Functional Mobility Tests Emerge as Gold Standard in Retinal Gene Therapy Trials

PHILADELPHIA, Pa. – October 2, 2025 – The highly challenging field of inherited retinal diseases (IRDs) is driving a paradigm shift in clinical trial design, with researchers increasingly relying on functional mobility assessments to measure treatment benefit. Given the genetic complexity and slow progression of over 100 distinct IRDs—which cost the U.S. and Canada an estimated $$$15 billion annually—traditional endpoints like central visual acuity are often insufficient.

The development of these novel functional endpoints is crucial for accelerating therapies that target the genetic defects found in up to three-quarters of IRD patients.

The Breakthrough Case: Luxturna and the MLMT

The shift to functional outcomes was catalyzed by Spark Therapeutics’ Luxturna (voretigene neparvovec), the only FDA-approved gene therapy for an eye disease. Its approval for RPE65-mediated Leber congenital amaurosis (LCA) was secured using the Multi-Luminance Mobility Test (MLMT).

The MLMT, developed by researchers at Children’s Hospital of Philadelphia (CHOP) and the University of Pennsylvania, tracks a patient’s ability to navigate an obstacle course under light conditions ranging from near-darkness to well-lit environments (1 to 400 lux). This successfully captured improvements in patients’ ability to perform activities of daily life, setting a new global standard for regulatory acceptance.

Evolving Assessment Tools for IRD Heterogeneity

The diversity of IRDs—where even patients with the same mutation may vary widely—demands assessment tools beyond the MLMT:

• Luminance Dependent Navigation Assessment (LDNA): Used by Ocugen in its Phase 3 trial for retinitis pigmentosa (RP), the LDNA employs a 10-level, logarithmically spaced scale to offer finer discrimination of change across the full spectrum of RP severity.
• Visual Navigation Course (VNC): Developed by Ora Clinical, this specialized mobility assessment has been accepted by the FDA as an integral endpoint in relevant U.S. clinical trials. It is highly adaptable to various patterns of vision loss, including central, light perception, or peripheral issues.

Maze Testing Goes Virtual

While physical mazes offer immediacy and realism, their logistical burden and difficulty in simulating every real-world scenario are significant drawbacks. This has driven the evolution toward virtual reality (VR) mazes, such as UPenn’s VR-O&M and Street Lab’s MOST. VR mazes offer scalability and standardization but currently face challenges with patient interface, motion sickness, and a lack of substantial regulatory validation. Researchers anticipate these issues will resolve as the technology evolves.

Regulatory Challenges and the Search for Simplicity

Regulatory bodies, including the FDA, continue to set expectations for what constitutes a clinically meaningful improvement. For conditions with slower progression, such as RP, there is ongoing debate about whether low luminance visual acuity (LLVA) changes—like a 5-letter gain—carry the same clinical relevance as the established 15-letter threshold used in other vision trials.

Mobility assessments, however, offer an intuitive impact that helps bridge the interpretation gap for regulators, payers, and patients. Despite past examples where mobility tests were unsuccessful—such as trials for Nanoscope’s MCO-010 and Janssen’s X-linked RP therapy—maze-based mobility remains central to IRD drug development.

The field’s future likely lies in fully customizable, virtual mobility assessments that can be precisely tailored to the specific disease, genotype, and patient severity, alongside large-scale natural history studies to validate that intervention truly alters the disease trajectory.