Safe and low-dose but therapeutically effective adenovirus-mediated hepatocyte growth factor gene therapy for type 1 diabetes in mice

Aims: Hepatocyte growth factor (HGF) is a multifunctional cytokine that plays important roles in pancreatic physiology. Approvals of gene therapy drugs have highlighted gene therapy as an innovative new drug modality, but the very recent reports of deaths in clinical trials have provided a warning that high-dose gene therapy can cause dangerous liver toxicity. The present study aimed to develop a safe and low-dose but therapeutically effective adenovirus-mediated HGF gene therapy for streptozotocin (STZ)-induced type 1 diabetes (T1D) in mice. Main methods: A single intravenous injection of a low dose (3 x 10(8) plaque forming units) of adenoviral vector expressing the HGF gene under the transcriptional control of a strong promoter, i.e., the cytomegalovirus immediate-early enhancer and a modified chicken beta-actin promoter (Ad.CA-HGF), was given to T1D mice. Key findings: Low-dose HGF gene therapy significantly attenuated the elevation of blood glucose concentrations at the acute phase of T1D, and this effect persisted for several weeks. Temporal upregulation of plasma insulin at the acute phase was maintained at a normal level in Ad.CA-HGF-treated mice, suggesting that the therapeutic mechanism may involve protection of the remaining beta-cells by HGF. Liver enzymes in plasma were not elevated in any of the mice, including the Ad.CA-HGF-treated animals, all of which looked healthy, suggesting the absence of lethal adverse effects observed in patients receiving high intravenous doses of viral vectors. Significance: A low dose of intravenous Ad-mediated HGF gene therapy is clinically feasible and safe, and thus represents a new therapeutic strategy for treating T1D.

Automated summary

The study developed a safe and low-dose adenovirus-mediated gene therapy for T1D in mice, which effectively attenuated blood glucose levels and maintained plasma insulin at normal levels without causing liver toxicity. This clinically feasible and safe therapeutic strategy may offer a new treatment option for T1D.