clinical trials

SUPPORT SERVICES FOR THE PREVENTION AND TREATMENT THROUGH A COMPREHENSIVE CARE CONTINUUM FOR HIV-AFFECTED ADOLESCENTS IN RESOURCE CONSTRAINED SETTINGS IMPLEMENTATION SCIENCE NETWORK

Support Services for the Prevention and Treatment through a Comprehensive Care Continuum for HIV-affected Adolescents in Resource Constrained Settings Implementation Science Network (PATC3H-IN) (UG1/UM2) Program The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) requires support for logistical and operational coordination, website and communication management, analytic and data management, infrastructure for emerging research, regulatory, and monitoring of research activities for the Prevention and Treatment through a Comprehensive Care Continuum for HIV-affected Adolescents in Resource Constrained Settings Implementation Science Network (PATC3H-IN) (UG1/UM2) Program. The NICHD and partner NIH Institutes anticipate funding 8 PATC3H-IN UG1 awards in Asia and throughout sub-Saharan Africa in 2023 through a cooperative agreement mechanism for interventions of high public health significance: The prevention of new HIV infections among adolescents at risk, and the identification of, linkage to and retention in care of, and long-term viral suppression among youth living with HIV in low-to-middle income countries with high HIV burden. The PATC3H-IN network will expand and/or improve on successes achieved by its predecessor, PATC3H, to new geographic settings and/or risk populations and stimulate much needed implementation science (IS) research in the prevention of new HIV infections among adolescents at risk and the identification of, and linkage and retention to care of and long-term viral suppression among youth living with HIV in low-to-middle income countries (LMICs). PATC3H-IN will establish a network of investigators with multidisciplinary expertise on the youth-specific PHCC and in IS research, whose mission will be to evaluate promising prevention innovations contextually and developmentally tailored for HIV uninfected at-risk youth, and treatment and care interventions for youth living with HIV which have demonstrated efficacy and/or effectiveness in adolescent or adult populations and to translate them into public health practices. The structure of PATC3H-IN will consist of multiple interdependent functional components: (1) Five Clinical Research Centers (CRC) awarded through the UG1 grant mechanism; (2) one Implementation Science Coordinating Center (ISCC) to be awarded through a UM2 grant mechanism in 2024; and (3) a Scientific Leadership Committee (SLC). The CRCs will conduct clinical research and clinical trials, including implementation, effectiveness, and hybrid implementation-effectiveness studies at their 8-or more participating Clinical Research Performance Sites (CRPS). The ISCC will establish infrastructure to support research education and capacity building across PATC3H-IN, as well as infrastructure for stakeholder engagement in and dissemination of findings from PATC3H-IN and advanced statistical modeling support across PATC3H-IN. The ISCC will also provide infrastructure for conducting foundational research to support the work of clinical sites, including possible modeling studies and translation projects, as well as national surveys, and/or systematic collection and analysis of relevant policies and laws. Lastly, the SLC will be responsible for PATC3H-IN governance, oversight, and coordination, and will develop and implement the network research agenda, convening working groups as needed, prioritizing emerging research projects, efficiently managing the development of clinical protocols, implementing and completing clinical trials, and ensuring timely publication and communication of results.

I3-BC: Image-Based Infiltrating Immune Cell Detection and Outcomes in Breast Cancer Clinical Trials

