Methods for treating apolipoprotein E4-associated disorders
Inventors
Huang, Yadong • Andrews-Zwilling, Yaisa
Assignees
J David Gladstone Institutes A Testamentary Trust Established Under Of Will Of J David Gladstone • J David Gladstone Institutes
Publication Number
US-11959079-B2
Publication Date
2024-04-16
Expiration Date
2030-12-01
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Abstract
The present disclosure provides a method of increasing the functionality of a GABAergic interneuron in the hilus of the hippocampus of an individual having at least one apolipoprotein E4 (apoE4) allele. The method generally involves reducing tau levels in the interneuron.
Core Innovation
The invention provides a method of increasing the functionality of a GABAergic interneuron in the hilus of the hippocampus of an individual having at least one apolipoprotein E4 (apoE4) allele. This is achieved by reducing tau protein levels specifically in the interneuron. The method can involve administering a tau-specific interfering nucleic acid to reduce tau polypeptide levels or administering genetically modified stem cells that produce less tau.
The background highlights that apoE4 carriers have an increased risk of developing Alzheimer's disease (AD), characterized by early hippocampal damage and memory deficits. Tau protein plays a critical role in neuronal architecture by stabilizing intracellular microtubules. Its impairment by truncation, hyperphosphorylation, or isoform imbalance leads to neurofibrillary tangles, which correlate with clinical AD symptoms. Thus, malfunction of tau protein is central to AD pathology.
The disclosed method addresses the loss and dysfunction of hippocampal GABAergic interneurons associated with apoE4 and tau pathology. By reducing tau levels in these interneurons, the method increases their functionality, leading to improved cognitive functions such as learning and memory. The approach includes administering tau-targeting nucleic acids or genetically modified stem cells to increase GABAergic interneuron number and activity, thereby ameliorating apoE4-associated neurological deficits.
Claims Coverage
The patent includes one independent claim that describes a method of increasing GABAergic interneuron functionality by reducing tau levels with a targeted interfering nucleic acid.
Tau-specific interfering nucleic acid delivery to GABAergic interneurons
Administration of a tau-specific interfering nucleic acid that binds a contiguous stretch of at least 10 nucleotides within positions 5596-5807 of SEQ ID NO:2 to reduce tau polypeptide in GABAergic interneurons, combined with a carrier molecule providing targeted delivery to those interneurons.
Neuron-specific recombinant expression of tau-interfering nucleic acid
Using a recombinant expression vector encoding the tau-specific interfering nucleic acid operably linked to a neuron-specific promoter active in GABAergic interneurons to achieve selective tau knockdown.
Local administration route
Administering the tau-specific interfering nucleic acid via a local route, specifically intracranial administration, to target the hippocampal interneurons effectively.
Cognitive function improvement through increased GABAergic interneuron function
The method results in increased cognitive function, including learning and memory, as determined by cognitive assessments.
Use of antibody carrier molecule for targeted delivery
Utilizing an antibody carrier molecule that specifically binds to GABAergic interneurons to mediate targeted delivery of the tau-specific interfering nucleic acid.
The invention's independent claim covers administering tau-specific interfering nucleic acids to selectively reduce tau levels in hippocampal GABAergic interneurons of apoE4 carriers, employing neuron-specific expression and targeted delivery, local administration routes, and achieving cognitive improvement by increasing interneuron functionality.
Stated Advantages
Increased functionality and number of GABAergic interneurons in the hippocampus of individuals with at least one apoE4 allele.
Improvement in cognitive functions, including enhanced learning and memory performance.
Protection against apoE4-associated neurodegeneration and tau pathology.
Prevention or rescue of behavioral deficits related to Alzheimer's disease models by targeting tau in GABAergic interneurons.
Capability to improve cognitive deficits through modulation of GABAergic signaling using GABAA receptor potentiators or tau reduction.
Documented Applications
Treatment of apoE4-associated neurological disorders, including Alzheimer's disease, by increasing the function of hippocampal GABAergic interneurons.
Use in individuals carrying one or two apoE4 alleles experiencing cognitive impairments or at risk of apoE4-related neurodegenerative conditions.
Therapeutic administration of tau-specific interfering nucleic acids or genetically modified stem cells to enhance interneuron function and ameliorate memory and spatial learning deficits.
Use of GABAA receptor potentiators, such as pentobarbital, as adjunct therapies to rescue learning and memory deficits associated with apoE4 and tau pathology.
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