A5055778690- Circadian rhythm and melatonin
- Photoreceptor and optogenetics research
- Retinal Development and Disorders
- RNA Interference and Gene Delivery
- Drug Transport and Resistance Mechanisms
- Nanoparticle-Based Drug Delivery
- Barrier Structure and Function Studies
- Radiopharmaceutical Chemistry and Applications
- Sleep and Wakefulness Research
- Monoclonal and Polyclonal Antibodies Research
- DNA and Nucleic Acid Chemistry
- Click Chemistry and Applications
- Adenosine and Purinergic Signaling
- Glaucoma and retinal disorders
- Neuroinflammation and Neurodegeneration Mechanisms
- RNA Research and Splicing
- Cellular transport and secretion
- Light effects on plants
- Neuropeptides and Animal Physiology
- Epigenetics and DNA Methylation
- Receptor Mechanisms and Signaling
- Glycosylation and Glycoproteins Research
- Corneal Surgery and Treatments
- Amino Acid Enzymes and Metabolism
- Chemical Synthesis and Analysis
Denali Therapeutics (United States)
2020-2025
Kaiser Permanente South San Francisco Medical Center
2023
Stanford University
2017-2022
Johns Hopkins University
2010-2017
Engineering human IgG1 Fc binding to a brain endothelial cell–enriched receptor allows enhanced exposure of biotherapeutics in multiple species.
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...
Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs, with five subtypes named M1–M5) are a unique subclass of RGCs axons that project directly to many brain nuclei involved in non-image-forming functions such as circadian photoentrainment and the pupillary light reflex. Recent evidence suggests melanopsin-based signals also influence image-forming visual function, including adaptation, but mechanisms unclear. Intriguingly, small population M1 ipRGCs have...
Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report engineering and characterization a BBB transport vehicle targeting CD98 heavy chain (CD98hc or SLC3A2) heterodimeric amino acid transporters (TVCD98hc). The pharmacokinetic biodistribution properties CD98hc antibody (ATVCD98hc) are assessed in humanized knock-in mice cynomolgus monkeys. Compared to most existing platforms transferrin receptor, peripherally...
The visual system consists of two major subsystems, image-forming circuits that drive conscious vision and non-image-forming for behaviors such as circadian photoentrainment. While historically considered non-overlapping, recent evidence has uncovered crosstalk between these subsystems. Here, we investigated shared developmental mechanisms. We revealed an unprecedented role light in the maturation clock discovered intrinsically photosensitive retinal ganglion cells (ipRGCs) are critical this...
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....
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...
Targeting proteins highly expressed at the blood-brain barrier, including transferrin receptor (TfR) and CD98hc, is a transformative approach enabling more effective brain delivery of biotherapeutics for treatment neurological diseases. TfR-mediated promotes rapid, high uptake, while CD98hc-mediated slower with prolonged exposure. Here, we engineer huIgG Fc domain to bind both TfR CD98hc create dual transport vehicle (TV) platform that drives distinct properties. Dual TVs achieve...
In mammals, a subset of retinal ganglion cells (RGCs) expresses the photopigment melanopsin, which renders them intrinsically photosensitive (ipRGCs). These ipRGCs mediate various non-image-forming visual functions such as circadian photoentrainment and pupillary light reflex (PLR). Melanopsin phototransduction begins with activation heterotrimeric G protein unknown identity. Several studies melanopsin have implicated G-protein Gq/11 family, consists Gna11, Gna14, Gnaq Gna15, in...
Significance Molecules regulated by neuronal activity are necessary for circuits to adapt changing inputs. Specific classical major histocompatibility class I (MHCI) molecules play roles in circuit and synaptic plasticity, but the function of most members this family remains unexplored brain. Here, we show that a nonclassical MHCI molecule, Qa-1 (H2-T23), is expressed subset excitatory neurons visually driven cerebral cortex. Moreover, CD94/NKG2 heterodimers, cognate receptors Qa-1,...
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,...
Many biochemical, physiological, and behavioral processes such as glucose metabolism, body temperature, sleep-wake cycles show regular daily rhythms. These circadian rhythms are adjusted to the environmental light-dark cycle by a central pacemaker located in suprachiasmatic nucleus (SCN) order for occur at appropriate times of day. Here, we investigated expression function synaptic organizing protein, C1QL3, SCN. We found that C1ql3 is robustly expressed knockout mice have reduced density...
Abstract Transferrin receptor (TfR)-mediated transcytosis across the blood-brain barrier (BBB) is a promising strategy to improve delivery of biologics central nervous system (CNS). However, it remains unclear whether age and aging-related diseases impact TfR expression and/or BBB transport capacity. Here, we used TfR-targeted antibody vehicle (ATV ) enhance CNS in healthy mice 5xFAD mouse model Alzheimer’s disease (AD). Healthy neonates exhibited highest vascular ATV brain exposure, whereas...