Title Page
Contents
ABSTRACT 14
General Introduction 18
Chapter Ⅰ. 24-week Intramuscular Repeated Dose Toxicity Study of GX-188E in Mice 24
Ⅰ. Materials and Methods 26
1.1. Animals and maintenance 26
1.2. Preparation and treatment 27
1.3. In-life observations and measurements 29
1.4. Clinical pathology 30
1.5. Terminal procedures 31
1.6. Statistical analysis 32
Ⅱ. Results 35
2.1. Mortality, clinical observations and ophthalmology 35
2.2. Changes in body weights and food intake 39
2.3. Hematology and serum biochemistry 41
2.4. Organ weights 44
2.5. Macroscopic examination 47
2.6. Microscopic examination 49
Ⅲ. Discussion and Conclusion 57
Chapter Ⅱ. Eight-week Intramuscular Repeated Dose Toxicity Study of GX-188E combined with GX-I7 in Rats 60
Ⅰ. Materials and Methods 62
1.1. Animals and maintenance 62
1.2. Preparation and treatment 63
1.3. Group designation and dose selection 64
1.4. Animal observation 65
1.5. Ophthalmological examination 66
1.6. Hematology and serum biochemistry 66
1.7. Urinalysis 68
1.8. Necropsy, organ weights and histopathology 68
1.9. Lymphocyte analysis 70
1.10. Statistical analysis 70
Ⅱ. Results 72
2.1. Mortality, clinical observations, and ophthalmology 72
2.2. Changes in body weights and food intake 75
2.3. Hematology, serum biochemistry and urinalysis 78
2.4. Organ weights 86
2.5. Macroscopic and microscopic examination 91
2.6. Immune cell analysis 99
Ⅲ. Discussion and Conclusion 105
References 108
Abstract (Korean) 120
Table 1. Summary of clinical signs of female ICR mice treated with GX-188E administered once per two weeks for 24 weeks 37
Table 2. Summary of ophthalmology examinations of female ICR mice treated with GX-188E administered once per two weeks for 24 weeks 38
Table 3. Summary of food intake of female ICR mice treated with GX-188E administered once per two weeks for 24 weeks 40
Table 4. Hematological parameters of female ICR mice treated with GX-188E administered once per two weeks for 24 weeks 42
Table 5. Serum biochemical parameters of female ICR mice treated with GX-188E administered once per two weeks for 24 weeks 43
Table 6. Absolute organ weights of female ICR mice treated with GX-188E administered once per two weeks for 24 weeks 45
Table 7. Relative organ weights (% terminal body weight) of female ICR mice treated with GX-188E administered once per two weeks for... 46
Table 8. Summary of macroscopic findings observed in female ICR mice treated with GX-188E administered once per two weeks for 24 weeks 48
Table 9-1. Summary of histopathological changes observed in female ICR mice treated with GX-188E administered once per two weeks for... 51
Table 9-2. Summary of histopathological changes observed in female ICR mice treated with GX-188E administered once per two weeks for... 52
Table 9-3. Summary of histopathological changes observed in female ICR mice treated with GX-188E administered once per two weeks for... 53
Table 9-4. Summary of histopathological changes observed in female ICR mice treated with GX-188E administered once per two weeks for... 54
Table 10. Group designation for 24 weeks repeat administration of GX-188E or GX-I7 65
Table 11. Summary of clinical signs of female SD rats treated with GX-188E and GX-I7 administered once per two weeks for 8 weeks... 73
Table 12. Summary of ophthalmic findings of female SD rats treated with GX-188E and GX-I7 administered once per two weeks for 8... 74
Table 13. Summary of food intake of female SD rats treated with GX-188E and GX-I7 administered once per two weeks for 8 weeks... 77
Table 14-1. Hematological parameters of female SD rats treated with GX-188E and GX-I7 administered once per two weeks for 8 weeks... 80
Table 14-2. Hematological parameters of female SD rats treated with GX-188E and GX-I7 administered once per two weeks for 8 weeks... 81
