Improvement of Lipoplexes With a Sialic Acid Mimetic to Target the C1858T PTPN22 Variant for Immunotherapy in Endocrine Autoimmunity

• Published in: Frontiers in immunology Vol. 13; p. 838331
• Main Authors: Arena, Andrea, Belcastro, Eugenia, Ceccacci, Francesca, Petrini, Stefania, Conti, Libenzio Adrian, Pagliarosi, Olivia, Giorda, Ezio, Sennato, Simona, Schiaffini, Riccardo, Wang, Peng, Paulson, James C., Mancini, Giovanna, Fierabracci, Alessandra
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 09.03.2022
• Subjects: Autoimmunity; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - therapy; functionalized lipoplexes; Humans; Immunologic Factors; Immunology; Immunotherapy; Leukocytes, Mononuclear - metabolism; N-Acetylneuraminic Acid; PEGylated lipid F9; Phosphoric Monoester Hydrolases; Protein Tyrosine Phosphatase, Non-Receptor Type 22 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 22 - metabolism; RNA, Small Interfering - genetics; Sialic Acid Binding Immunoglobulin-like Lectins; T1D; variant PTPN22; variant PTPN22; functionalized lipoplexes; PEGylated lipid F9; T1D; immunotherapy
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.838331

The C1858T variant of the protein tyrosine phosphatase N22 ( PTPN22 ) gene is associated with pathophysiological phenotypes in several autoimmune conditions, namely, Type 1 diabetes and autoimmune thyroiditis. The R620W variant protein, encoded by C1858T, leads to a gain of function mutation with paradoxical reduced T cell activation. We previously exploited a novel personalized immunotherapeutic approach based on siRNA delivered by liposomes (lipoplexes, LiposiRNA) that selectively inhibit variant allele expression. In this manuscript, we functionalize lipoplexes carrying siRNA for variant C1858T with a high affinity ligand of Siglec-10 (Sig10L) coupled to lipids resulting in lipoplexes (LiposiRNA-Sig10L) that enhance delivery to Siglec-10 expressing immunocytes. LiposiRNA-Sig10L lipoplexes more efficiently downregulated variant C1858T PTPN22 mRNA in PBMC of heterozygous patients than LiposiRNA without Sig10L. Following TCR engagement, LiposiRNA-Sig10L more significantly restored IL-2 secretion, known to be paradoxically reduced than in wild type patients, than unfunctionalized LiposiRNA in PBMC of heterozygous T1D patients.