Compositions and methods for suppressing MSUT2
Inventors
Kraemer, Brian • Wheeler, Jeanna M. • McMillan, Pamela • Strovas, Timothy J. • Baker, Jeremy
Assignees
University of Washington • US Department of Veterans Affairs
Publication Number
US-11439658-B2
Publication Date
2022-09-13
Expiration Date
2039-04-12
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Abstract
Described herein are compositions and methods for treating Alzheimer's disease or dementia. The compositions include mammalian suppressor of taupathy 2 inhibitors (MSUT2). The MSUT2 inhibitors can be small interfering RNAs, guide RNAs, or small molecules. The methods include reducing accumulation of phosphorylated and aggregated human tau.
Core Innovation
The invention provides compositions and methods for treating Alzheimer's disease or dementia by inhibiting the mammalian suppressor of tauopathy 2 (MSUT2). The MSUT2 inhibitors include small interfering RNAs (siRNAs), guide RNAs (gRNAs), and small molecules. The methods involve administering a therapeutically effective amount of the MSUT2 inhibitor to reduce accumulation of phosphorylated and aggregated human tau protein.
The invention addresses the problem of neurodegenerative diseases such as Alzheimer's disease, characterized by cellular disruption of proteostasis manifesting in amyloid plaques and neurofibrillary tangles (NFTs). Existing therapeutic strategies focused on amyloid have not succeeded, and there is a need for tau-targeted therapies, as tau pathology correlates better with dementia severity. The invention aims to provide tau-targeted therapies by modulating the MSUT2 protein, which has been linked to modifying tau toxicity.
Claims Coverage
The patent claims five independent methods focusing on the administration of an MSUT2 inhibitor siRNA to subjects for different therapeutic effects related to tauopathy and neuroinflammation.
Use of siRNA targeting MSUT2 to inhibit its expression
Administering a mammalian suppressor of tauopathy 2 (MSUT2) inhibitor comprising a double stranded small interfering RNA (siRNA) having specified sequences in the first strand to inhibit expression of MSUT2 polynucleotide in a subject, where the siRNA second strand is complementary to mediate RNA interference, and administering intravenously or intrathecally.
Use of siRNA targeting MSUT2 to reduce phosphorylated and aggregated tau
Administering the same double stranded siRNA MSUT2 inhibitor as above to reduce phosphorylated and aggregated human tau protein in a subject via intravenous or intrathecal administration.
Use of siRNA targeting MSUT2 to potentiate neuroinflammatory response
Administering the specified siRNA MSUT2 inhibitor intravenously or intrathecally to potentiate a neuroinflammatory response to pathological tau protein in a subject.
Use of siRNA targeting MSUT2 to decrease astrocytosis or microgliosis
Administering the specified siRNA MSUT2 inhibitor intravenously or intrathecally to decrease astrocytosis or microgliosis in a subject.
Use of siRNA targeting MSUT2 to reduce neuroinflammation
Administering the specified siRNA MSUT2 inhibitor intravenously or intrathecally to reduce neuroinflammation in a subject.
The claims focus on methods of treatment by administering MSUT2 inhibitors, specifically siRNA molecules comprising defined sequences, to modulate tauopathy-related pathology and neuroinflammatory processes in subjects, with administration routes intravenous or intrathecal.
Stated Advantages
Loss of MSUT2 function reduces accumulation of pathological tau species, protects neurons, ameliorates cognitive impairment, and decreases neuroinflammation in tauopathy mouse models.
MSUT2 overexpression exacerbates pathological tau deposition, neuronal loss, and neuroinflammatory responses, indicating MSUT2 levels critically influence neuronal vulnerability to tau pathology.
MSUT2 binds poly(A) RNA and interacts with PABPN1 in a macromolecular complex regulating tau proteostasis, identifying RNA processing as a targetable mechanism in neurodegeneration.
Targeting MSUT2 offers potential therapeutic benefits with minimal effects on development or overall brain function, supporting its role as a viable drug target for tauopathies.
Documented Applications
Treatment of Alzheimer's disease and dementia by administering MSUT2 inhibitors to reduce tau pathology and neuroinflammation.
Use of CRISPR-Cas systems comprising gRNAs targeting MSUT2 for gene expression modulation.
Screening methods to identify small molecules capable of inhibiting MSUT2 binding to poly(A) RNA, thereby preventing tau aggregation.
Use of alpha-screen and fluorescence polarization assays for discovering MSUT2 inhibitors.
Potential therapeutic intervention in tauopathy disorders including Alzheimer's disease, progressive supranuclear palsy, chronic traumatic encephalopathy, frontotemporal lobar degeneration, and other tauopathies.
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