Table 15-1. Serum biochemical parameters of female SD rats treated with GX-188E and GX-I7 administered once per two weeks for 8... 82
Table 15-2. Serum biochemical parameters of female SD rats treated with GX-188E and GX-I7 administered once per two weeks for 8... 83
Table 16-1. Urinalysis parameters of female SD rats treated with GX-188E and GX-I7 administered once per two weeks for 8 weeks... 84
Table 16-2. Urinalysis parameters of female SD rats treated with GX-188E and GX-I7 administered once per two weeks for 8 weeks... 85
Table 17-1. Absolute organ weights of female SD rats treated with GX-188E and GX-I7 administered once per two weeks for 8 weeks... 87
Table 17-2. Absolute organ weights of female SD rats treated with GX-188E and GX-I7 administered once per two weeks for 8 weeks... 88
Table 18-1. Relative organ weights of female SD rats treated with GX-188E and GX-I7 administered once per two weeks for 8 weeks... 89
Table 18-2. Relative organ weights of female SD rats treated with GX-188E and GX-I7 administered once per two weeks for 8 weeks... 90
Table 19. Summary of gross observations of female SD rats treated with GX-188E and GX-I7 administered once per two weeks for 8... 92
Table 20. Major histopathological changes of female SD rats treated with GX-188E and GX-I7 administered once per two weeks for 8... 93
Table 21. Summary of lymphocyte analysis of female SD rats treated with GX-188E and GX-I7 administered once per weeks for 8... 104
Figure 1. Intramuscular injection using electroporation system for transfection of GX-188E. Electroporation system (A) and injection site... 28
Figure 2. Survival changes of female ICR mice treated with GX-188E administered once per two weeks for 24 weeks. 36
Figure 3. Body weight changes of female ICR mice treated with GX-188E administered once per two weeks for 24 weeks. 39
Figure 4. Histopathological changes in the injection site (gastrocnemius muscle) of female ICR mice treated with GX-188E. Histological... 55
Figure 5. Histopathological changes in the skeletal muscle of female ICR mice treated with GX-188E. Histological changes in injection sites... 56
Figure 6. Survival changes of female SD rats treated with GX-188E and GX-I7 administered once per two weeks for 8 weeks and followed... 72
Figure 7. Body weight changes of female SD rats treated with GX-188E and GX-I7 administered once per two weeks for 8 weeks... 76
Figure 8. Neutrophils and lymphocytes changes of female SD rats treated with GX-188E and GX-I7 administered once per two weeks for... 79
Figure 9. Histopathological changes in the injection site (gastrocnemius muscle) of female SD rats treated with GX-188E and GX-I7 in main... 94
Figure 10. Histopathological changes in the injection site (gastrocnemius muscle) of female SD rats treated with GX-188E and GX-I7 in... 95
Figure 11. The severity of histopathological changes in the injection site (gastrocnemius muscle) of female SD rats treated with GX-188E... 96
Figure 12. Histopathological changes in the skeletal muscle of female SD rats treated with GX-188E and GX-I7 in main group. Rat were... 97
Figure 13. Histopathological changes in the vagina and cervix of female SD rats treated with GX-188E and GX-I7 in main group. Rat... 98
Figure 14. The proportion of total T cells gated on FSClow SSClow in spleen immune cell of female SD rats treated with GX-188E and...[이미지참조] 100
Figure 15. The proportion of CD4⁺ T cells and CD8⁺ T cells gated on CD3⁺ in spleen immune cell of female SD rats treated with GX-188E... 101
Figure 16. The proportion of total B cells gated on FSClow SSClow in spleen immune cell of female SD rats treated with GX-188E and...[이미지참조] 102
Figure 17. The percentage and corrected quantity of total T cells, CD4⁺ T cells and CD8⁺ T cells in spleen immune cell of female SD... 103