PROJECT SUMMARY Tumor infiltrating lymphocytes (TILs) represent an accessible biomarker of the tumor-immune microenvironment (TIME) in breast cancer, demonstrating consistent association with response to neoadjuvant chemotherapy and outcomes in HER2-positive and triple-negative breast cancer. Despite efforts to standardize TIL enumeration from hematoxylin and eosin stained tumor slides, TILs have not gained widespread adoption due to inter- observer variability, and time limitations in pathologic assessment, among others. Further, other key elements of the microenvironment, such as tumor-associated macrophages (TAMs), do not yet have standardized approaches for quantification or characterization. As a result, there is no assessment of the TIME for the vast majority of breast cancers diagnosed in the US and around the world. However, the rapid growth of digital pathology offers the potential to leverage computational approaches to overcome these limitations and democratize access to TIL and TAM enumeration. The overall goal of this project is to determine if computational approaches to TILs (existing) and TAMs (to be developed within this grant) are comparable to pathologist- enumerated TILs and TAMs and, further, associated with relevant patient outcomes from two phase III breast cancer clinical trials. Prior to project initiation, we have developed both a compute-intensive artificial intelligence- based TILs approach, an open source software (QuPath)-based TILs approach, and expertise in RNAseq-based immune quantification. We will first focus on TILs - benchmarking the two computational and RNAseq immune approaches against pathologist TIL counts (‘gold standard’) then evaluating association of each with event-free survival in two completed clinical trials (Aim 1). In parallel, we will develop a novel computational approache to enumerate and phenotype TAMs by using immunohistochemical staining for macrophage markers on the same slide with standard H&E, then apply in the same two clinical trials (Aim 2). Our approach is innovative because we will benchmark diverse approaches at scale in relevant clinical studies. The study is significant because we will determine if computational approaches to TILs/TAMs align with pathologist estimates and clinical outcomes, then ensure these algorithms are available to the community. Our long-term goal is to democratize computational TIL and TAM enumeration as pathology decision-support to facilitate integration of accessible tumor-immune microenvironment into clinical trials and care.

Implementing a New Paradigm for Antifungal Drug Development

About 30% of the drugs currently in clinical use function through covalent modification of their target. Yet, until recently, none of these covalent drugs were specifically designed to utilize this irreversible mode of action. It is our hypothesis that the production of a new class of covalent inactivators, designed to selectively modify new drug targets, will lead to novel agents with efficacy against both native and drug-resistant pathogenic fungal species. Because of their novelty these agents will also offer a greater opportunity to bypass the existing mechanisms of drug resistance. Pathogenic fungal infections remain among the leading causes of human mortality, and this threat is rising due to the increasing prevalence of drug- resistance strains and the paucity of effective antifungal drugs against the more virulent fungal species. Our proposed new drug target is an enzyme that plays a critical role in a uniquely microbial pathway that is essential for the survival of fungal organisms. To test our hypothesis and achieve the goals of this project we plan to complete the following specific aims during the initial R21 phase of this project: (1) Optimization of the potency of novel enzyme inactivators. Our goals here are to use our strong preliminary results to address critical barriers that must be overcome to convert potent enzyme inactivators into advanced drug candidates, thereby achieving higher target selectivity and increasing compound reactivity once bound to the target; (2) Enhance the antifungal capability of these enzyme inactivators. Our strategy for this aim is focused on the incorporation of conjugate partners into this new class of covalent inactivators, enabling them to potentially utilize the existing nutrient uptake systems to achieve toxic levels in Candida species; (3) Examine the target selectivity of our new antifungal agents. Results from fungal growth inhibition and fungal killing assays will be used to evaluate and rank the efficacy of our compounds against both wild-type and drug-resistant Candida strains. Specific milestones are presented to evaluate our achievement of these initial aims. Once accomplished we will immediately proceed to the R33 phase of this project, with the aims of: (4) Pharmacological evaluation of lead candidates, though ranking the drug candidates based on their ADME, pharmacokinetic and toxicity properties; and then (5) Evaluate the efficacy of our candidates against pathogenic fungal infections. A systematic infection animal model will be utilized for candidate screening to identify the best agents against disseminated fungal infections, followed by further efficacy screening in an oral infection model. Completion of these aims will produce, refine and evaluate a new class of antifungal agents with a novel mode of action against an unexplored but essential fungal target. The agents with the most promising drug profiles will then be moved into advanced preclinical trials used to select the most effective new antifungal agents.

