precision medicine

Assessing the Efficacy of Mindfulness Apps

PROJECT SUMMARY: Rates of depression continue to rise and the mental health impact of COVID-19 has only accelerated trends. While mental health apps, specifically mindfulness apps, are not a panacea, they are popular tools that millions are turning to today for easy access, affordable, and low-stigma help. But increased reliance on mindfulness apps has not been supported by rigorous scientific evidence exemplified by few studies employing appropriate control conditions. Thus, this research is designed to focus on using 100% remote but robust methodology to assess the efficacy of mindfulness apps by applying a novel precision medicine framework. Our study first assesses the impact of the Digital Working Alliance by matching people with depression with a mindfulness app that may better support their personalized needs. We will compare those randomized to the to this matching condition to a digital placebo to better evaluate the efficacy of these mindfulness apps. For the first six weeks, participants will be asked to use the mindfulness app or digital placebo daily, and if not engaged, will receive reminders, allowing for the analysis of clinical outcomes during ideal usage patterns. For an additional six weeks, participants will be asked to use the app or digital placebo naturally, allowing for the elucidation of naturalistic usage patterns and evaluation if these usage patterns impact clinical outcomes. Across the entire study, we will capture smartphone-based digital phenotypes of behaviors (eg sleep, step, screen time), environments (eg home time, greenspace exposure), and symptoms (longitudinal ecological momentary assessment) to create personalized and predictive models of response that can be utilized to better understand factors impacting the efficacy of mindfulness apps, and in the future, better tailor apps to each person.

Validating Causality of Disputed Mitochondrial Variants in Inborn Errors of Metabolism

PROJECT SUMMARY Primary mitochondrial disease (PMD) encompasses multi-systemic disorders caused by impaired mitochondrial function. PMDs arise from pathogenic variants in either nuclear genes encoding mitochondrial proteins, or in the mitochondrial DNA (mtDNA) genome. Clinical diagnosis is challenging due to phenotypic heterogeneity, underscoring the importance of genetic diagnosis. ACMG/AMP guidelines provide a well-established framework for interpreting nuclear DNA variants while diagnosing genetic diseases. Their application to mtDNA variants, however, remains challenging due to unique features of mtDNA: maternal inheritance, heteroplasmy, threshold effects, and effect of transfer or ribosomal RNA rather than coding variants. To address these challenges, the ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, co-chaired by the Multi-PIs of this study, developed widely adopted ACMG/AMP revised guidelines for mtDNA variant interpretation. Over the past five years, this global expert panel has curated more than 280 mtDNA variant. Because of the lack of functional data of individual mtDNA variants in the literature, 23 previously reported pathogenic (P) variants were classified as Variants of Uncertain Significance (VUS), hindering definitive PMD diagnoses and therapeutic development. This R01 project aims to resolve the pathogenicity of these 23 mtDNA VUS through functional validation, leveraging advanced mtDNA base editing and single-cell genomics in in vitro and in vivo models. In Aim 1, we will create human 143B cell line models for 20 VUS using cutting-edge mtDNA editing techniques, optimized for efficiency and minimal off-target effects. Single-cell genomics (mtscATAC-seq and scRNA-seq) will assess heteroplasmy and genomic changes, while functional assays will evaluate mitochondrial ATP production, oxidative phosphorylation, membrane potential, and redox stress. Aim 2 will develop zebrafish models for 17 conserved VUS, characterizing phenotypic and mitochondrial outcomes to corroborate in vitro findings and PMD patient phenotypes. This study will clarify longstanding uncertainties regarding the pathogenicity of these mtDNA VUSs which were nonetheless reported to be pathogenic with often strong genetic evidence but limited functional data. The study will also establish valuable cell and zebrafish models and provide mechanistic insights of PMDs. The resulting resources will be shared with the scientific community to accelerate research and therapeutic advancements for novel precision medicine approaches for PMDs.

