A5102728961- Alzheimer's disease research and treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Endoplasmic Reticulum Stress and Disease
- RNA regulation and disease
- Genetic factors in colorectal cancer
- Tryptophan and brain disorders
- Cellular transport and secretion
- Inflammation biomarkers and pathways
- Occupational and environmental lung diseases
- Cancer Genomics and Diagnostics
- Glycosylation and Glycoproteins Research
- RNA Interference and Gene Delivery
- RNA Research and Splicing
- Genomics, phytochemicals, and oxidative stress
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- DNA and Nucleic Acid Chemistry
- Nanoparticle-Based Drug Delivery
- Ubiquitin and proteasome pathways
- Peroxisome Proliferator-Activated Receptors
- Viral Infectious Diseases and Gene Expression in Insects
- NF-κB Signaling Pathways
- Advanced biosensing and bioanalysis techniques
- Neurogenetic and Muscular Disorders Research
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Sirtuins and Resveratrol in Medicine
Denali Therapeutics (United States)
2020-2025
Kaiser Permanente South San Francisco Medical Center
2023
Genentech
2014
Harlem Hospital Center
2003
San Francisco General Hospital
2003
Exomes, transcriptomes and copy-number alterations in a sample of more than 70 primary human colonic tumours were analysed an attempt to characterize the genomic landscape; addition finding genes associated with commonly mutated signalling pathways, recurrent gene fusions involving R-spondin family members also found occur approximately 10% tumours, revealing potential new therapeutic target. An analysis exomes, colon matched normal controls has identified 35,000 protein-altering somatic...
<h3>Background</h3> There is microscopic spatial and temporal heterogeneity of pathological changes in idiopathic pulmonary fibrosis (IPF) lung tissue, which may relate to pathophysiological mediators disease clinical progression. We assessed relationships between gene expression patterns, features, systemic biomarkers identify that reflect the aggregate burden patients with IPF. <h3>Methods</h3> Gene microarrays (N=40 IPF; 8 controls) immunohistochemical analyses (N=22 biopsies. Clinical...
An enzyme transport vehicle enables brain delivery of lysosomal enzymes across the blood-brain barrier in mice.
Abstract Loss-of-function variants of TREM2 are associated with increased risk Alzheimer’s disease (AD), suggesting that activation this innate immune receptor may be a useful therapeutic strategy. Here we describe high-affinity human TREM2-activating antibody engineered monovalent transferrin (TfR) binding site, termed transport vehicle (ATV), to facilitate blood–brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced...
Genetic mutations underlying familial Alzheimer's disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression mutated transgenes have yielded key insights mechanisms disease, those are subject to artifacts, including random genetic integration transgene, ectopic expression and non-physiological protein levels. The engineering novel using knock-in approaches addresses some limitations. With...
Antisense oligonucleotides (ASOs) are promising therapeutics for treating various neurological disorders. However, ASOs unable to readily cross the mammalian blood-brain barrier (BBB) and therefore need be delivered intrathecally central nervous system (CNS). Here, we engineered a human transferrin receptor 1 (TfR1) binding molecule, oligonucleotide transport vehicle (OTV), tool ASO across BBB in TfR knockin (TfR mu/hu KI) mice nonhuman primates. Intravenous injection systemic delivery of...
While apolipoprotein E (APOE) is the strongest genetic modifier for late-onset Alzheimer's disease (LOAD), molecular mechanisms underlying isoform-dependent risk and relevance of ApoE-associated lipids remain elusive. Here, we report that impaired low-density lipoprotein (LDL) receptor (LDLR) binding lipidated ApoE2 (lipApoE2) avoids LDLR recycling defects observed with lipApoE3/E4 decreases uptake cholesteryl esters (CEs), which are linked to neurodegeneration. In human neurons, addition...
Blood brain barrier-crossing molecules targeting transferrin receptor (TfR) and CD98 heavy chain (CD98hc) are widely reported to promote enhanced delivery of therapeutics. Here, we provide a comprehensive unbiased biodistribution characterization TfR CD98hc antibody transport vehicles (ATVTfR ATVCD98hc) compared control IgG. Mouse whole-body tissue clearing reveals distinct organ localization for each molecule. In the brain, ATVTfR ATVCD98hc achieve exposure parenchymal distribution even...
A recent study identified the ADAM33 gene as a promising candidate contributing to asthma. In Puerto Rican and Mexican populations, we have genotyped six single nucleotide polymorphisms (SNPs) that were used in Genetics of Asthma Latino Americans Study. We chose these two populations because United States, Ricans highest asthma prevalence, morbidity, mortality Mexicans lowest. transmission disequilibrium test analyze associations between variants asthma, severity, bronchodilator...
Abstract Many subtypes of cortical interneurons (CINs) are found in adult mouse cortices, but the mechanism generating their diversity remains elusive. We performed single-cell RNA sequencing on embryonic medial ganglionic eminence (MGE), major birthplace for CINs, and MGE-like cells differentiated from stem cells. Two distinct cell types were identified as proliferating neural progenitors immature neurons, both which comprised sub-populations. Although lineage development MGE was...