Pathogenic mechanisms of expanded ZFHX3 in SCA4 cerebellar organoids

Spinocerebellar ataxia type 4 (SCA4) is a disabling neurodegenerative disease characterized by progressive cerebellar ataxia, and the causative GGC-repeat expansion in ZFHX3 (ZHFX3-exp) was just discovered this year by our lab and others. Our research aims to understand how ZFHX3-exp causes SCA4 and to identify molecular therapeutic targets that can be quickly advanced into clinical trials. SCA4 is one of the four poly-glycine diseases that share the presence of neuronal intranuclear inclusion (NIIs) as a disease hallmark. In SCA4, NIIs are positive for ZFHX3, p62 and ubiquitin, indicating the loss of proteostasis as a mechanism of neurodegeneration. In addition, ZFHX3 RNA-gain-of-function may also contribute to neurodegeneration. Beyond this, knowledge of the disease mechanisms that underly SCA4 is extremely limited and there are currently no disease-modifying treatments for SCA4 or other polyG/NII diseases. There are no SCA4 mouse models and because of the high GC content in the repeat expansion complicates the production of SCA4 mouse models. We propose a novel approach to characterizing SCA4 Purkinje cell (PC) pathogenesis using human cerebellar organoids. Our approach allows for rapidly advancing the understanding of the pathogenesis and potential treatments of SCA4. Using cerebellar organoids will enable investigation on functional PCs, cerebellar neurodegeneration and the testing of potential therapeutic strategies. In aim 1, we will generate cerebellar organoids from five SCA4 patient-derived iPSC lines, and normal control iPSCs from individuals of the same family. These iPSC lines are already established in our laboratory. In aim 2, we will investigate PC viability, NII protein composition, proteostasis pathways, RNA gain-of-function and cell-type-specific dysregulated pathways by single nucleus RNA sequencing. In addition, we will study potential therapeutic targets by lentiviral knockdown and single nucleus RNA sequencing. SCA4 patient iPSCs express overabundant STAU1 and ATXN2. We will evaluate how lowering the abundance of these proteins modifies the PC molecular phenotype. Together, these experiments will establish a model to greatly enhance the understanding of human PC neurodegeneration, the pathological mechanisms of SCA4 and possible avenues of treatment.

Targeting subtype specification as a driver of PDAC health disparities

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is refractory to current treatment strategies due in part to adaptive mechanisms of chemoresistance. Racial health disparities also confound the treatment and care of these patients. Blacks (people with African genetic ancestry) have significantly higher incidence rates of PDAC and decreased survival times compared to Caucasians (White genetic ancestry) even after socioeconomic status and tumor stages are controlled. Therefore, it is possible different racial groups exhibit unique molecular characteristics in PDAC tumors that contribute to these health disparities. The unique molecular characteristics that distinguish PDAC tumors between racial groups exhibiting disparities have the potential to identify new therapeutic targets. In a previous study, we identified 4 distinct subtypes of PDAC (Metabolic, Progenitor-like, Proliferative, and Inflammatory) that can be distinguished using multivariate analysis of quantitative proteomic data. While these PDAC subtypes are predictive of therapeutic response, this has not yet been analyzed in disparity factor balanced studies. We have examined the proteomes of primary PDAC tumors using quantitative mass spectrometry and identified unique protein signatures for Blacks and Whites. PDAC tumors from Black patients display features consistent with the Inflammatory subtype of PDAC, which is characterized by an inflamed microenvironment expressing complement proteins that can promote resistance to chemotherapy. Therefore, it is possible that race influences subtype and Blacks could preferentially develop the more aggressive and treatment refractory Inflammatory subtype. Strategies are needed to modulate subtype to improve response to chemotherapy. Toward this goal, our proteomic analysis identified polycomb repressor complex 1 (PRC1) protein RNF2 as being upregulated in PDACs from Blacks compared to Whites. We have also discovered that RNF2 regulates mRNA expression of the PDAC subtype specification factor GATA6 and inhibiting RNF2 promotes a molecular shift toward the more chemosensitive Classical subtype of PDAC. Therapeutic targeting can be achieved with Tazemetostat that inhibits the upstream PRC2 to prevent RNF2 binding the GATA6 promoter leading to its increased expression. Additionally, the Inflammatory subtype characterized by innate immune complement protein activation could be targeted with another FDA approved drug, Avacopan, which has not previously been studied in PDAC. Therefore, the Specific Aims of this proposal are designed to: 1) Evaluate the extent to which Tazemetostat treatment impacts chemotherapy-induced subtype plasticity in patient derived organoids; and 2) To determine the extent to which strategies targeting pathways associated with PDAC disparities affect progression and subtype characteristics in vivo. The successful completion of these aims has the potential to be moved quickly into phase I clinical trials since both Tazemetostat and Avacopan are FDA approved drugs. Furthermore, if successful, this project has the potential to mitigate health disparities in PDAC and broadly improve patient outcomes by implementing new precision interventions. The mouse models we propose faithfully recapitulate pancreatic cancer's clinical syndrome, histopathology and molecular properties, including the often-unique features of the stromal and immune responses that constitute the complex desmoplasia of this disease, which cannot be addressed using in vitro model systems