Targeted Prodrug Cytokines for Metastatic Breast Cancer Immunotherapy

Project Summary. Our approach directly addresses key limitations in targeting and treating metastatic breast cancer, where we propose the selective activation of modular immune-modulating cytokines within the hypoxic and ROS-active TME for delivery across the BBB, providing the necessary pre-clinical data for future clinical translation. The in vitro and in vivo investigations of this novel immunotherapeutic in immunocompetent models will allow our team to study the interplay between tumor-driven immune activation, cytokine signaling, and anti-tumor immunity in both primary and metastatic sites, and establish a robust groundwork for subsequent clinical validation within the OSUCCC. This proposal addresses two key challenges in developing a novel immunotherapy strategy for breast cancer by answering two hypotheses: (1) can a modular immunotherapy platform with tumor-selective activation of prodrug recombinant cytokines overcome these limitations in drug delivery, and (2) can the development of nanobody-cytokine fusions that can selectively target primary breast cancer tumors and cross the BBB to reach metastatic tumor sites? The first hypothesis focuses on achieving tumor environment-specific activation of prodrug-based recombinant cytokines. Protein cytokines are highly potent, and while others have tried to block their activity using a fused genetic linker to ‘mask’ functionality, no one has yet attempted to use a non-canonical-based chemical strategy to achieve this inhibition. Immune-modulating cytokines will be recombinantly expressed with integrated ncAAs that block cytokine activity until the function is regenerated in the breast cancer TME. Once the cytokine activity is controlled, our second hypothesis will be to achieve selective delivery of the cytokine via fusion to nanobodies. While success has been found in targeting primary tumors in drug and protein delivery, a key challenge remains in reaching secondary metastatic tumors in hard-to-reach sites (i.e., brain). Engineered nanobodies, with affinity for breast cancer tumors and the ability to bind to BBB transcytosis receptors, will enable selective delivery to metastatic breast-to-brain tumors, resulting in tumor- specific activation, immune responses, and improved therapeutic outcomes. This system can significantly improve therapeutic outcomes for patients with mBC by integrating selective activation and delivery mechanisms to reduce off-target effects and enhance tumor-specific immune responses in both primary and secondary metastatic tumor sites. Optimizing drug delivery systems to tune immune responses could offer more effective and less invasive treatment options when compared to traditional and engineered cell-based approaches. Our momentum towards precision medicine and targeted therapies holds significant promise for improving outcomes for mBC patients, and has the potential to serve as a pan-cancer treatment for aggressive metastatic cancers from the following aims: (1) generating a modular platform for tumor-specific activation of prodrug cytokines, (2) evaluating cytokine delivery and anti-cancer immune phenotypes in mBC.

Characterizing the causal role of large-scale network interactions in supporting complex cognition

Neuroimaging has greatly extended our capacity to study the workings of the human brain. Despite the wealth of knowledge this tool has generated however, there are still critical gaps in our understanding. While tremendous progress has been made in mapping areas of the brain that are specialized for particular stimuli, or cognitive processes, we still know very little about how large-scale interactions between different cortical networks facilitate the integration of information and the execution of complex tasks. Yet even the simplest behavioral tasks are complex, requiring integration over multiple cognitive domains. Our knowledge falls short not only in understanding how this integration takes place, but also in what drives the profound variation in behavior that can be observed on almost every task, even within the typically developing (TD) population. The search for the neural underpinnings of individual differences is important not only philosophically, but also in the service of precision medicine. We approach these questions using a three-pronged approach. First, we create a battery of behavioral tasks from which we can calculate objective measures for different aspects of the behaviors of interest, with sufficient variance across the TD population. Second, using these individual differences in behavior, we identify the neural variance which explains the behavioral variance at the network level. Finally, using covert neurofeedback, we perturb the networks hypothesized to correspond to each of these components, thus directly testing their casual contribution. I will discuss our overall approach, as well as a few of the new directions we are currently pursuing.

Brain mosaicism in epileptogenic cortical malformations

Focal Cortical Dysplasia (FCD) is the most common focal cortical malformation leading to intractable childhood focal epilepsy. In recent years, we and others have shown that FCD type II is caused by mosaic mutations in genes within the PI3K-AKT-mTOR-signaling pathway. Hyperactivation of the mTOR pathway accounts for neuropathological abnormalities and seizure occurrence in FCD. We further showed from human surgical FCDII tissue that epileptiform activity correlates with the density of mutated dysmorphic neurons, supporting their pro-epileptogenic role. The level of mosaicism, as defined by variant allele frequency (VAF) is thought to correlate with the size and regional brain distribution of the lesion such that when a somatic mutation occurs early during the cortical development, the dysplastic area is smaller than if it occurs later. Novel approaches based on the detection of cell-free DNA from the CSF and from trace tissue adherent to SEEG electrodes promise future opportunities for genetic testing during the presurgical evaluation of refractory epilepsy patients or in those that are not eligible for surgery. In utero-based electroporation mouse models allow to express somatic mutation during neurodevelopment and recapitulate most neuropathological and clinical features of FCDII, establishing relevant preclinical mouse models for developing precision medicine strategies.

