In Vivo Delivery of Nucleic Acid-Formulated Microparticles as a Potential Tolerogenic Vaccine for the Treatment of Type 1 Diabetes
Valentina Di Caro1,2, Nick Giannoukakis1,3, Massimo Trucco1
1 Division of Immunogenetics, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
2 Ri.Med Foundation, via Bandiera 11, 90133, Palermo, Italy
3 Department of Pathology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
Abstract
Originally conceived as a method to silence transcription/translation of nascent RNA, nucleic acids aimed at downregulating gene expression have been shown to act at multiple levels. Some of the intriguing features of these gene-silencing nucleic acids include the activation of molecular signals in immune cells that confer tolerogenic properties. We have discovered a method to induce stable tolerogenic ability to dendritic cells ex vivo using a mixture of phosphorothioate-modified antisense DNA targeting the primary transcripts of CD40, CD80 and CD86. Autologous human dendritic cells generated in the presence of these oligonucleotides prevent and reverse type 1 diabetes (T1D) in the non-obese diabetic (NOD) strain mouse model of the human disease, and have been shown to be safe in established diabetic human patients. Even though this ex vivo approach is clinically feasible, the next step beyond a cell therapy approach to develop a "population-targeting" microsphere formulation of the three antisense oligonucleotides. Effectively, such a product could constitute an "off-the-shelf" vaccine. Herein, we describe the progress made in developing this approach, and we provide insight into potential molecular mechanisms of action.
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