Gastric cancer is the second leading cause of worldwide mortality, yet underlying genomic alterations remain poorly understood. Here we perform exome and transcriptome sequencing SNP array assays to characterize 51 primary gastric tumours 32 cell lines. Meta-analysis data previously published sets reveals 24 significantly mutated genes in microsatellite stable (MSS) 16 instable (MSI) tumours. Over half patients our collection could potentially benefit from targeted therapies. We identify 55...
Abstract Antisense oligonucleotides (ASO) are promising therapies for neurological disorders, though they unable to cross the blood-brain barrier (BBB) and must be delivered directly central nervous system (CNS). Here, we use a human transferrin receptor (TfR)-binding molecule transport ASO across BBB in mice non-human primates, termed oligonucleotide vehicle (OTV). Systemically OTV drives significant, cumulative, sustained knockdown of target multiple CNS regions all major cell types....
Abstract IL-13 can bind to two distinct receptors: a heterodimer of IL-13Rα1/IL-4Rα and IL-13Rα2. Whereas engagement by leads the activation STAT6, molecular events triggered binding IL-13Rα2 remain incompletely understood. IL-4 signal through complex but does not interact with Idiopathic pulmonary fibrosis is progressive generally fatal parenchymal lung disease unknown etiology no current pharmacologic treatment options that substantially prolong survival. Preclinical models fibrotic...
A small-molecule inhibitor of the kinase TPL2 shows efficacy in rodent models inflammation.
Abstract The Alzheimer’s disease (AD) human genetic landscape indicates microglia are an important cell type in the brain that modifies risk. A common loss-of-functon(LOF) coding variant paired immunoglobulin-like 2 receptor alpha (PILRA) is associated with reduced risk of AD, however mechanisms underlying this protective effect poorly defined. Here we identify biological functions PILRA, immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor, iPSC-derived and chimeric...
<title>Abstract</title> The Alzheimer’s disease (AD) genetic landscape identified microglia as a key disease-modifying cell type. A known AD protective variant in paired immunoglobulin-like type 2 receptor alpha (PILRA), shown to reduce risk APOE4 carriers, is enriched cohort of healthy centenarians; however, mechanisms underlying effects are undefined. Here we identify biological functions PILRA, an ITIM-domain containing receptor, human iPSC-derived (iMG) and chimeric mice....
Microglia are implicated in modifying neurodegenerative disease risk the central nervous system (CNS). GPR34 is a microglia-enriched G-protein coupled receptor that detects cytotoxic lipids upregulated Alzheimers Disease (AD). Since dysregulated lipid metabolism occurs disease, we hypothesized could act with other sensors, such as TREM2, to regulate microglial function. Here, report knockout (KO) rescues cholesterol TREM2 KO iPSC-derived microglia (iMG) and alone promotes fatty acid...
Abstract Anti-amyloid β-peptide (Aβ) immunotherapy was developed to reduce amyloid plaque pathology and slow cognitive decline during progression of Alzheimer’s disease. Efficient clearance has been proven in clinical trials testing anti-Aβ antibodies, with the impact on endpoints correlating extent removal. However, treatment is associated adverse side-effects, such as oedema haemorrhages, which are potentially linked induced immune response. To improve safety profile these molecules, it...
The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that activated to multiple sources of cellular stress. Although acute activation this restores homeostasis, intense or prolonged ISR perturbs cell function and may contribute neurodegeneration. DNL343 an investigational CNS-penetrant small molecule inhibitor designed activate the initiation factor 2B (eIF2B) suppress aberrant activation. reduced CNS activity neurodegeneration dose-dependent manner two established...
The blood-brain barrier (BBB) poses a significant challenge drug delivery to the brain. BBB-crossing molecules are emerging as new class of therapeutics with potential for central nervous system (CNS) indications. In particular, transferrin receptor (TfR)- and CD98 heavy chain (CD98hc)-targeting have been demonstrated cross BBB enhanced brain delivery. Previously, we reported TfR CD98hc antibody transport vehicles (ATVTfR ATVCD98hc) that utilize these receptors improve CNS delivery1,2. Here,...
The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that activated to multiple sources of cellular stress. Although acute activation this restores homeostasis, intense or prolonged ISR perturbs cell function and may contribute neurodegeneration. DNL343 an investigational CNS-penetrant small-molecule inhibitor designed activate the initiation factor 2B (eIF2B) suppress aberrant activation. reduced CNS activity neurodegeneration dose-dependent manner two established...
ABSTRACT The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that activated to multiple sources of cellular stress. Although acute activation this restores homeostasis, intense or prolonged ISR perturbs cell function and may contribute neurodegeneration. DNL343 an investigational CNS-penetrant small molecule inhibitor designed activate the initiation factor 2B (eIF2B) suppress aberrant activation. reduced CNS activity neurodegeneration dose-dependent manner two...