Optimization and Preclinical Validation of QTE Therapy for Friedreich's Ataxia

ABSTRACT Friedreich's ataxia (FRDA), the most prevalent inherited ataxia, causes debilitating neurodegeneration and cardiac issues, typically leading to mortality by age 35. Current treatments, including the FDA-approved omaveloxolone, offer limited efficacy and present notable side effects. We propose an innovative approach with QTE therapy, targeting the underlying molecular mechanisms of FRDA. Our initial studies have shown that QTE therapy modulates important FRDA target protein levels, improves cardiac function, mitigates iron overload, and significantly increases survival rates in FRDAkd mice, outperforming existing treatments. In Aim 1 of this project, we focus on optimizing the QTE dosage and formulation through Physiologically-Based Pharmacokinetic (PBPK) modeling, assessing drug synergy, bioavailability, and blood-brain barrier penetration. In Aim 2, we will evaluate the optimized dosage’s efficacy in reversing behavioral and pathological deficits in FRDAkd mice, using comprehensive neurological and cardiac assessments. We aim to demonstrate significant improvements in cardiac function and neurological health, surpassing current treatment benchmarks. Our team is well-equipped to transition QTE therapy from preclinical research to clinical trials. In this project, we will focus on dosage and formulation optimization through PBPK modeling and conduct comprehensive efficacy testing in FRDAkd mice. For the next phase, we will collaborate with regulatory strategy experts, drug manufacturing specialists, formulation and packaging experts, and clinical trial professionals. This will guide us toward IND submission and the initiation of clinical trials. Our commercial strategy will be developed in partnership with a patient advocacy group to leverage orphan drug benefits, promote community engagement, and establish alliances with firms experienced in rare diseases. This approach is designed to streamline the market entry and distribution of QTE therapy, offering a novel, effective, and safer treatment alternative for FRDA patients.