Atsena Therapeutics, based in Durham, North Carolina, has announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for ATSN-201, for the treatment of X-linked retinoschisis (XLRS). The ATSN-201 treatment uses a novel “spreading capsid” technique to achieve therapeutic levels of gene expression in photoreceptors of the central retina, while avoiding the surgical risks of foveal detachment. According to the company, “Fast Track” designation is granted by the FDA for treatments intended to address serious or life-threatening diseases that have demonstrated the potential to meet an unmet medical need. Treatments that receive Fast Track designation may benefit from more frequent interactions with the FDA throughout drug development. ASTN-201 (rAAV.SPR-hGRK1-hRS1syn) is a subretinal gene therapy product being developed to introduce the functional human retinoschisin (hRS1) gene to photoreceptors.
X-linked retinoschisis (XLRS) is an uncommon inherited retinal degeneration (IRD), with a prevalent estimate ranging from 1 to 5,000 to 1 in 25,000 cases, mainly affected in males however, a number of female carriers may exhibit the phenotype due to altered X-inactivation. XLRS is caused by mutations in the RS1 gene, encoding a retinal protein, retinoschisin, which plays a key role in maintaining the retinal structure. The protein is expressed and localized in the surface of photoreceptor and bipolar cells, functioning in cell-to-cell adhesion, maintaining tissue integrity and homeostasis, and regulates apoptosis signalling. The deficiency or absence of retinoschisin in XLRS leads to photoreceptor degeneration due to cell apoptosis and disruption of the retinal layers. The disorder causes schisis (or splitting) of the neural retina leading to reduced visual acuity and disturbances in central vision, strabismus or nystagmus, affecting from an early age impacting daily function, including difficulty with reading and obtaining a driver’s license. Mutations of the RS1 gene comprise >200 alterations, most of which are missense and the majority occur in exon 4-6, corresponding to the discoidin domain of the protein. The disease can be highly variable make it challenging to correlate genotype-to-phenotype for patients
Figure 1. Highlighted at Atsena Therapeutics’ website*, the company shows to schisis (or splitting) of the neural retina leading to reduced visual acuity caused by mutations in the RS1 gene, and; delivery optimization of AAV.-RS1.SPR (spread) allowing for subretinal injection in the peripheral retina, avoiding foveal detachment and potential trauma and efficiently transduces the vector to foveal photoreceptors covering a larger area resulting in wider area of retinal transduction.(* https://atsenatx.com/wp-content/uploads/2023/12/ESGCT2023_INDXLRS-1.pdf)
The company stated that there are no approved treatments for XLRS, which is typically diagnosed in early childhood and affects ~30,000 males in the U.S. and the EU. The safety and tolerability of ATSN-201 is being evaluated in the “LIGHTHOUSE” study, a Phase I/II, dose-escalation and dose-expansion clinical trial in male patients, aged six years and older with a clinical diagnosis of XLRS caused by mutations in the RS1 gene. Enrollment for this study is ongoing, detailed in ClinicalTrials.gov with the identifier: NCT05878860. Following the announcement, Patrick Ritschel, Chief Executive Officer of Atsena Therapeutics commented that, “we are pleased that the FDA has granted Fast Track designation to ATSN-201, reinforcing its potential to address the significant unmet need in XLRS. This designation, along with the previously granted Orphan Drug and Rare Pediatric Disease designations, marks an important milestone in advancing the development of ATSN-201.”