A5079915918- RNA Research and Splicing
- Prion Diseases and Protein Misfolding
- RNA regulation and disease
- Single-cell and spatial transcriptomics
- Advanced Fluorescence Microscopy Techniques
- Trace Elements in Health
- Genetic Neurodegenerative Diseases
- Nuclear Structure and Function
- Neurological diseases and metabolism
- Neuroscience and Neuropharmacology Research
- Hereditary Neurological Disorders
- Barrier Structure and Function Studies
- Cellular transport and secretion
- Axon Guidance and Neuronal Signaling
- Advanced Neuroimaging Techniques and Applications
- Advanced Electron Microscopy Techniques and Applications
- Photosynthetic Processes and Mechanisms
- RNA Interference and Gene Delivery
Broad Institute
2021-2024
Massachusetts General Hospital
2023-2024
Center for Pain and the Brain
2023
Yale University
2022
Abstract Antisense oligonucleotides (ASOs) dosed into cerebrospinal fluid (CSF) distribute broadly throughout the central nervous system (CNS). By modulating RNA, they hold promise of targeting root molecular causes disease and potential to treat myriad CNS disorders. Realization this requires that ASOs must be active in disease-relevant cells, ideally, monitorable biomarkers also reflect ASO activity these cells. The biodistribution such centrally delivered have been deeply characterized...
Summary Understanding the molecular anatomy and neural connectivity of brain requires imaging technologies that can map 3D nanoscale distribution specific proteins in context ultrastructure. Light electron microscopy (EM) enable visualization either labels or anatomical ultrastructure, but combining specificity with is challenging. Here, we present pan-Expansion Microscopy tissue (pan-ExM-t), an all-optical mouse method combines ∼24-fold linear expansion biological samples fluorescent...
Prion protein (PrP) concentration controls the kinetics of prion replication and is a genetically pharmacologically validated therapeutic target for disease. In order to evaluate PrP as pharmacodynamic biomarker assess its contribution known disease risk factors, we developed plate-based immunoassay reactive across 6 species interest applicable brain cerebrospinal fluid (CSF). varied dramatically different regions in mice, cynomolgus macaques, humans. expression did not appear contribute...
Abstract Neurofilament light (NfL) concentration in cerebrospinal fluid (CSF) and blood serves as an important biomarker neurology drug development. Changes NfL are generally assumed to reflect changes neuronal damage, while little is known about the clearance of from biofluids. We observed increase 3.5-fold plasma 5.7-fold CSF asymptomatic individual at risk for genetic prion disease following 6 weeks’ treatment with oral minocycline a dermatologic indication. Other biomarkers remained...
Pharmacologic lowering of PrP expression is efficacious against prion disease in animal models and now being tested clinically. 50% increases both survival time healthy life prion-infected mice, but does not prevent symptom onset nor halt progression. Additional drug candidates should seek to reduce even lower levels. Divalent siRNA a novel oligonucleotide modality with promising potency, durability, biodistribution data preclinical models, inspiring us this technology new candidate for...
Antisense oligonucleotides (ASOs) dosed into cerebrospinal fluid (CSF) distribute broadly throughout the brain and hold promise of treating myriad diseases by modulating RNA. CNS tissue is not routinely biopsied in living individuals, leading to reliance on CSF biomarkers inform drug target engagement. Animal models can link parenchyma, but our understanding how individual cells contribute bulk signal limited. Here we employed single nucleus transcriptomics from mice treated with RNase H1...
Abstract Lowering expression of prion protein (PrP) is a well-validated therapeutic strategy in disease, but additional modalities are urgently needed. In other diseases, small molecules have proven capable modulating pre-mRNA splicing, sometimes by forcing inclusion cryptic exons that reduce gene expression. Here, we characterize exon located human PRNP ’s sole intron and evaluate its potential to PrP through incorporation into the 5’ untranslated region (5’UTR). This homologous 2...
Abstract Prion protein (PrP) concentration controls the kinetics of prion replication and is a genetically pharmacologically validated therapeutic target for disease. In order to evaluate PrP as pharmacodynamic biomarker assess its contribution known disease risk factors, we developed plate-based immunoassay reactive across six species interest applicable brain cerebrospinal fluid (CSF). varies dramatically between different regions in mice, cynomolgus macaques, humans. expression does not...