Targeted Therapy Using Designer Insulin Receptor Agonists for Congenital Severe Insulin Resistance Syndromes

About This Grant

SUMMARY Severe insulin resistance syndromes, including Donohue and Rabson-Mendenhall syndromes, are rare, life- threatening disorders caused by mutations in the insulin receptor (IR) that impair insulin binding and receptor activation. There are currently no FDA-approved therapies that directly target the receptor defect, and existing interventions provide only limited, short-term benefit. This proposal aims to address this urgent unmet need in rare disease therapeutics by advancing RF-409, a first- in-class, synthetic IR agonist. RF-409 was developed using structure-guided computational protein design to engage both insulin-binding sites (site-1 and site-2) and induce conformational changes that stabilize the IR in its active state. RF-409 exhibits high affinity and specificity for IR, activates both metabolic and mitogenic signaling pathways, and demonstrates strong thermostability and bioactivity in vivo. Preclinical studies show that RF-409 lowers blood glucose more efficiently and with longer duration than insulin in wild-type, type 1 diabetic (Streptozotocin-induced), and high-fat diet–induced obese mouse models. Notably, RF-409 is also effective in activating IR mutants that are unresponsive to insulin. To enable rigorous efficacy testing, we developed a validated knock-in mouse model (IR-D707A) carrying a patient-derived, insulin-binding–defective mutation. These mice exhibit neonatal lethality and severe insulin resistance, closely mirroring human severe insulin resistance phenotypes. RF-409, but not insulin, activates IR in this mouse model, providing a robust, disease-relevant platform for therapeutic evaluation. Aim 1 will characterize the pharmacokinetic and pharmacodynamic profile of RF-409 in wild-type, diabetic, and conditional IR-D707A mice. Time-resolved LC-MS analysis will be used to define systemic exposure and tissue distribution. Glucose-lowering efficacy and downstream IR signaling will be measured to establish PK/PD relationships and guide dose selection. Aim 2 will assess the physiological and therapeutic impact of RF-409 in the IR-D707A mouse model. We will evaluate metabolic, mitogenic, and survival outcomes following chronic administration in both adult and neonatal animals to determine therapeutic benefit in a rare disease model. RF-409 is well-characterized, highly specific, and production-ready. Its activity in both preclinical and disease- specific models support its potential as a therapeutic for rare insulin receptoropathies. Completion of this project will generate critical efficacy and mechanistic data to support IND-enabling development and may lay the foundation for a new class of targeted therapies for receptor-level metabolic diseases.