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Principal Investigator: Yupeng Chen
Organization: UNIVERSITY OF CONNECTICUT STORRS
Fiscal Year: 2022
Award: $388,857
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Abstract
More than 6 million Americans are living with Alzheimer’s disease (AD). AD is a neurodegenerative disease
driven by abnormal accumulation of amyloid-β (Aβ) in the brain. Currently, we have very limited therapeutic
approaches to treat AD. Aducanumab, designed to bind and inhibit toxic Aβ in the brain, is the only disease-
modifying drug approved by The FDA, however, the clinical outcomes of Aducanumab were not satisfied.
Therefore, there is a great need to develop novel therapeutic strategies against AD. Recently, RNA therapeutics
were shown to inhibit disease gene expression, thereby reducing or abolishing diseased protein production. To
realize RNA therapeutics, a key challenge is delivering the RNA across the blood brain barrier (BBB) which is a
structural and functional roadblock for over 98% of small molecule drugs and nearly all large-molecule
therapeutics.
The goal of our proposed study is to develop novel DNA-inspired nanomaterials for the delivery of RNA
therapeutics that penetrate the BBB for AD treatment. This study is built on our R01 project studying these
nanomaterials for RNA delivery. We have successfully developed a family of delivery vehicles called Janus base
nanopieces (NPs) which are rod-shaped nanoparticles formed by bundles of DNA-mimicking Janus base
nanotubes (JBNTs) with RNA cargoes incorporated inside via charge interactions. Our recent publications have
shown NPs can effectively deliver RNA therapeutics that inhibit disease gene expression. Moreover, we
serendipitously found NPs had an excellent ability to penetrate BBB. Our preliminary results showed NPs were
~11 times more efficient than lipid nanoparticles to deliver a fluorescence-labeled RNA into a mouse brain. In
addition, previous studies have found that Aβ accumulation can be prevented by downregulation of β- and γ-
secretases or upregulation of a CX3CL1 peptide. These targets are likely to result in potent therapeutics.
Combining all the information together, we hypothesized that we are able to develop and optimize NPs to
deliver therapeutic RNAs across BBB into the brain to treat AD. To test the hypothesis, we will accomplish two
specific aims: 1) To develop a library of Janus base NPs for RNA delivery and assess their delivery efficiency
to penetrate BBB in vitro and in vivo. 2) To evaluate treatment outcomes of the developed NPs in an established
AD mouse model. Completion of the proposed study will lay a solid foundation for the development of RNA
therapeutics against AD and provide valuable preliminary results for future grant applications to realize a novel
disease-modifying RNA therapeutic to treat AD.
Terms: <ABCD-3><AD dementia><AD model><ADAM10 protein><Aducanumab><Alzheimer><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's disease dementia><Alzheimer's disease model><Alzheimers Dementia><Alzheimers disease><American><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Applications Grants><Aβ><BACE><BACE1><BIIB037><Binding><Blood - brain barrier anatomy><Blood-Brain Barrier><Brain><Brain Nervous System><C3Xkine><CX3CL1><CX3CL1 gene><CXC3><CXC3C><Cartilage><Cartilaginous Tissue><Charge><Chronic Disease><Chronic Illness><Clinical><DNA><Degenerative Neurologic Diseases><Degenerative Neurologic Disorders><Deoxyribonucleic Acid><Development><Disease><Disease Progression><Disorder><Down-Regulation><Downregulation><Drugs><Encephalon><Evaluation><FDA approved><Family><Fluorescence><Formulation><Foundations><Funding><Future><Gene Expression><Goals><Grant Proposals><Health><Hemato-Encephalic Barrier><In Vitro><Joint Diseases><Label><Length><Libraries><Mediating><Medication><Messenger RNA><Mice><Mice Mammals><Mission><Molecular Interaction><Murine><Mus><NIH><Nanotubes><National Institutes of Health><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Non-Polyadenylated RNA><Outcome><PSEN1><Peptides><Pharmaceutic Preparations><Pharmaceutical Preparations><Primary Senile Degenerative Dementia><Process><Production><Proteins><Public Health><Publications><Publishing><RNA><RNA Gene Products><RNA based therapeutics><RNA delivery><Research><Ribonucleic Acid><Rod><S182 protein><SCYD1><Scientific Publication><Short interfering RNA><Small Interfering RNA><Solid><Technology><Testing><Therapeutic><Time><Translating><Treatment Efficacy><Treatment outcome><United States National Institutes of Health><Up-Regulation><Upregulation><a beta peptide><abeta><abeta accumulation><abeta aggregation><aduhelm><alzheimer model><amyloid beta><amyloid beta accumulation><amyloid beta aggregation><amyloid β accumulation><amyloid β aggregation><amyloid-b protein><arthropathic><arthropathies><arthropathy><aβ accumulation><aβ aggregation><base><beta amyloid fibril><beta secretase><beta-secretase 1><beta-site APP cleaving enzyme 1><beta-site amyloid precursor protein cleaving enzyme 1><bloodbrain barrier><chronic disorder><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><delivery vector><delivery vehicle><dementia of the Alzheimer type><design><designing><developmental><drug/agent><gamma secretase><gamma secretase complex><in vivo><in vivo Model><insight><intervention efficacy><joint disorder><lipid based nanoparticle><lipid nanoparticle><mRNA><memapsin 2><mouse model><murine model><nano materials><nano particle><nano tubes><nano-sized particle><nanomaterials><nanoparticle><nanosized particle><native protein drug><neurodegenerative illness><new drug treatments><new drugs><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><pharmaceutical protein><presenilin 1 protein><presenilin-1><prevent><preventing><primary degenerative dementia><protein drug agent><protein expression><protein-based drug><secretase><self assembly><senile dementia of the Alzheimer type><siRNA><small molecule><soluble amyloid precursor protein><therapeutic RNA><therapeutic efficacy><therapeutic protein><therapy efficacy><β-secretase><β-secretase 1><β-site APP cleaving enzyme 1><γ-secretase>