Immune function in X-linked retinoschisis subjects in an AAV8-RS1 phase I/IIa gene therapy trial

• Published in: Molecular therapy 2021-06, Vol.29 (6), p.2030-2040
• Main Authors: Mishra, Alaknanda, Vijayasarathy, Camasamudram, Cukras, Catherine A., Wiley, Henry E., Sen, H. Nida, Zeng, Yong, Wei, Lisa L., Sieving, Paul A.
• Format: Article
• Language: English
• Subjects: AAV8 vector; cytokines; Cytokines - blood; Cytokines - metabolism; Dependovirus - genetics; Disease Management; Eye Proteins - genetics; gene therapy clinical trial; Genetic Diseases, X-Linked - etiology; Genetic Diseases, X-Linked - therapy; Genetic Predisposition to Disease; Genetic Therapy - methods; Genetic Vectors; Humans; immune function; Immunity; Immunity, Cellular; ocular inflammation; Original; retinoschisin; Retinoschisis - genetics; Retinoschisis - immunology; Retinoschisis - metabolism; Retinoschisis - therapy; T cells; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Treatment Outcome; X-linked retinoschisis
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2021.02.013

This study explored systemic immune changes in 11 subjects with X-linked retinoschisis (XLRS) in a phase I/IIa adeno-associated virus 8 (AAV8)-RS1 gene therapy trial (ClinicalTrials.gov: NCT02317887). Immune cell proportions and serum analytes were compared to 12 healthy male controls. At pre-dosing baseline the mean CD4/CD8 ratio of XLRS subjects was elevated. CD11c+ myeloid dendritic cells (DCs) and the serum epidermal growth factor (EGF) level were decreased, while CD123+ plasmacytoid DCs and serum interferon (IFN)-γ and tumor necrosis factor (TNF)-α were increased, indicating that the XLRS baseline immune status differs from that of controls. XLRS samples 14 days after AAV8-RS1 administration were compared with the XLRS baseline. Frequency of CD11b+CD11c+ DCc was decreased in 8 of 11 XLRS subjects across all vector doses (1e9–3e11 vector genomes [vg]/eye). CD8+human leukocyte antigen-DR isotype (HLA-DR)+ cytotoxic T cells and CD68+CD80+ macrophages were upregulated in 10 of 11 XLRS subjects, along with increased serum granzyme B in 8 of 11 XLRS subjects and elevated IFN-γ in 9 of 11 XLRS subjects. The six XLRS subjects with ocular inflammation after vector application gave a modestly positive correlation of inflammation score to their respective baseline CD4/CD8 ratios. This exploratory study indicates that XLRS subjects may exhibit a proinflammatory, baseline immune phenotype, and that intravitreal dosing with AAV8-RS1 leads to systemic immune activation with an increase of activated lymphocytes, macrophages, and proinflammatory cytokines. [Display omitted] Systemic immune status was evaluated in X-linked retinoschisis subjects in an ocular AAV8-RS1 gene therapy trial. Baseline changes before dosing showed altered CD4/CD8 T cell ratios, dendritic cell subsets, and pro-inflammatory cytokine levels. Vector application caused systemic immune activation with an increase of activated cytotoxic lymphocytes, macrophages, and pro-inflammatory cytokines.