A5037933328- Neurogenesis and neuroplasticity mechanisms
- DNA and Nucleic Acid Chemistry
- Alzheimer's disease research and treatments
- Genetics and Neurodevelopmental Disorders
- RNA Interference and Gene Delivery
- Cancer-related Molecular Pathways
- Advanced biosensing and bioanalysis techniques
- Neurological diseases and metabolism
- RNA Research and Splicing
- Memory and Neural Mechanisms
- Spinal Cord Injury Research
- Neural dynamics and brain function
- Nerve injury and regeneration
- Prion Diseases and Protein Misfolding
- Pluripotent Stem Cells Research
- Neuroscience and Neuropharmacology Research
- Epigenetics and DNA Methylation
- Mitochondrial Function and Pathology
Denali Therapeutics (United States)
2023-2024
Kaiser Permanente South San Francisco Medical Center
2023
Massachusetts Institute of Technology
2017-2021
Washington University in St. Louis
2014
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...
Increased p25, a proteolytic fragment of the regulatory subunit p35, is known to induce aberrant activity cyclin-dependent kinase 5 (Cdk5), which associated with neurodegenerative disorders, including Alzheimer's disease. Previously, we showed that replacing endogenous p35 noncleavable mutant (Δp35) attenuated amyloidosis and improved cognitive function in familial disease mouse model. Here, address role p25/Cdk5 tauopathy, generated double-transgenic mice by crossing overexpressing human...
Recent increases in human longevity have been accompanied by a rise the incidence of dementia, highlighting need to preserve cognitive function an aging population. A small percentage individuals with pathological hallmarks neurodegenerative disease are able maintain normal cognition. Although molecular mechanisms that govern this neuroprotection remain unknown, exhibit resilience (CgR) represent unique source therapeutic insight. For both humans and animal models, living enriched,...
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 Aberrant activity of cyclin-dependent kinase (Cdk5) has been implicated in various neurodegenerative diseases. This effect is mediated by pathological cleavage the Cdk5 activator p35 to produce truncated product p25, exhibiting increased stability and altered substrate specificity. The benefit blocking p25 production demonstrated rodent human models. However, important Cdk5/p35 functions developing adult brain have made it challenging selectively target detrimental effects Cdk5/p25...