Featured image: Atsena Therapeutics co-founders Shannon Boye and Sanford Boye, and a non-human primate retina stained for adeno-associated virus-vectored protein is displayed on the screen. Courtesy of Atsena Therapeutics.
Gene therapy development has accelerated in recent years bringing life-changing possibilities for subjects affected by Leber congenital amaurosis (LCA). LCA refers to a group of inherited retinal diseases (IRDs) that cause severe vision loss from infancy. The evaluation of the efficacy of these therapies necessitated the development of diagnostic modalities specifically designed to assess the visual function of populations with severe vision loss. As a result, two new endpoints emerged in recent years: the multi-luminance mobility test (MLMT) and the full-field stimulus threshold (FST).
Gene therapies for LCA are gaining momentum.
LUXTURNA, a gene therapy developed by Spark Therapeutics for LCA caused by mutations in the gene RPE65, was, in December 2017, the first gene therapy to receive U.S. Food and Drug Administration (FDA) approval for IRDs. More recently, in May 2024, the New England Journal of Medicine published the results of the BRILLIANCE study sponsored by Editas Medicine, on gene therapy for CEP290-associated LCA.
The latest breakthrough was announced in September 2024: the Lancet reported the results of a phase 1/2 trial sponsored by Atsena Therapeutics on the safety and efficacy of ATSN-101, a breakthrough gene therapy to enable visual gains in patients with LCA. ATSN-101 targets specifically the mutation of the GUCY2D gene, which may cause up to 20% of LCA cases. GUCY2D was the first gene to be linked with LCA among more than twenty identified to date.
The clinical trial of ATSN-101 took place at two sites: the University of Pennsylvania and Oregon Health & Science University. It involved a total of 15 human subjects with genetically confirmed mutations of GUCY2D. The ATSN-101 treatment was delivered subretinally. Most of the vision gains were acquired in the first month and remained steady. The trial results indicated that the therapy was safe and well-tolerated thus far.
Assessing the efficacy of gene therapies required new endpoints.
The MLMT and FST tests matured significantly in recent years, driven by the development of new gene therapies for LCA. These tests, along with best-corrected visual acuity (BCVA) tests, played a central role in evaluating the efficacy of the therapies during the trials.
Other well-established ophthalmic modalities were not considered suitable. For example, electroretinography (ERG), a well-known and reliable visual electrophysiology test, is not sensitive enough in subjects with severe vision loss such as those affected by LCA. Automated perimetry and microperimetry are difficult to use with LCA patients who have difficulty fixating. They are also difficult to perform in dark-adapted conditions, which is necessary to assess LCA conditions mediated by rod photoreceptors. Imaging modalities, such as optical coherence tomography (OCT) and fundus autofluorescence (FAF) are used to verify the structural integrity of photoreceptors, a screening factor for trial inclusion. However, these imaging modalities are not involved in assessing the efficacy of gene therapies for IRDs.
MLMT and FST are effective and complementary endpoints.
The MLMT is a standardized, lab-based test in which participants are observed navigating a course with obstacles of varying heights under different levels of illumination. The MLMT course occupies a 5×10 ft area with multiple possible configurations. Subjects are evaluated on their ability to navigate a marked path with steps and doors, all while avoiding obstacles. The tests are recorded, and the videos are sent to grading centers.
The advantage of the MLMT is that it creates a relatively realistic environment in which to assess a subject’s ability to move about independently. However, the test is difficult to replicate at scale due to its footprint. A virtual reality mobility maze would improve accessibility to the test and has the potential to reduce test time, automate grading, and ensure identical presentation across clinical sites.
The FST test is a psychophysical measure of whole-field retinal light sensitivity. It can also determine if visual gains are mediated by cone or rod photoreceptors by the appropriate selection of the stimulus wavelength. Results in gene therapy trials show a very strong agreement between the MLMT and FST tests. This validates that the FST, which is much easier to deploy at scale, is a reasonable alternative to the MLMT. In the long term, this may help facilitate the translation of gene therapies for IRDs to mainstream clinical therapies.