Diabetes is a disease in which blood glucose levels are above normal. Most of the food we eat is turned into glucose, or sugar, for our bodies to use for energy. The pancreas, an organ that lies near the stomach, makes a hormone called insulin to help glucose get into the cells of our bodies. When you have diabetes, your body either doesn't make enough insulin or can't use its own insulin as well as it should. This causes sugar to build up in your blood. Diabetes can cause serious health complications including heart disease, blindness, kidney failure, and lower-extremity amputations. Diabetes is the seventh leading cause of death in the United States (CDC - Basics about Diabetes).
Efficacy:
During the 25- week period of monitoring, the GAD65-plasmid DNA vaccination effectively prevented IDDM in young female NOD mice (1/13; 8% incidence). We also immunized mice with GM-CSF encoding GAD65 bicistronic vector (since it is known to recruit antigen-presenting cells, inducing a stronger immune response). However, GAD65–GM-CSF-plasmid DNA immunization (1/8; 12.5% incidence) did not alter the incidence of diabetes (P = 0.6477 vs GAD65-plasmid DNA). Female NOD mice in the control group readily became diabetic beginning at 17 weeks of age (3/12; 25% incidence) and reached a 75% incidence (9/12) at 23 weeks of age (P = 0.001 vs GAD65-plasmid DNA; P = 0.006 vs GAD65– GM-CSF-plasmid DNA) (Balasa et al., 2001).
2. Autoimmune diabetes DNA vaccine pND2-GAD65-BAX encoding GAD and BAX
Efficacy:
Data revealed that the only mice showing a significant decrease in diabetes onset were those receiving plasmid pND2-SGAD55-BAX (47% diabetic) compared to mice receiving plasmid pND2-GAD65 (93% diabetic), pND2-GAD65-BAX (87% diabetic), and untreated mice (93% diabetic). Insulitis scoring showed that the decrease in diabetes incidence observed with mice receiving plasmid pND2-SGAD55-BAX was associated with a significant decrease in islet inflammation when compared to untreated mice, and mice receiving either plasmid pND2, pND2-SRUC3, -GAD65-BAX, or -GAD65 (Li et al., 2004).
Efficacy:
A Kaplan- Meier plot of diabetes onset, together with statistical analysis, indicated that mice that received injection of pND2- SGAD55 plasmid DNA had a significant reduction in diabetes compared with untreated control animals (P = 0.05; log-rank test). In contrast, mice that received pND2-GAD65 did not show significant diabetes reduction compared with the same controls (P = 0.37; log-rank test) (Filippova et al., 2001).
4. Insulin-dependent diabetes mellitus DNA vaccine JwGAD65 + IL-4
a fusion protein consisting of a portion of murine GAD65 and IgGFc (Tisch et al., 2001)
f. Gene Engineering of
Gad65
Type:
DNA vaccine construction
Description:
Vector Jw4303 expressed a secreted fusion protein consisting of a fragment of glutamic acid decarboxylase 65 (GAD65) linked to IgGFc (Tisch et al., 2001).
Efficacy:
After monitoring animals up to 58 wk of age, the majority of unimmunized nonobese diabetic (NOD) mice (70%) or animals immunized with JwHEL + IL-4 (75%) or JwGAD65 (83%) had developed diabetes. In contrast, only 17% of NOD mice immunized with JwGAD65 + IL-4 developed diabetes (p = 0.03 vs unimmunized, p = 0.01 vs JwHEL + IL-4, χ2 test) (Tisch et al., 2001).
IV. References
1. Balasa et al., 2001: Balasa B, Boehm BO, Fortnagel A, Karges W, Van Gunst K, Jung N, Camacho SA, Webb SR, Sarvetnick N. Vaccination with glutamic acid decarboxylase plasmid DNA protects mice from spontaneous autoimmune diabetes and B7/CD28 costimulation circumvents that protection. Clinical immunology (Orlando, Fla.). 2001; 99(2); 241-252. [PubMed: 11318596].
2. Bot et al., 2001: Bot A, Smith D, Bot S, Hughes A, Wolfe T, Wang L, Woods C, von Herrath M. Plasmid vaccination with insulin B chain prevents autoimmune diabetes in nonobese diabetic mice. Journal of immunology (Baltimore, Md. : 1950). 2001; 167(5); 2950-2955. [PubMed: 11509644].
4. Filippova et al., 2001: Filippova M, Liu J, Escher A. Effects of plasmid DNA injection on cyclophosphamide-accelerated diabetes in NOD mice. DNA and cell biology. 2001; 20(3); 175-181. [PubMed: 11313020].
5. Li et al., 2004: Li AF, Hough J, Henderson D, Escher A. Co-delivery of pro-apoptotic BAX with a DNA vaccine recruits dendritic cells and promotes efficacy of autoimmune diabetes prevention in mice. Vaccine. 2004; 22(13-14); 1751-1763. [PubMed: 15068859].
6. Solvason et al., 2008: Solvason N, Lou YP, Peters W, Evans E, Martinez J, Ramirez U, Ocampo A, Yun R, Ahmad S, Liu E, Yu L, Eisenbarth G, Leviten M, Steinman L, Garren H. Improved efficacy of a tolerizing DNA vaccine for reversal of hyperglycemia through enhancement of gene expression and localization to intracellular sites. Journal of immunology (Baltimore, Md. : 1950). 2008; 181(12); 8298-8307. [PubMed: 19050246].
7. Tisch et al., 2001: Tisch R, Wang B, Weaver DJ, Liu B, Bui T, Arthos J, Serreze DV. Antigen-specific mediated suppression of beta cell autoimmunity by plasmid DNA vaccination. Journal of immunology (Baltimore, Md. : 1950). 2001; 166(3); 2122-2132. [PubMed: 11160264].
8. Urbanek-Ruiz et al., 2001: Urbanek-Ruiz I, Ruiz PJ, Paragas V, Garren H, Steinman L, Fathman CG. Immunization with DNA encoding an immunodominant peptide of insulin prevents diabetes in NOD mice. Clinical immunology (Orlando, Fla.). 2001; 100(2); 164-171. [PubMed: 11465945].
9. Wolfe et al., 2002: Wolfe T, Bot A, Hughes A, Möhrle U, Rodrigo E, Jaume JC, Baekkeskov S, von Herrath M. Endogenous expression levels of autoantigens influence success or failure of DNA immunizations to prevent type 1 diabetes: addition of IL-4 increases safety. European journal of immunology. 2002; 32(1); 113-121. [PubMed: 11754351].
