Improvement of lipoplexes with a sialic acid mimetic to target the C1858T PTPN22 variant for immunotherapy in endocrine autoimmunity

Variants of the protein tyrosine phosphatase N22 (PTPN22) gene, such as the C1858T variant, are associated with pathophysiological phenotypes in several autoimmune conditions including 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 expression of variant alleles. In this manuscript we functionalize lipoplexes carrying siRNA for variant T1858 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. These LiposiRNA-Sig10L lipoplexes more efficiently downregulated variant T1858 PTPN22 mRNA in PBMC of heterozygous patients than LiposiRNA without Sig10L. Following TCR engagement by anti-CD3/CD28 stimulation, LiposiRNA treatment restored in PBMC of heterozygous T1D patients IL-2 secretion which is known to be paradoxically reduced than in wild type patients. Under the same experimental conditions LiposiRNA-Sig10L more significantly restored IL-2 secretion than original LiposiRNA.