo-sufficiency as female carriers have no evidence of the disease and demonstrate preservation of visual function and retinal structure across their lifespan. As a consequence, using gene transfer as a therapeutic intervention may be capable to partially restore XLRS gene therapy. The XLRS disease is caused by mutations in the RS1 gene coded by the retinoschisin protein secreted principally in the outer retina.
The open-label, dose-escalation and dose-expansion study is seeking a total enrollment of 18 boys and men aged 6 years to 64 years with XLRS caused by pathogenic or likely pathogenic mutations in RS1. The primary outcome measure is safety and tolerability as assessed by dose-limiting toxicities and treatment-emergent adverse events, while secondary outcome measures include the change of BCVA over a 1-year period, low-luminance visual acuity, visual function as assessed by contrast sensitivity, full-field electroretinogram (ffERG) parameters, change in microperimetry, change in static perimetry, change in spectral domain optical coherence tomography (SD-OCT), change in fundus autofluorescence (FAF), and the change in the National Eye Institute’s Visual Function Questionnaire 25 (NEI VFQ-25) score and the change in the Cardiff Visual Ability Questionnaire for Children (CVAQC) score for paediatric subjects. According to the report, the gene therapy treatment is to be injected intravitreally to deliver functional RS1in order to spread laterally and allow transduction of the therapy in the central retina, “despite an injection site outside the macula. The central retina, the main area for disease activity in XLRS, would otherwise need to be reached with risky detachment of the fovea through surgery”. Commenting on the milestone, Mark Pennesi, MD, PhD, a professor in ophthalmology and chief of the Paul H. Casey Ophthalmic Genetics Division Molecular and Medical Genetics in the School of Medicine at Oregon Health & Science University, stated that, “considering the lack of available therapies for XXLRS, this is very exciting news for the inherited retinal disease community. While attempts to deliver gene therapy through intravitreal routes faced challenges, subretinal treatment utilizing spreading AAV vectors has the potential to be the breakthrough we need to achieve efficacy.”