2018 Pilot Projects

Description

Degeneration of the light-sensing photoreceptor cells in the human retina is a common cause of blindness worldwide. There are two types of photoreceptor in the eye: rods which are active in dim light and cones which are active in bright light. Photoreceptor degeneration is often caused by mutations in genes that are specifically turned on in rods. In this proposal, we seek to develop a novel therapy to prevent rod photoreceptor degeneration caused by mutations in rod genes. Our strategy relies on genetic ‘reprogramming’ of rod photoreceptors into cells with features of both rods and cones. Prior studies suggest that by reprogramming the rods in this way, it may be possible to forestall the progression of photoreceptor degeneration. If our studies are successful, they will pave the way for future reprogramming-based therapies in human patients with blindness.

Updated April 2021

Description

Chemotherapy-induced peripheral neuropathy is the most prevalent dose-limiting toxicity caused by anti-cancer therapy and can cause permanent disability. Most chemotherapy-induced neuropathies are characterized by early nerve fiber breakdown (axonal degeneration). We developed a gene therapy strategy in mice that potently blocks axonal degeneration. To translate its benefit to the clinic, we need a means to identify patients most at risk of developing a chemotherapy-induced peripheral neuropathy and, thus, most likely to benefit from axon-protective therapy. Neurofilament light chain is a major scaffolding protein that is released by damaged axons and is a sensitive biomarker in chronic neurodegenerative diseases. In this proposal, we combine experiments in mice and evaluation of blood samples from patients treated with a high dose of the chemotherapeutic agent vincristine to determine if serum Neurofilament light chain levels can be used as a i) biomarker for acute axonal degeneration and ii) predictor of severe and/or chronic neuropathy. If successful, this study will promote future axon protective trials by objectively identifying patients most likely to benefit from axon protective therapy and provide an outcome measure for assessment of the effectiveness of the axon protective agent.

Updated April 2021

Description

Alzheimer’s disease is the most common neurodegenerative disease; however, there are currently no effective means of prevention or treatment. Human genetic and animal models have recently implicated the TREM2 gene in microglial function and in AD pathogenesis. In this proposal, we will study the mechanism by which a novel regulator of TREM2 influences AD risk using molecular and biochemical approaches in stem cell models. The results of this project will provide the mechanistic framework needed to develop treatments that restore or enhance TREM2 functions in order to prevent neurodegenerative disease.

Grants and Awards

“Brain Single-nuclei and iPS-derived cells transcriptomic analysis to define the contribution of neuronal and glial pathw”
NIH/NIA 1R56AG067764 (PI, Harari)
Public Health Relevance Statement, NARRATIVE: Alzheimer’s disease (AD) is the most common neurodegenerative disease, but currently there is no effective means of prevention or treatment. Genetic mutations and risk variants provide support to the amyloid cascade hypothesis, cholesterol metabolism and immune response in the etiology of AD. In this project, we will generate a detailed molecular atlas of AD brains carriers of pathogenic mutations, risk variants, non-carrier AD, and neuropath-free controls to determine the specific pathways and molecular networks disrupted in the distinct brain cell-types that lead to AD.

“Defining the Mechanisms by Which MS4A Genes Regulate TREM2 in Alzheimer Disease”
NIH/NIA 1R01AG062734 (PI, Karch)
Public Health Relevance Statement, Narrative: Alzheimer’s disease is the most common neurodegenerative disease; however, there are currently no effective means of prevention or treatment. Human genetic and animal models have recently implicated the TREM2 gene in microglial function and in AD pathogenesis. In this proposal, we will study the mechanism by which a novel regulator of TREM2 influences AD risk using human genomic and stem cell approaches.

“Molecular Mechanisms of the Central Regulator of TREM2 Dysfunction”
Chan Zuckerberg Initiative Neurodegeneration Challenge Network

“Novel MS4A4A-Targeting Therapeutics for Alzheimer’s Disease” (page 4)
Edward N. and Della L. Thome Memorial Foundation Awards Program in Alzheimer’s Disease Drug Discovery Research

Updated April 2021

Description

Glioblastoma, the most common primary malignant brain tumor in adults, remains a challenging disease with no current cure. A main reason for our lack of significant progress in this cancer is the profound heterogeneity of these tumors—among tumors in different patients and even among cancer cells in an individual patient. We are particularly interested in an important subpopulation of glioblastoma cells called tumor-initiating cells (also cancer stem cells), which are found in all glioblastoma tumors and are thought to drive tumor growth and treatment resistance. In this project, using gene-editing techniques and human neural stem cells, we will model the major genetic subtypes of glioblastoma and identify how specific gene mutations give rise to tumor-initiating cells. In this manner, we will be able to understand the major differences and common features among the different genetic subtypes of human GBM. The long-term goal of this project is to develop individualized therapeutic strategies based on tumor genetics, which will potentially lead to novel, durable treatments for glioblastoma patients.

Description

Amyotrophic lateral sclerosis (ALS) is an invariably fatal neurodegenerative disease with no effective treatments for the symptoms or therapies that modify the disease course. In this study, we will be using Medicare Part D medication data obtained from the Centers for Medicare and Medicaid to identify prescription medications associated with a lower risk of developing ALS. Within those medications associated with a lower risk of ALS, we will prioritize the top candidates and test these medications in an ALS mouse model system. This innovative proposal represents a new collaboration between two highly experienced Washington University School of Medicine researchers with unique but complementary expertise. The ultimate goal of this project is to identify prescription medications that can be repurposed to modify the disease course for this catastrophic neurodegenerative disease.

Publications

Camacho-Soto A, Searles Nielsen S, Faust IM, Bucelli RC, Miller TM, Racette BA. Incidence of amyotrophic lateral sclerosis in older adults (2022) Muscle and Nerve

Kreple CJ, Searles Nielsen S, Schoch KM, Shen T, Shabsovich M, Song Y, Racette BA, Miller TM. Protective effects of lovastatin in a population-based ALS study and mouse model. (2023, Jan 10) Annals of Neurology.

Updated January 2023