Glycoengineering core a(1,3)-fucose motifs to enhance HIV-1 envelope vaccine immunogenicity

Project Summary The HIV-1 envelope glycoprotein (Env) is the sole target of neutralizing antibodies (NAbs). We previously developed a vaccine platform integrating three innovations: (1) the uncleaved prefusion-optimized (UFO) trimer design to stabilize Env; (2) multilayered single-component self-assembling protein nanoparticles (1c-SApNPs) for multivalent trimer display; and (3) enzymatic trimming of oligomannose glycans on CHO cell-produced Env immunogens. Glycan trimming substantially improved Env immunogenicity by enhancing tier 2 NAb elicitation, reducing off-target responses to immunodominant glycan sites, and increasing responder rates. These vaccine candidates are now in phase 1 clinical trials (NCT06541093; NCT06905275). Building on this foundation, we propose a novel strategy to enhance immunogenicity by incorporating core α(1,3)-fucose into HIV-1 Env. Core α(1,3)-fucose, a key allergenic epitope in many plant and insect glycoproteins, is highly immunogenic in humans and other mammals. Our central hypothesis is that the targeted introduction of core α(1,3)-fucose will convert the glycan shield from an immune-evasive barrier into an immunogenic trigger that promotes NAb induction. Glycoengineered cell lines expressing α(1,3)-fucose will enable production of highly immunogenic Env vaccines suitable for preclinical and clinical testing. Importantly, particulate display of these Env trimers on 1c-SApNPs can suppress IgE-mediated allergic pathways by inducing high-affinity protective IgGs, ensuring vaccine safety. Aim 1 will focus on producing core α(1,3)-fucosylated HIV-1 Env immunogens. We will begin by developing a transient insect cell expression system using BTI-TN-5B1-4 (“High Five” or Hi5) cells to produce Env with short paucimannose glycans bearing native α(1,3)-fucose. To further enhance α(1,3)-fucosylation, we will co-express exogenous core α(1,3)-fucosyltransferases in insect and CHO cells. We will validate glycan profiles and characterize the biochemical, biophysical, structural, and antigenic properties of the resulting immunogens. Aim 2 will assess the immunogenicity of these glycoengineered HIV-1 Env immunogens. Using our previously established glycan-trimmed Env immunogens as benchmarks, we will immunize mice, rabbits, and nonhuman primates (NHPs). Mice will be used for early-stage immunogen and adjuvant screening; rabbits to evaluate glycan hole-targeting NAb responses; and key vaccine formulations will advance to NHP studies. We will assess autologous and heterologous tier 2 NAb responses and vaccine responder rates. Aim 3 will elucidate the functional, structural, repertoire, and mechanistic basis of vaccine-induced immunity. We will isolate NAbs via Env-specific single-cell sorting and antibody cloning, map epitopes by electron microscopy (EM) and X-ray crystallography, perform next-generation sequencing (NGS) of B-cell repertoires, and trace NAb lineages. Finally, we will investigate antigen trafficking, retention, presentation, and germinal center (GC) reactions in lymph nodes. Together, these studies will define a new class of glycoengineered HIV-1 vaccines and establish core α(1,3)-fucose as a novel immunomodulatory tool to overcome glycan shield-mediated immune evasion.

Applied cognitive neuroscience to improve learning and therapeutics

Advancements in cognitive neuroscience have provided profound insights into the workings of the human brain and the methods used offer opportunities to enhance performance, cognition, and mental health. Drawing upon interdisciplinary collaborations in the University of California San Diego, Human Performance Optimization Lab, this talk explores the application of cognitive neuroscience principles in three domains to improve human performance and alleviate mental health challenges. The first section will discuss studies addressing the role of vision and oculomotor function in athletic performance and the potential to train these foundational abilities to improve performance and sports outcomes. The second domain considers the use of electrophysiological measurements of the brain and heart to detect, and possibly predict, errors in manual performance, as shown in a series of studies with surgeons as they perform robot-assisted surgery. Lastly, findings from clinical trials testing personalized interventional treatments for mood disorders will be discussed in which the temporal and spatial parameters of transcranial magnetic stimulation (TMS) are individualized to test if personalization improves treatment response and can be used as predictive biomarkers to guide treatment selection. Together, these translational studies use the measurement tools and constructs of cognitive neuroscience to improve human performance and well-being.

