Preclinical evaluation of KH631, a novel rAAV8 gene therapy product for neovascular age-related macular degeneration

Abstract

The upregulation of vascular endothelial growth factor (VEGF) is strongly associated with the development of choroidal neovascularization (CNV) in patients with neovascular age-related macular degeneration (nAMD). Currently, the standard treatment for nAMD involves frequent intravitreal injections of anti-VEGF agents, which inhibit the growth of new blood vessels and prevent leakage. However, this treatment regimen places a significant burden on patients, their families, and healthcare providers due to the need for repeated visits to the clinic for injections. Gene therapy, which enables the sustained expression of anti-VEGF proteins after a single injection, can dramatically reduce the treatment burden. KH631 is a recombinant adeno-associated virus 8 vector that encodes a human VEGF receptor fusion protein, and it is being developed as a long-term treatment for nAMD. In preclinical studies using non-human primates, subretinal administration of KH631 at a low dose of 3×108 vg/eye resulted in remarkable retention of the transgene product in the retina and prevented the formation and progression of grade IV CNV lesions. Furthermore, sustained transgene expression was observed for more than 96weeks. These findings suggest that a single subretinal injection of KH631 has the potential to offer a one-time, low-dose treatment for nAMD patients.