A series of glucagon analogues will be designed, produced at milligram levels, tested for solution stability and both in vitro and in vivo activity with the goal of providing a long term treatment for hyperinsulinism.
In severe persistent HI, repeated hypoglycemic episodes can ultimately lead to permanent seizure disorders, learning disabilities, cerebral palsy, blindness and even death. Clinical studies have demonstrated the effectiveness of both short-term and long-term treatment with glucagon for severe forms of HI and continuous subcutaneous administration of glucagon has been recommended both because of the potential improvement in patient outcome and high costs of surgical intervention followed by long-term annual care costs. However, the instability of glucagon in solution creates both administration problems and potential complications due to infusion tube blockage. These instability problems have limited the use of glucagon for severe persistent HI. To overcome this problem, we propose to develop a series of solution stable glucagon analogs and test them both in-vitro and in-vivo. These analogs when formulated in a conventional sterile diluent will maintain not only the standard 95% potency requirement throughout a 2 year storage period at 4C but more importantly will offer an extended ?in use? stability period of at least 6 months at 40C. Such analogs will be capable to be implemented in pump system for the long-term management of severe persistent HI without concern for complications due to glucagon instability and pump clogging issues.
