Altered Mitochondrial Retrograde Signaling in Response to mtDNA Depletion or a Ketogenic Diet

Neurodegenerative diseases affect a staggering proportion of the population. Many neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease exhibit significant metabolic and bioenergetic changes both systemically and in the central nervous system. Accordingly, abnormalities in mitochondrial function are also present early in the pathogenesis of neurodegenerative diseases, leading to dysregulation of mitochondrial and metabolic signaling pathways and general neuronal dependence on anaerobic metabolism. Specifically, the electron transport chain function is reduced both systemically and in brains of individuals affected by Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. The goal of this dissertation is to better understand the mechanisms of mitochondrial retrograde signaling that may play a role in neurodegeneration. In our first study, we show that mtDNA depletion of neuroblastoma cell lines significantly alters mitochondrial retrograde signaling in such a way that promotes upregulation of respiratory chain subunits, but inhibits mitochondrial mass as a whole. Further investigation into the bioenergetic status of these mtDNA-depleted cells suggests that these non-respiratory mitochondria are unable to contribute to the cell energetically, and are thus a metabolic liability. This study provides insight into mitochondrial signaling processes that may be present in neurodegenerative disorders. Next, we examine the role of a ketogenic diet on mitochondrial signaling pathways in mouse brains. We show in this study that a ketogenic diet promotes a number of favorable metabolic changes in mice including reduction of systemic insulin resistance, an increase in the mitochondrial master regulator PGC1α and its relative PGC1β, and an increase in some elements of mitochondrial mass. This study lays mechanistic groundwork for the potential use of a ketogenic diet in neurodegenerative disorders. We then describe the generation of cybrid lines to evaluate the role of mtDNA in Alzheimer's disease, mild cognitive impairment, amyotrophic lateral sclerosis, and normal aging. These lines have shown us that mtDNA from individuals with these various conditions confer significant mitochondrial dysfunction to their respective cell lines, and that these lines will continue to provide significant insight into the role of mtDNA and mitochondrial function in disease states and aging. Finally, we show that the pan-neurotrophin receptor p75NTR is necessary for estrogen-induced sympathetic nerve remodeling in the mouse uterus. This physiological phenomenon involves cyclical degeneration and regeneration of sympathetic nerves to uterine smooth muscle, and is an important model for studying axonal changes in normal degenerative and regenerative events

Phase 1 dose expansion and biomarker study assessing first-in-class tumor microenvironment modulator VT1021 in patients with advanced solid tumors

Abstract Background Preclinical studies have demonstrated that VT1021, a first-in-class therapeutic agent, inhibits tumor growth via stimulation of thrombospondin-1 (TSP-1) and reprograms the tumor microenvironment. We recently reported data from the dose escalation part of a phase I study of VT1021 in solid tumors. Here, we report findings from the dose expansion phase of the same study. Methods We analyzed the safety and tolerability, clinical response, and biomarker profile of VT1021 in the expansion portion of the phase I study (NCT03364400). Safety/tolerability is determined by adverse events related to the treatment. Clinical response is determined by RECIST v1.1 and iRECIST. Biomarkers are measured by multiplexed ion beam imaging and enzyme-linked immunoassay (ELISA). Results First, we report the safety and tolerability data as the primary outcome of this study. Adverse events (AE) suspected to be related to the study treatment (RTEAEs) are mostly grade 1–2. There are no grade 4 or 5 adverse events. VT1021 is safe and well tolerated in patients with solid tumors in this study. We report clinical responses as a secondary efficacy outcome. VT1021 demonstrates promising single-agent clinical activity in recurrent GBM (rGBM) in this study. Among 22 patients with rGBM, the overall disease control rate (DCR) is 45% (95% confidence interval, 0.24-0.67). Finally, we report the exploratory outcomes of this study. We show the clinical confirmation of TSP-1 induction and TME remodeling by VT1021. Our biomarker analysis identifies several plasmatic cytokines as potential biomarkers for future clinical studies. Conclusions VT1021 is safe and well-tolerated in patients with solid tumors in a phase I expansion study. VT1021 has advanced to a phase II/III clinical study in glioblastoma (NCT03970447)