Attending to the ups and downs of Lewy body dementia: An exploration of cognitive fluctuations

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) share similarities in pathology and clinical presentation and come under the umbrella term of Lewy body dementias (LBD). Fluctuating cognition is a key symptom in LBD and manifests as altered levels of alertness and attention, with a marked difference between best and worst performance. Cognition and alertness can change over seconds or minutes to hours and days of obtundation. Cognitive fluctuations can have significant impacts on the quality of life of people with LBD as well as potentially contribute to the exacerbation of other transient symptoms including, for example, hallucinations and psychosis as well as making it difficult to measure cognitive effect size benefits in clinical trials of LBD. However, this significant symptom in LBD is poorly understood. In my presentation I will discuss the phenomenology of cognitive fluctuations, how we can measure it clinically and limitations of these approaches. I will then outline the work of our group and others which has been focussed on unpicking the aetiological basis of cognitive fluctuations in LBD using a variety of imaging approaches (e.g. SPECT, sMRI, fMRI and EEG). I will then briefly explore future research directions.

Fidelity and Replication: Modelling the Impact of Protocol Deviations on Effect Size

Cognitive science and cognitive neuroscience researchers have agreed that the replication of findings is important for establishing which ideas (or theories) are integral to the study of cognition across the lifespan. Recently, high-profile papers have called into question findings that were once thought to be unassailable. Much attention has been paid to how p-hacking, publication bias, and sample size are responsible for failed replications. However, much less attention has been paid to the fidelity by which researchers enact study protocols. Researchers conducting education or clinical trials are aware of the importance in fidelity – or the extent to which the protocols are delivered in the same way across participants. Nevertheless, this idea has not been applied to cognitive contexts. This seminar discusses factors that impact the replicability of findings alongside recent models suggesting that even small fidelity deviations have real impacts on the data collected.

Can we have jam today and jam tomorrow ?Improving outcomes for older people living with mental illness using applied and translational research

This talk will examine how approaches such as ‘big data’ and new ways of delivering clinical trials can improve current services for older people with mental illness (jam today) and identify and deliver new treatments in the future (jam tomorrow).

PET imaging in brain diseases

Talk 1. PET based biomarkers of treatment efficacy in temporal lobe epilepsy A critical aspect of drug development involves identifying robust biomarkers of treatment response for use as surrogate endpoints in clinical trials. However, these biomarkers also have the capacity to inform mechanisms of disease pathogenesis and therapeutic efficacy. In this webinar, Dr Bianca Jupp will report on a series of studies using the GABAA PET ligand, [18F]-Flumazenil, to establish biomarkers of treatment response to a novel therapeutic for temporal lobe epilepsy, identifying affinity at this receptor as a key predictor of treatment outcome. Dr Bianca Jupp is a Research Fellow in the Department of Neuroscience, Monash University and Lead PET/CT Scientist at the Alfred Research Alliance–Monash Biomedical Imaging facility. Her research focuses on neuroimaging and its capacity to inform the neurobiology underlying neurological and neuropsychiatric disorders. Talk 2. The development of a PET radiotracer for reparative microglia Imaging of neuroinflammation is currently hindered by the technical limitations associated with TSPO imaging. In this webinar, Dr Lucy Vivash will discuss the development of PET radiotracers that specifically image reparative microglia through targeting the receptor kinase MerTK. This includes medicinal chemistry design and testing, radiochemistry, and in vitro and in vivo testing of lead tracers. Dr Lucy Vivash is a Research Fellow in the Department of Neuroscience, Monash University. Her research focuses on the preclinical development and clinical translation of novel PET radiotracers for the imaging of neurodegenerative diseases.

