Preclinical Study on the Long-Term Efficacy and Safety of Sustained-Release Gas6 Liposomes Combined With MERTK Gene Therapy for Retinitis Pigmentosa.

PURPOSE: Our previous studies in Royal College of Surgeons (RCS) rats demonstrated that co-administration of MER proto-oncogene tyrosine kinase (MERTK) and its ligand Gas6 effectively protected photoreceptors and improved visual function. To facilitate clinical translation, we developed Gas6-loaded sustained-release liposomes (Gas6 Lips) using liposomes with superior biocompatibility and enhanced release stability as the delivery vehicle, and subsequently evaluated their long-term efficacy and safety in RCS rats and nonhuman primates. METHODS: Gas6 Lips were synthesized using a thin-film hydration method and characterized for morphology, encapsulation efficiency, and release profile. A GMP-grade adeno-associated virus serotype 2 (AAV2)-BEST1-hMERTK vector was constructed. Experimental groups included the AAV-hMERTK group, the combination group with AAV-hMERTK and Gas6 Lips, and the control group. Therapeutic efficacy was assessed in RCS rats using electroretinography (ERG) and histological analysis. Long-term safety was evaluated in cynomolgus monkeys over 12 months. RESULTS: Gas6 Lips had an average size of 144.1 nm and sustained Gas6 release for over 5 weeks. In RCS rats, the combination group exhibited significantly higher ERG b-wave amplitudes (52.116 ± 9.747 µV vs. 36.186 ± 7.156 µV, P < 0.01) and greater outer nuclear layer preservation (14.47 ± 1.43 µm vs. 10.41 ± 1.19 µm, P < 0.01) compared with the AAV-hMERTK group. These therapeutic effects persisted for over 7 weeks. In primates, no significant changes in retinal structure, ERG, or systemic immune responses were observed, with only transient and reversible mild ocular inflammation in the early post-treatment phase. CONCLUSIONS: Gas6 Lips combined with AAV2-BEST1-hMERTK effectively preserved retinal structure and function in RCS rats and demonstrated long-term safety in primates, supporting its potential for clinical translation. TRANSLATIONAL RELEVANCE: This can provide preclinical efficacy and safety data for the clinical translation of Gas6 Lips for the treatment of retinal pigmentosa (RP).