Growing a world-class precision medicine industry

Monash Biomedical Imaging is part of the new $71.2 million Australian Precision Medicine Enterprise (APME) facility, which will deliver large-scale development and manufacturing of precision medicines and theranostic radiopharmaceuticals for industry and research. A key feature of the APME project is a high-energy cyclotron with multiple production clean rooms, which will be located on the Monash Biomedical Imaging (MBI) site in Clayton. This strategic co-location will facilitate radiochemistry, PET and SPECT research and clinical use of theranostic (therapeutic and diagnostic) radioisotopes produced on-site. In this webinar, MBI’s Professor Gary Egan and Dr Maggie Aulsebrook will explain how the APME will secure Australia’s supply of critical radiopharmaceuticals, build a globally competitive Australian manufacturing hub, and train scientists and engineers for the Australian workforce. They will cover the APME’s state-of-the-art 30 MeV and 18-24 MeV cyclotrons and radiochemistry facilities, as well as the services that will be accessible to students, scientists, clinical researchers, and pharmaceutical companies in Australia and around the world. The APME is a collaboration between Monash University, Global Medical Solutions Australia, and Telix Pharmaceuticals. Professor Gary Egan is Director of Monash Biomedical Imaging, Director of the ARC Centre of Excellence for Integrative Brain Function and a Distinguished Professor at the Turner Institute for Brain and Mental Health, Monash University. He is also lead investigator of the Victorian Biomedical Imaging Capability, and Deputy Director of the Australian National Imaging Facility. Dr Maggie Aulsebrook obtained her PhD in Chemistry at Monash University and specialises in the development and clinical translation of radiopharmaceuticals. She has led the development of several investigational radiopharmaceuticals for first-in-human application. Maggie leads the Radiochemistry Platform at Monash Biomedical Imaging.

Identification and treatment of advanced, rupture-prone plaques to reduce cardiovascular mortality

Atherosclerosis is the underlying cause of major cardiovascular events, including heart attack and stroke. The build-up of plaque in coronary arteries can be a major risk for events, but risk is significantly higher in patients with vulnerable rather than stable plaque. Diagnostic imaging of vulnerable plaque is extremely useful for both stratifying patient risk and for determining effectiveness of experimental intervention in reducing cardiovascular risk. In the preclinical setting, being able to distinguish between stable and vulnerable plaque development and pair this with biochemical measures is critical for identification of new experimental candidates. In this webinar, Professor Stephen Nicholls and Dr Kristen Bubb from the Victorian Heart Institute will discuss the benefits of being able to visualise vulnerable plaque for both clinical and preclinical research. Professor Stephen Nicholls is a clinician-researcher and the Head of the Victorian Heart Institute. He is the lead investigator on multiple large, international, cardiovascular outcomes trials. He has attracted over $100 million in direct research funding and published more than 400 peer-reviewed manuscripts. He is focused on both therapeutic intervention to reduce vascular inflammation and lipid accumulation and precision medicine approaches to prevent cardiovascular mortality. Dr Kristen Bubb is a biomedical researcher and Group Leader within the Monash Biomedicine Discovery Institute Cardiovascular Program and Victorian Heart Institute. She focuses on preclinical/translational research into mechanisms underlying vascular pathologies including atherosclerosis and endothelium-driven hypertension within specific vascular systems, including pulmonary and pregnancy-induced. She has published >30 high impact papers in leading cardiovascular journals and attracted category 1&2 funding of >$750,000.

Mechanistic insights from a mouse model of HCN1 developmental epileptic encephalopathy

Pathogenic variants in HCN1 are associated with severe developmental and epileptic encephalopathies (DEE). We have engineered the Hcn1 M294L heterozygous knock-in (Hcn1M294L) mouse which is a homolog of the de novo HCN1 M305L recurrent pathogenic variant. The mouse recapitulates the phenotypic features of patients including having spontaneous seizures and a learning deficit. In this talk I will present experimental work that probes the molecular and cellular mechanisms underlying hyper-excitability in the mouse model. This will include testing the efficacy of currently available antiepileptic drugs and a novel precision medicine approach. I will also briefly touch on how disease biology can give insights into the biophysical properties of HCN channels.

Comprehensive delineation and precision medicine of GRIN-related neurodevelopmental disorders, a primary disturbance of the NMDA receptor

Targeting M-current: A new precision medicine approach in Dravet syndrome

FENS Forum 2024