Frontiers in Immunology (Mar 2022)

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

  • Andrea Arena,
  • Eugenia Belcastro,
  • Francesca Ceccacci,
  • Stefania Petrini,
  • Libenzio Adrian Conti,
  • Olivia Pagliarosi,
  • Ezio Giorda,
  • Simona Sennato,
  • Riccardo Schiaffini,
  • Peng Wang,
  • James C. Paulson,
  • Giovanna Mancini,
  • Alessandra Fierabracci

DOI
https://doi.org/10.3389/fimmu.2022.838331
Journal volume & issue
Vol. 13

Abstract

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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.

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