Non-invasive Imaging for Therapeutic Efficacy (NITE) in Ndufs4 Mouse Model of Leigh Syndrome

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

ABSTRACT Leigh Syndrome (LS) is a devastating childhood-onset neurodegeneration disease, affecting 1 in 40,000 live births, caused by genetic defects in mitochondrial electron transport chain (ETC) Complex I. More than 75 genes have been identified for LS, including the nuclear-encoded ETC Complex I subunit NADH dehydrogenase (ubiquinone) Fe-S protein 4 (NDUFS4, 5q11.2). There is no cure for LS. Current clinical management for LS is palliative. There is an urgent need for cure. Large-scale randomized trials are challenging for LS, due to low numbers of patients with defects in the various genes. While several clinical trials are underway, the absence of robust non-invasive surrogate endpoints targeting the causal etiology [i.e. impaired ETC Complex I] has hampered their progress. Animal models have been invaluable in modeling LS and therapeutic development. However, current mitochondrial functional assays are invasive thus not feasible for in vivo longitudinal evaluation. In addition, different brain regions could have varied degrees of dysfunction or sensitivity to drug treatments. Furthermore, LS is a multi- system syndrome, affecting all organs, especially energy-demanding organs like brain, muscle, and heart. Using death as an endpoint to evaluate therapeutic efficacy, a common practice for animal studies, is not only time consuming but, more importantly, lacks specificity for multi-system disease as LS. There is a critical knowledge gap in LS field - lacking in vivo non-invasive and robust tools targeting causal etiology (impaired ETC Complex I) to evaluate therapeutic efficacy both preclinically and clinically. The goal of this study is to establish novel Non-invasive Imaging for Therapeutic Efficacy (NITE) for LS in Ndufs4 knockout (KO) mice. We will test the preclinical utility of 4D Oxy-wavelet MRI as a valid surrogate endpoint for LS therapy with three types of therapeutic interventions targeting different aspects of LS pathogenesis: two known established therapies (chronic hypoxia and gene therapy) and one new therapy (dodecanedioic acid). In the short term, this project will demonstrate that NITE is a robust and sensitive non-invasive imaging biomarker of preclinical therapeutic efficacy to accelerate therapeutic screening in animal models. Furthermore, this project will demonstrate the effect of bypassing an ETC Complex I defect through the anaplerotic compound dodecanedioic acid (DC12) for TCA cycle that generates succinate, potentially establishing a novel therapeutic intervention in LS and other Complex I symptomatology. In the long term, NITE can be optimized for clinical translation for differential diagnosis, prognosis, and clinical trials.