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Publications

Journal Article Ppublish

PubMed: 40579035 DOI: 10.21873/invivo.13994

Long-term Safety Pharmacology and Musculoskeletal Changes of HMGB1 Box A Gene Therapy in Middle-aged Monkeys.

In Vivo 39(4):1965-1983

Authors: Sukanya Jaroenporn, Tayanee Chundee, Sakawdaurn Yasom, Lalitta Suriya-Arunroj, Motee Chimngam, Nutchanat Suttisan, Suchinda Malaivijitnond, Apiwat Mutirangura

Affiliations

  • Department of Biology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand;.
  • Zoology Program, Department of Biology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
  • Center of Excellence in Molecular Genetics of Cancer and Human Disease, Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
  • Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
  • National Primate Research Center of Thailand-Chulalongkorn University, Saraburi, Thailand.
  • Department of Biology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
  • Center of Excellence in Molecular Genetics of Cancer and Human Disease, Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand;.

Abstract

BACKGROUND/AIM

HMGB1 Box A gene therapy is a promising therapeutic approach for age-associated diseases, based on evidence from in vitro and in vivo studies in rodents. This study aimed to evaluate long-term safety and musculoskeletal change of the Box A gene in non-human primates.

MATERIALS AND METHODS

Perimenopausal monkeys were intravenously injected with a control plasmid (PC group) or Box A plasmid (Box A group) once a week for eight weeks, and were observed for one year. The safety pharmacology, blood biochemistry and hematology, bone mineral density, bone geometry, and muscle density were assessed and compared between the groups.

RESULTS

The safety pharmacological tests, general clinical observations, and evaluation of the central nervous, cardiovascular, and respiratory systems revealed no safety concerns. The response of the musculoskeletal system to Box A showed that the radius and tibia exhibited opposing bone density and size changes between the PC and Box A groups. Box A attenuated the age-related increase in bone mass and decrease in bone size at the radial metaphysis. Box A promoted cortical bone accumulation in the tibial diaphysis. The PC group, but not the Box A group, showed elevated blood glucose levels starting from the 48 th week of the experiment. Box A group trended to gain less weight than the PC group, without experiencing muscle loss.

CONCLUSION

This study indicated that Box A was safe over a 56-week observation period, causing no adverse clinical symptoms. Notably, it mitigated age-associated phenotypes, including improved bone health, lowered blood glucose, and reduced weight gain in perimenopausal monkeys. These results suggest Box A as a safe rejuvenation medicine.

MeSH

Genes, Blood Glucose, Safety, Muscles, Blood, Signs And Symptoms, Aged, Pharmacology, Genes, Vif, Research, Therapeutics, Bone Density, Plasmids, Rejuvenation, Hmgb1 Protein