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Principal Investigator: Abraam M. Yakoub
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2024
Award: $765,148
Funding agency: National Institute on Aging
Project Summary
Neurodegenerative diseases, especially Alzheimer’s Disease (AD) and Parkinson’s Disease (PD), affect
millions of people globally and represent a US major healthcare burden. AD is the world’s most common cause
of dementia, and is the sixth leading cause of death in the US. PD is motor disabling condition that advances to
cognitive deficits. Currently there exist no effective therapies for AD or PD; even some of the drugs used to
ameliorate symptoms, such as in PD, cause serious long-term side effects that may be worse than the disease
itself. In AD and PD, accumulation of Amyloid-β (Aβ) or α-Synuclein (α-Syn) and their subsequent aggregation,
cause neuronal toxicity, including neuroinflammation, synaptic deficits and neurodegeneration, leading to
cognitive or motor deficits. In this application, we conceive an innovative genetic tool (named Autophagon, or
AFN) to be developed as a gene therapy that helps target toxic Aβ or α-Syn species to autophagy, an
important degradative pathway that is usually impaired in AD and PD. AFN will feature a synthetic gene
fragment to help sequester Aβ or α-Syn aggregates and deliver them to the autophagic vesicles for clearance
from the neurons. Using viral vectors, we will deliver AFN to cells or to mouse brain via specific stereotaxic
injections. First, we will test AFN in vitro using 2D and 3D (brain organoid) neuronal cultures derived from
iPSCs harboring APP/PSEN1 or α-Syn mutations that drive Aβ or α-Syn aggregation, respectively, and assess
the ability of AFN to suppress aggregate formation and neuronal toxicity. Second, we will use mouse models of
AD (with a genetic knock-in of human APP mutations that cause Aβ aggregation) and PD (expressing
aggregation-prone mutant human α-Syn) to test the therapeutic potential of AFN and its ability to prevent
aggregate formation, neurodegeneration, and cognitive or motor deficits in vivo. If successful, the proposed
project will have a major impact on the neurodegenerative diseases field, by developing an effective potential
gene therapy for AD and PD, and set the foundation for the next steps of preclinical and clinical testing of this
suggested therapy. It may also provide a proof-of-concept for therapy development for other
neurodegenerative disorders associated with protein aggregation.
Terms: <3-D><3-Dimensional><3D><AD dementia><AD model><Abnormal Movements><Abscission><Affect><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's disease model><Alzheimer's disease therapy><Alzheimer's therapy><Alzheimers Dementia><Amentia><Ammon Horn><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Animal Model><Animal Models and Related Studies><Animals><Arrhythmia><Artificial Genes><Autophagocytosis><Autophagosome><Aβ><Basic Research><Basic Science><Brain><Brain Nervous System><Brain region><Cardiac Arrhythmia><Cause of Death><Cell Aggregation><Cell Body><Cells><Chemicals><Chimera Protein><Chimeric Proteins><Clinical Evaluation><Clinical Testing><Clinical Trials><Cognitive><Cognitive deficits><Cornu Ammonis><DNA Therapy><Dangerousness><Degenerative Neurologic Disorders><Degradation Pathway><Degradative Pathway><Dementia><Deposit><Deposition><Development><Disabling condition><Disabling health condition><Disease><Disorder><Drug Therapy><Drug usage><Drugs><Dyskinesias><Dyskinetic syndrome><EGFP protein><Encephalon><Engineering><Excision><Exhibits><Extirpation><Foundations><Fusion Protein><Future><Gene Transfer Clinical><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Intervention><Genetic defect><Glutamates><Heart Arrhythmias><Hippocampus><Human><Impairment><In Vitro><Induced pluripotent stem cell derived human neuron><Injections><Knock-in><L-Glutamate><Learning><Licensing><Medication><Memory Deficit><Memory impairment><Mice><Mice Mammals><Modern Man><Motor><Murine><Mus><Mutation><NAC precursor><Names><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron Degeneration><Neurons><Organoids><Outcome><PARK1 protein><PARK4 protein><PSEN1><Paralysis Agitans><Parkinson><Parkinson Disease><Pathogenesis><Pathogenicity><Pathway interactions><Patients><Peptides><Persons><Pharmaceutical Preparations><Pharmacotherapy><Poly A><Poly(rA)><Population><Precision therapeutics><Preclinical Testing><Primary Parkinsonism><Primary Senile Degenerative Dementia><Process><Proteins><Psychoses><Receptor Protein><Removal><S182 protein><SNCA><SNCA protein><Specificity><Substantia Nigra><Substantia nigra structure><Surgical Removal><Synapses><Synaptic><Synthetic Genes><Testing><Therapeutic><Therapeutic Effect><Toxic effect><Toxicities><Vesicle><Viral Vector><a beta peptide><a-syn><a-synuclein><abeta><abeta accumulation><abeta aggregation><alleviate symptom><alpha synuclein><alpha synuclein gene><alphaSP22><alzheimer model><ameliorating symptom><amyloid beta><amyloid beta accumulation><amyloid beta aggregation><amyloid β accumulation><amyloid β aggregation><amyloid-b protein><asyn><autophagy><aβ accumulation><aβ aggregation><beta amyloid fibril><beta-synuclein><clinical test><cognitive defects><decrease symptom><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><delivery vector><delivery vehicle><design><designing><develop therapy><developmental><disease model><disorder model><drug candidate><drug treatment><drug use><drug/agent><effective therapy><effective treatment><enhanced green fluorescent protein><fewer symptoms><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genome mutation><genomic therapy><glutamatergic><healthcare burden><hiPSC-derived neurons><hippocampal><human iPSC-derived sensory neuron><iPS><iPSC><iPSC-derived human neuron><iPSCs><in vivo><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><innovate><innovation><innovative><insoluble aggregate><intervention development><knockin><memory dysfunction><model of animal><motor deficit><mouse model><murine model><mutant><name><named><naming><nerve cell death><nerve cell loss><neural degeneration><neural inflammation><neurodegeneration><neurodegenerative><neurodegenerative illness><neuroinflammation><neuroinflammatory><neurological degeneration><neuron cell death><neuron cell loss><neuron death><neuron loss><neuron toxicity><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal degeneration><neuronal loss><neuronal survival><neuronal toxicity><neurotoxicity><non A-beta component of AD amyloid><non A4 component of amyloid precursor><novel><pathway><phosphoneuroprotein 14><polyadenylate><pre-clinical testing><precision therapies><precision treatment><presenilin 1 protein><presenilin-1><prevent><preventing><primary degenerative dementia><promoter><promotor><protein aggregate><protein aggregation><receptor><recruit><reduce symptoms><relieves symptoms><research clinical testing><resection><senile dementia of the Alzheimer type><side effect><soluble amyloid precursor protein><symptom alleviation><symptom reduction><symptom relief><synapse><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic evaluation><therapeutic testing><therapy development><three dimensional><tool><treatment development><α synuclein gene><α-syn><α-synuclein>