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Principal Investigator: Tomasz Nowakowski
Organization: UNIVERSITY OF CALIFORNIA BERKELEY
Fiscal Year: 2024
Award: $764,437
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary
Microglial inflammation has been implicated the pathology of a host of neurological conditions, including
neurodevelopmental disorders such as autism and Down Syndrome; neurogenerative disorders such as
Alzheimer's disease (AD), Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and Huntington’s disease;
and neuropathic pain. Gene therapy utilizing adeno-associated viral (AAV) vectors has emerged as a highly
promising strategy for treating central nervous system (CNS) disorders, and an immunosuppressive gene
therapy to inhibit immune signaling pathways in microglia would thus be highly promising for treating this broad
range of chronic conditions. However, this signaling pathway serves protective roles in other CNS cells including
neurons, such that therapeutic delivery would need to be not only efficient but targeted to microglia.
By leveraging our expertise in viral engineering, single cell analysis, machine learning, and human and
non-human primate models, we propose to develop a technology platform for genetically accessing specific cell
types in the adult primate brain, in particular microglia. We will integrate directed evolution of AAV with molecular
barcoding, single cell next generation sequencing (NGS), machine learning, and human tissue and non-human
primate (NHP) brain models to develop AAVs for selective delivery to primate microglia. Additionally, to further
enhance the specificity of these technologies, we will apply analogous library selection, NGS, and machine
learning approaches to engineer short, synthetic promoters and to identify endogenous enhancers for selective
microglial gene expression. Finally, these capabilities will be applied to deliver potential therapeutic gene cargoes
to microglia in vitro and in vivo.
In sum, we propose a high-risk, innovative research program that will, if successful, advance our capacity
to selectively modulate immune signaling in microglia, work that if successful will have implications for treating a
broad range of neurological conditions. Furthermore, this work will establish a broadly impactful technology
platform that integrates vector engineering, next generation sequencing, and machine learning to engineer tools
for cell specific genetic manipulation, which can in principle be applied to in principle any cell or tissue in the
central nervous system or body. We thus anticipate that our experienced, multidisciplinary team can offer strong
contributions to technology development, neuroscience, and fundamental and translational biology in other
systems.
Terms: <21+ years old><AAV vector><AAV-based vector><AD dementia><ASD><ATAC sequencing><ATAC-seq><ATACseq><Adult><Adult Human><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Amyotrophic Lateral Sclerosis><Amyotrophic Lateral Sclerosis Motor Neuron Disease><Assay for Transposase-Accessible Chromatin using sequencing><Autism><Autistic Disorder><Bar Codes><Basal Transcription Factor><Basal transcription factor genes><Binding Sites><Biology><Biomedical Engineering><Body Tissues><Brain><Brain Nervous System><CNS Diseases><CNS Nervous System><CNS disorder><Capsid><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Central Nervous System><Central Nervous System Diseases><Central Nervous System Disorders><Chronic><Clinical Trials><Collaborations><Combining Site><Complement><Complement Proteins><DNA Therapy><Data><Degenerative Neurologic Disorders><Directed Molecular Evolution><Disease><Disorder><Down's Syndrome><Early Infantile Autism><Encephalon><Engineering><Enhancers><Exhibits><Future><Gehrig's Disease><Gene Delivery><Gene Expression><Gene Transfer Clinical><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Intervention><Genomics><Hortega cell><Human><Huntington Chorea><Huntington Disease><Huntington's><Huntington's Disease><Huntingtons Disease><Immune signaling><Immunoglobulin Enhancer-Binding Protein><Immunomodulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Vitro><Infantile Autism><Inflammation><Inflammatory><Inflammatory Response><Injections><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Intravenous><Kanner's Syndrome><Langdon Down syndrome><Libraries><Lou Gehrig Disease><Machine Learning><Mediating><Metallothionein><Methods><Microglia><Modeling><Modern Man><Molecular><Mongolism><NF-kB><NF-kappa B><NF-kappaB><NFKB><NGS Method><NGS system><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neuraxis><Neurobiology><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurodevelopmental Disorder><Neurologic><Neurologic Degenerative Conditions><Neurological><Neurological Development Disorder><Neuron Degeneration><Neurons><Neurosciences><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Paralysis Agitans><Parkinson><Parkinson Disease><Pathology><Primary Parkinsonism><Primary Senile Degenerative Dementia><Primates><Primates Mammals><Reactive Site><Receptor Protein><Regulatory Element><Research><Role><Safety><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Single cell seq><Slice><Specificity><Surface><System><Technology><Therapeutic><Tissues><Transcription Factor NF-kB><Transcription Factor Proto-Oncogene><Transcription factor genes><Trisomy 21><Variant><Variation><Viral><Viral Vector><Work><adeno-associated viral vector><adeno-associated virus vector><adulthood><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><autism spectral disorder><autism spectrum disorder><autistic spectrum disorder><barcode><bio-engineered><bio-engineers><bioengineering><biological engineering><biological signal transduction><cell type><chromosome 21 trisomy syndrome><complementation><congenital acromicria syndrome><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><directed evolution><efficacy validation><experience><gene manipulation><gene repair therapy><gene therapeutics><gene therapy><gene-based therapeutic><gene-based therapeutics><gene-based therapy><genes therapeutic><genes therapeutics><genetic manipulation><genetic therapy><genetically manipulate><genetically perturb><genome editing><genomic editing><genomic therapy><gitter cell><high risk><human disease><human tissue><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunosuppressive activity><immunosuppressive function><immunosuppressive response><in vivo><innovate><innovation><innovative><insight><interventional strategy><kappa B Enhancer Binding Protein><knock-down><knockdown><machine based learning><mesoglia><microglial cell><microgliocyte><morbus Down><mouse model><multidisciplinary><murine model><neural degeneration><neurobiological><neurodegeneration><neurodegenerative><neurodegenerative illness><neurodevelopmental disease><neurological degeneration><neuronal><neuronal degeneration><neuropathic pain><next gen sequencing><next generation sequencing><nextgen sequencing><non-human primate><nonhuman primate><novel><nuclear factor kappa beta><overexpress><overexpression><painful neuropathy><perivascular glial cell><primary degenerative dementia><programs><promoter><promotor><pseudohypertrophic progressive muscular dystrophy><receptor><selective expression><selectively expressed><senile dementia of the Alzheimer type><single cell analysis><single cell next generation sequencing><single cell sequencing><social role><tech development><technology development><technology platform><technology system><therapeutic gene><tool><trafficking><transcription factor><trisomy 21 syndrome><validate efficacy><vector>