(P22-052-25) Safety Assessment of a Potential Anti-diabetic Agent in a Pre-clinical Model

Objectives: We and others have reported that Insparin, a protein derived from Adenovirus 36, has anti-diabetic potential. Transgenic, vector-mediated expression, or nanoparticle (NP)-encapsulated delivery of Insparin, improved cellular glucose uptake, enhanced blood glucose disposal, and significantly improved HbA1c in diabetic mice on a high-fat diet (HFD). Along with its efficacy, ensuring the safety of Insparin is an essential step toward its clinical application. In this study, we tested the safety following long term administration of Insparin-NP (INSP) in diabetic animals.

Methods: INSP or void-NP were prepared using soy phosphatidylcholine. 14-16 wk old C57BL/6J mice fed a 45% HFD for 8 wk were treated with daily SC injection of void-NP or 145µg INSP for 7 wk (43 doses, n = 10 / group). Post-treatment, plasma AST and ALT were measured. To determine post-treatment adverse effects, mice continued on HFD and were sacrificed 1 or 6 months later. At 1 or 6 months post-treatment, spleen, liver, kidney, lung, pancreas, heart, brain, and injection site areas were necropsied, paraffin embedded, followed by H&E staining and histopathological evaluation with the help of a commercial histopathology service.

Results: After 7 wk INSP treatment, AST was 1536 ± 764 ng/mL for Void-NP and 690 ± 69 ng/mL for the INSP group (p=0.3) and ALT was 837 ± 535 ng/mL and 294 ± 47 ng/mL for Void-NP and INSP groups, respectively (p=0.3). Upon sacrifice, no tumors were observed in mice. One month after stopping NP administration, all changes observed in major organs were HFD-induced, and no adverse changes were observed in mice treated with INSP. Six months after stopping NP treatment, both groups showed lipid accumulation in livers, and pancreas showed islet cell hyperplasia. However, no treatment related differences were observed between groups.

Conclusions: Long-term INSP administration did not deteriorate liver function, and did not promote tumor formation or treatment specific histopathological changes. Although additional safety studies are needed, these data support safety of INSPARIN and its continued development as an antidiabetic drug.

Funding Sources: Insparin Inc.