Additionally, the integration of therapy and monitoring should be reasonably designed with minimal potential biosafety risks. However, these methods still have some limitations in clinical application, such as viral vector application, additional exogenous signal stimulation or bioelectronic device requirements, implantation and maintenance of engineered exogenous cells, and so on. These studies prove that gene therapy is an alternative way to supply exogenous insulin for the long-term precise control of T1D. Inducible secretion has been previously achieved by the accumulation ( 14) or conditional storage of insulin in the endoplasmic reticulum (ER) ( 15). Compared with transcriptional regulation, direct regulation of insulin secretion can provide faster blood glucose regulation. Therefore, these systems have a risk of inducing postprandial hyperglycemia and subsequent hypoglycemia in the treatment of T1D. However, most exogenous signal-induced therapeutic systems have focus on transcriptional regulation in target cells, which usually causes a certain time lag between signal reception and insulin expression/secretion. Synthetic biology has provided new insights into the intelligent therapeutic approaches for T1D ( 8– 13). Compared with the viral delivery/expression system, the ex vivo implantation of engineered cells, and the exogenous inducer system, the GAIS system combines the advantages of biosafety, effectiveness, persistence, precision, and convenience, providing therapeutic potential for the treatment of type 1 diabetes. Additionally, this system offers sufficient biosafety, as evidenced by the assays of immunological and inflammatory safety, ER stress, and histological evaluation. In vitro and in vivo experiments systematically demonstrated the effects of the GAIS system, including glucose-activated and repeatable SIA secretion, long-term precise blood glucose control, recovered HbA 1c levels, improved glucose tolerance, and ameliorated oxidative stress. In the GAIS system, the conditional aggregation domain–furin cleavage sequence–SIA fusion protein was encoded by the intramuscularly delivered plasmid and temporarily kept in the endoplasmic reticulum (ER) because it binds to the GRP78 protein then, upon hyperglycemia, the SIA was released and secreted into the blood. In this study, a glucose-activated single-strand insulin analog (SIA) switch (GAIS) was constructed to achieve repeatable pulse activation of SIA secretion in response to hyperglycemia. Genetic modification of non–β-cells to produce insulin is a promising therapeutic strategy for type 1 diabetes however, it is associated with issues, including biosafety and precise regulation of insulin supply.
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