Type 1 Diabetes (T1D) is a chronic, life-threatening autoimmune disorder characterized by profound insulin deficiency that results from progressive destruction of insulin-producing pancreatic β-cells. For over a century, exogenous insulin delivery was the only option to help T1D patients manage persistent hyperglycemia and reduce the risk of severe microvascular and macrovascular complications. Recent exploratory treatments use complex cell-based therapies requiring long-term immunosuppression. This abstract describes a unique AAV-mediated gene therapy approach to drive skeletal muscle expression of human glucokinase (GcK) and human insulin (INS). One-time IM administration to the quadriceps, gastrocnemius and tibialis anterior muscles of STZ-induced diabetic mice resulted in dose-related increases of pharmacologically active INS at fasting levels (~1 ng/mL) and human C-peptide that decreased fed and fasted blood glucose, lowered HbA1c by >5% at the highest dose, and reduced AUCGlu upon oral glucose challenge. Elevated triglycerides seen in control STZ-treated animals were normalized. No hypoglycemia or other adverse effects were observed through 8 weeks. No immunosuppression was required. Next steps in evaluation of KT-A112 involve a rolling dose-escalation study in STZ-treated NHPs.
C.Smith: Consultant; Horizon Therapeutics plc, Employee; Kriya Therapeutics. F.Bosch: None. M.Rhodes: None. W.W.Harrington: Consultant; Kriya Therapeutics. M.Stone: None. U.Karadge: None. J.Liu: None. W.J.Quinn: Employee; Kriya Therapeutics. A.Bassiri: None. J.Mallory: Employee; Kriya Therapeutics. V.Jimenez: None.
