A5091832390- RNA Research and Splicing
- Alzheimer's disease research and treatments
- Neurogenetic and Muscular Disorders Research
- RNA modifications and cancer
- Parkinson's Disease Mechanisms and Treatments
- Dementia and Cognitive Impairment Research
- X-ray Diffraction in Crystallography
- Axon Guidance and Neuronal Signaling
- Nerve injury and regeneration
- Crystallization and Solubility Studies
- Neurogenesis and neuroplasticity mechanisms
- Amyotrophic Lateral Sclerosis Research
- RNA Interference and Gene Delivery
- RNA and protein synthesis mechanisms
- Genetic Neurodegenerative Diseases
- CRISPR and Genetic Engineering
- Sphingolipid Metabolism and Signaling
- Developmental Biology and Gene Regulation
- Cholesterol and Lipid Metabolism
- Neuroinflammation and Neurodegeneration Mechanisms
- Peroxisome Proliferator-Activated Receptors
- Endoplasmic Reticulum Stress and Disease
- Amino Acid Enzymes and Metabolism
- Wnt/β-catenin signaling in development and cancer
- Muscle Physiology and Disorders
Novartis (Switzerland)
2007-2024
Novartis Institutes for BioMedical Research
2024
University of California, San Francisco
2020-2024
Novartis (United States)
2015-2023
University College London
2020-2021
Biomedical Research Institute
2020
Universitat Autònoma de Barcelona
2020
University of Gothenburg
2020
Hospital de Sant Pau
2020
University of California, Los Angeles
2020
Huntington's Disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the huntingtin (HTT) gene. The mutant HTT (mHTT) protein causes neuronal dysfunction, causing motor, cognitive and behavioral abnormalities. Current treatments for HD only alleviate symptoms, but cerebral spinal fluid (CSF) or central nervous system (CNS) delivery antisense oligonucleotides (ASOs) virus vectors expressing RNA-induced silencing (RNAi) moieties...
Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA caused by deletion or loss function mutation survival motor neuron 1 (SMN1) gene. In humans, second closely related gene SMN2 exists; however it codes for less stable SMN protein. recent years, significant progress has been made toward disease modifying treatments modulating pre-mRNA splicing. Herein, we describe discovery LMI070/branaplam, small molecule that...
The release of paused RNA polymerase II into productive elongation is highly regulated, especially at genes that affect human development and disease. To exert control over this rate-limiting step, we designed sequence-specific synthetic transcription factors (Syn-TEFs). These molecules are composed programmable DNA-binding ligands flexibly tethered to a small molecule engages the machinery. By limiting activity targeted loci, Syn-TEFs convert constituent modules from broad-spectrum...
To test the hypothesis that plasma total tau (t-tau) and neurofilament light chain (NfL) concentrations may have a differential role in study of frontotemporal lobar degeneration syndromes (FTLD-S) clinically diagnosed Alzheimer disease (AD-S), we determined their diagnostic prognostic value FTLD-S AD-S sensitivity to pathologic diagnoses.We measured t-tau NfL with Simoa platform 265 participants: 167 FTLD-S, 43 AD-S, 55 healthy controls (HC), including 82 pathology-proven cases (50...
We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk disease progression.Baseline NfL concentrations were measured with single-molecule array in original (n = 277) and validation 297) cohorts. C9orf72, GRN, MAPT mutation noncarriers from same families classified by severity (asymptomatic, prodromal, full phenotype) using CDR Dementia Staging Instrument plus behavior...
Abstract Sphingosine‐1‐phosphate (S1P) receptors are widely expressed in the central nervous system where they thought to regulate glia cell function. The phosphorylated version of fingolimod/FTY720 (FTY720P) is active on a broad spectrum S1P and parent compound currently phase III clinical trials for treatment multiple sclerosis. Here, we aimed identify which type(s) receptor(s) targeted by FTY720P. Using calcium imaging mixed cultures from embryonic rat cortex show that astrocytes major...
Identification of fluid biomarkers for progressive supranuclear palsy (PSP) is critical to enhance therapeutic development. We implemented unbiased DNA aptamer (SOMAmer) proteomics identify novel CSF PSP biomarkers.
Significance Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is a devastating neurodegenerative disease caused by reduced levels Survival Motor Neuron (SMN) gene activity. Despite well-characterized aspects involvement SMN in small nuclear ribonucleoprotein biogenesis, circuitry affecting activity remains obscure. Here, we use Drosophila as model system to integrate results from large-scale and proteomic studies bioinformatic analyses define unique interactome...
Lipid metabolism in mammals is orchestrated by a family of transcription factors called sterol regulatory element-binding proteins (SREBPs) that control the expression genes required for uptake and synthesis cholesterol, fatty acids, triglycerides. SREBPs are thus essential insulin-induced lipogenesis cellular membrane homeostasis biogenesis. Although multiple players have been identified activation SREBPs, gaps remain our understanding how coordinated with other physiological pathways.To...
Abstract The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. We leveraged aptamer-based proteomics (> 4,000 proteins) to identify dysregulated communities co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations ( C9orf72 , GRN MAPT ) compared 39 noncarrier controls. Network analysis identified 31 protein co-expression modules. Proteomic...
Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by low levels of functional survival motor neuron protein (SMN) resulting from deletion or loss function mutation the 1 (SMN1) gene. Branaplam (1) elevates full-length SMN in vivo modulating splicing related gene SMN2 to enhance exon-7 inclusion and increase SMN. The intramolecular hydrogen bond present 2-hydroxyphenyl pyridazine core enforces planar conformation biaryl system critical for compound activity....
Abstract The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related factors that demonstrate ‘pro-aging’ or ‘pro-youthful’ effects on the mouse brain. clinical relevance and combined of these humans unclear. We examined five previously identified brain rejuvenation in cerebrospinal fluid adults with autosomal dominant forms frontotemporal sporadic Alzheimer’s disease. Our cohort included 100 observationally followed carrying mutations (Mage =...
ABSTRACT Branaplam is a therapeutic agent currently in clinical development for the treatment of infants with type 1 spinal muscular atrophy (SMA). Since preclinical studies showed that branaplam had cell-cycle arrest effects, we sought to determine whether may affect postnatal cerebellar and brain neurogenesis. Here, describe novel approach developmental neurotoxicity testing (DNT) central nervous system (CNS) active drug. The effects orally administered were evaluated SMA neonatal mouse...