Genetic-based brain machine interfaces for visual restoration

Visual restoration is certainly the greatest challenge for brain-machine interfaces with the high pixel number and high refreshing rate. In the recent year, we brought retinal prostheses and optogenetic therapy up to successful clinical trials. Concerning visual restoration at the cortical level, prostheses have shown efficacy for limited periods of time and limited pixel numbers. We are investigating the potential of sonogenetics to develop a non-contact brain machine interface allowing long-lasting activation of the visual cortex. The presentation will introduce our genetic-based brain machine interfaces for visual restoration at the retinal and cortical levels.

Multimodal imaging in Dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is a synucleinopathy but more than half of patients with DLB also have varying degrees of tau and amyloid-β co-pathology. Identifying and tracking the pathologic heterogeneity of DLB with multi-modal biomarkers is critical for the design of clinical trials that target each pathology early in the disease at a time when prevention or delaying the transition to dementia is possible. Furthermore, longitudinal evaluation of multi-modal biomarkers contributes to our understanding of the type and extent of the pathologic progression and serves to characterize the temporal emergence of the associated phenotypic expression. This talk will focus on the utility of multi-modal imaging in DLB.

Neural mechanisms of altered states of consciousness under psychedelics

Interest in psychedelic compounds is growing due to their remarkable potential for understanding altered neural states and their breakthrough status to treat various psychiatric disorders. However, there are major knowledge gaps regarding how psychedelics affect the brain. The Computational Neuroscience Laboratory at the Turner Institute for Brain and Mental Health, Monash University, uses multimodal neuroimaging to test hypotheses of the brain’s functional reorganisation under psychedelics, informed by the accounts of hierarchical predictive processing, using dynamic causal modelling (DCM). DCM is a generative modelling technique which allows to infer the directed connectivity among brain regions using functional brain imaging measurements. In this webinar, Associate Professor Adeel Razi and PhD candidate Devon Stoliker will showcase a series of previous and new findings of how changes to synaptic mechanisms, under the control of serotonin receptors, across the brain hierarchy influence sensory and associative brain connectivity. Understanding these neural mechanisms of subjective and therapeutic effects of psychedelics is critical for rational development of novel treatments and for the design and success of future clinical trials. Associate Professor Adeel Razi is a NHMRC Investigator Fellow and CIFAR Azrieli Global Scholar at the Turner Institute of Brain and Mental Health, Monash University. He performs cross-disciplinary research combining engineering, physics, and machine-learning. Devon Stoliker is a PhD candidate at the Turner Institute for Brain and Mental Health, Monash University. His interest in consciousness and psychiatry has led him to investigate the neural mechanisms of classic psychedelic effects in the brain.

Psychological mechanisms and functions of 5-HT and SSRIs in potential therapeutic change: Lessons from the serotonergic modulation of action selection, learning, affect, and social cognition

Uncertainty regarding which psychological mechanisms are fundamental in mediating SSRI treatment outcomes and wide-ranging variability in their efficacy has raised more questions than it has solved. Since subjective mood states are an abstract scientific construct, only available through self-report in humans, and likely involving input from multiple top-down and bottom-up signals, it has been difficult to model at what level SSRIs interact with this process. Converging translational evidence indicates a role for serotonin in modulating context-dependent parameters of action selection, affect, and social cognition; and concurrently supporting learning mechanisms, which promote adaptability and behavioural flexibility. We examine the theoretical basis, ecological validity, and interaction of these constructs and how they may or may not exert a clinical benefit. Specifically, we bridge crucial gaps between disparate lines of research, particularly findings from animal models and human clinical trials, which often seem to present irreconcilable differences. In determining how SSRIs exert their effects, our approach examines the endogenous functions of 5-HT neurons, how 5-HT manipulations affect behaviour in different contexts, and how their therapeutic effects may be exerted in humans – which may illuminate issues of translational models, hierarchical mechanisms, idiographic variables, and social cognition.

Hughlings Jackson Lecture: Making Progress in Progressive MS – the Ultimate Challenge!

