Vaccination Against Amyloidogenic Aggregates in Pancreatic Islets Prevents Development of Type 2 Diabetes Mellitus

Abstract

Type 2 diabetes mellitus (T2DM) is a chronic progressive disease characterized by insulin resistance and insufficient insulin secretion to maintain normoglycemia. The majority of T2DM patients bear amyloid deposits mainly composed of islet amyloid polypeptide (IAPP) in their pancreatic islets. These—originally β-cell secretory products—extracellular aggregates are cytotoxic for insulin-producing β-cells and are associated with β-cell loss and inflammation in T2DM advanced stages. Due to the absence of T2DM preventive medicaments and the presence of only symptomatic drugs acting towards increasing hormone secretion and action, we aimed at establishing a novel disease-modifying therapy targeting the cytotoxic IAPP deposits in order to prevent the development of T2DM. We generated a vaccine based on virus-like particles (VLPs), devoid of genomic material, coupled to IAPP peptides inducing specific antibodies against aggregated, but not monomeric IAPP. Using a mouse model of islet amyloidosis, we demonstrate in vivo that our vaccine induced a potent antibody response against aggregated, but not soluble IAPP, strikingly preventing IAPP depositions, delaying onset of hyperglycemia and the induction of the associated pro-inflammatory cytokine Interleukin 1β (IL-1β). We offer the first cost-effective and safe disease-modifying approach targeting islet dysfunction in T2DM, preventing pathogenic aggregates without disturbing physiological IAPP function.

Anti-IAPP Monoclonal Antibody Improves Clinical Symptoms in a Mouse Model of Type 2 Diabetes

“…Production of VLPs-Based Vaccine VLPs Obtained from the Coat Protein of the Bacteriophage Qβ were expressed in E. coli strain JM109, with the expression vector pQβ10, and purified, as previously described [22]. The N-terminal IAPP peptide with disulfide bond (S-S) (H-KCNTATCATGGK[Aoa]-NH2 was purchased from Pepscan (Lelystad, The Netherlands), and chemically coupled to VLPs via the heterobifunctional S-4FB crosslinker (Solulink, San Diego, CA, USA), as previously described in Roesti et al (2020) [20].…”

“…Female C57BL/6 mice were immunized subcutaneously at 6 weeks of age with 10 µg of conjugated vaccine, followed by a boost injection on day 14. ELISA assays were performed as previously described [20] to check antibody titers. Splenocytes were further collected at and processed as described in the following section.…”

“…Our strategy is to eliminate these pathogenic aggregates, and therefore delay or prevent T2DM. We have previously demonstrated that, by generating a virus-like particle conjugate vaccine against the N-terminal of human IAPP (VLP-N-terminal vaccine), the generated antibody (Ab) response had a high avidity for amyloidogenic aggregates, but a low affinity for soluble hIAPP [20]. This left the physiological response induced by IAPP intact, but prevented IAPP fibril formation, inflammation, and β-cell loss.…”

Focus on the Lymphatic Route to Optimize Drug Delivery in Cardiovascular Medicine

“…To target the lymphatic system exclusively, this type of injection must be combined with the use of macromolecules. As described in Table 2 , subcutaneous injections are used as treatment for various conditions [ 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 ].…”

Genomic Medicine and Advances in Vaccine Technology and Development in the Developing and Developed World

“…Type 2 diabetes is also a disease in which the immune system plays a key role. Roesti et al developed a vaccine against amyloidogenic aggregates in pancreatic islets of mice, and the results were quite interesting: vaccination seemed to delay the onset of hyperglycemia and prevent the disease from progressing [ 43 ].…”