Key Findings
The preclinical evaluation of ATSN-301, a dual vector system using the AAV.SPR capsid and smCBA promoter, demonstrated that the treatment is well tolerated across all tested doses. A six-month GLP toxicology study identified the No Observed Adverse Effect Level (NOAEL) as 1.2E11 vg/eye. In cynomolgus macaques, the AAV.SPR capsid enabled supraphysiological MYO7A expression at distal retinal sites and the macula without the need for foveal detachment.
Technical Details
Because the MYO7A coding sequence exceeds the standard packaging capacity of adeno-associated virus (AAV), researchers utilized dual AAV hybrid and overlap platforms. To optimize the reconstitution of the full-length protein in retinal pigment epithelium and photoreceptors, the team implemented the following modifications:
- Adjustment of cDNA split points.
- Reduction of non-coding sequences.
These optimizations resulted in higher levels of full-length MYO7A and a substantial reduction in truncated protein production.
Background & Context
Usher syndrome type 1B (USH1B) is caused by mutations in the MYO7A gene and represents over 50% of all USH1 cases. It is characterized as the most severe form of the syndrome, where patients are born with profound deafness and vestibular dysfunction, later developing progressive retinitis pigmentosa. Currently, there are no approved treatments for this condition.
Significance & Outlook
The ability to achieve effective protein expression without foveal detachment is a critical safety consideration for USH1B patients who still possess remaining central vision. By overcoming the packaging limitations of AAV and demonstrating safety in non-human primates, ATSN-301 provides a viable path toward clinical intervention for patients with this severe genetic disorder.
Source: https://doi.org/10.64898/2026.10.24.760972
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