Development of an Improved Adenovirus Vector and Its Application to the Treatment of Lifestyle-Related Diseases

• Published in: Biological & pharmaceutical bulletin Vol. 47; no. 5; pp. 886 - 894
• Main Author: Shimizu, Kahori
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.05.2024; Japan Science and Technology Agency
• Subjects: Acyltransferase; Adenoviridae - genetics; adenovirus vector; Adenoviruses; Animals; Apolipoprotein E4; diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - therapy; Expression vectors; Fatty liver; Functional foods & nutraceuticals; Gene therapy; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Glucose; Glucose metabolism; Glucose tolerance; Hepatotoxicity; Humans; Hyperglycemia; Insulin Resistance; Insulin secretion; Life Style; lifestyle-related disease; Lifestyles; lipid; Lipoprotein lipase; Liver - metabolism; Liver diseases; Medical innovations; Medical treatment; metabolic dysfunction-associated steatotic liver disease; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - therapy; Pathophysiology; Transgenes; Vectors (Biology); Zinc finger proteins; adenovirus vector; gene therapy; diabetes; lipid; lifestyle-related disease; metabolic dysfunction-associated steatotic liver disease
• ISSN: 0918-6158; 1347-5215; 1347-5215
• DOI: 10.1248/bpb.b23-00837

The number of patients with lifestyle-related diseases such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), has continued to increase worldwide. Therefore, development of innovative therapeutic methods targeting lifestyle-related diseases is required. Gene therapy has attracted considerable attention as an advanced medical treatment. Safe and high-performance vectors are essential for the practical application of gene therapy. Replication-incompetent adenovirus (Ad) vectors are widely used in clinical gene therapy and basic research. Here, we developed a novel Ad vector, named Ad-E4-122aT, exhibiting higher and longer-term transgene expression and lower hepatotoxicity than conventional Ad vectors. We also elucidated the mechanisms underlying Ad vector-induced hepatotoxicity during the early phase using Ad-E4-122aT. Next, we examined the therapeutic effects of the genes of interest, namely zinc finger AN1-type domain 3 (ZFAND3), lipoprotein lipase (LPL), and lysophospholipid acyltransferase 10 (LPLAT10), on lifestyle-related diseases using Ad-E4-122aT. We showed that the overexpression of ZFAND3 in the liver improved glucose tolerance and insulin resistance. Liver-specific LPL overexpression suppressed hepatic lipid accumulation and improved glucose metabolism. LPLAT10 overexpression in the liver suppressed postprandial hyperglycemia by increasing glucose-stimulated insulin secretion. Furthermore, we also focused on foods to advance research on the pathophysiology and treatment of lifestyle-related diseases. Cranberry and calamondin, which are promising functional foods, attenuated the progression of MASLD/NAFLD. Our findings will aid the development of new therapeutic methods, including gene therapy, for lifestyle-related diseases such as T2DM and MASLD/NAFLD.