On April 22, 2021, Dr. Alan J Thompson of the University College London and the UCL Institute of Neurology, London, UK will deliver the Hughlings Jackson Lecture entitled, “Making Progress in Progressive MS – the Ultimate Challenge!” Established in 1935, the Hughlings Jackson Lecture is The Neuro’s premier scientific lecture. It honors the legacy of British neurologist John Hughlings Jackson (1835-1911) who pioneered the development of neurology as a medical specialty. Talk Abstract : The international focus on progressive MS, driven by the Progressive MS Alliance amongst others, together with recent encouraging results from clinical trials have raised the profile and emphasised the importance of understanding, treating and ultimately preventing progression in MS. Effective treatment for Progressive MS is now regarded as the single most important issue facing the MS community. There are several important challenges to developing new treatments for progressive MS. Fundamental to any development in treatment is a better understanding of the mechanisms of tissue injury underpinning progression which will in turn allow the identification of new targets against which treatments can be directed. There are additional complications in determining when progression actually starts, determining the impact of aging and defining the progressive clinical phenotypes – an area which has become increasingly complex in recent months. Evaluating potential new treatments in progressive MS also poses particular challenges including trial design and the selection of appropriate clinical and imaging outcomes - in particular, identifying an imaging biomarker for phase II trials of progressive MS. Despite these challenges, considerable progress is being made in developing new treatments targeting the innate immune system and exploring neuroprotective strategies. Further advances are being driven by a number of international networks, funded by the Progressive MS Alliance. Overall we are seeing encouraging progress as a result of co-ordinated global collaboration which offers real possibilities for truly effective treatment of progression.

Gene Therapy for Neurodegeneration

One of the major challenges in developing therapeutics for the neurodegenerative disorders is the blood-brain barrier, limiting the availability of systemically administered therapies such as recombinant proteins or monoclonal antibodies from reaching the brain. Direct central nervous system (CNS) gene therapy using adeno-associated virus vectors expressing a therapeutic protein, monoclonal antibody or inhibiting RNA-coding sequences has two characteristics ideal for therapy of neurodegenerative disorders: circumventing the blood-brain barrier by directly expressing the therapy in the brain and the ability to provide persistent therapy with only a single administration. There are several critical parameters relevant to successful CNS gene therapy, including choice of vector, design of the gene to be expressed, delivery/route of administration, dose and anti-vector immune responses. The presentation will focus on these issues, the current status of clinical trials of gene therapy for neurodegeneration and specific challenges that will need to be overcome to ensure the success of these therapies.

Cognition, behaviour and clinical trials in SYNGAP1

Multimodal brain imaging to predict progression of Alzheimer’s disease

Cross-sectional and longitudinal multimodal brain imaging studies using positron emission tomography (PET) and magnetic resonance imaging (MRI) have provided detailed insight into the pathophysiological progression of Alzheimer’s disease. It starts at an asymptomatic stage with widespread gradual accumulation of beta-amyloid and spread of pathological tau deposits. Subsequently changes of functional connectivity and glucose metabolism associated with mild cognitive impairment and brain atrophy may develop. However, the rate of progression to a symptomatic stage and ultimately dementia varies considerably between individuals. Mathematical models have been developed to describe disease progression, which may be used to identify markers that determine the current stage and likely rate of progression. Both are very important to improve the efficacy of clinical trials. In this lecture, I will provide an overview on current research and future perspectives in this area.

Biomarkers for Addiction Treatment Development: fMRI Drug Cue Reactivity as an Example

This webinar is mainly focused on “Biomarkers for Addiction Treatment Development: fMRI Drug Cue Reactivity as an Example”. Biomarkers and Biotypes of Drug Addiction: funding opportunities at NIDA, Tanya Ramey (NIDA, US) Neuroimaging-based Biomarker Development for Clinical Trials, Owen Carmicheal (Pennington Biomedical Research Center, USA) ENIGMA-Addiction Cue Reactivity Initiative (ACRI) and Checklist, Hamed Ekhtiari (Laureate Institute for Brain Research, USA) ENIGMA-ACRI Checklist: Participant Characteristics, General fMRI Information, General Task Information, Cue Information, Task-related Assessments, Pre-Post Scanning Consideration (James Prisciandaro, Medical University of South Carolina, USA; Marc Kaufman, McLean Hospital/Harvard Medical School, USA; Anna Zilverstand, University of Minnesota; Torsten Wüstenberg, Charité Medical University Berlin, Germany; Falk Kiefer, University of Heidelberg, Germany; Amy Janes, Harvard Medical School, USA) How to Add fMRI Drug Cue Reactivity to the ENIGMA Consortium: Road Ahead, Hugh Garavan, University of Vermont)