Targeting G3BP aggregation to prevent neurodegeneration
Inventors
Kar, Amar N. • Sahoo, Pabitra • Twiss, Jeffery • McGill, Sean
Assignees
Publication Number
US-11851462-B2
Publication Date
2023-12-26
Expiration Date
2040-05-22
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Abstract
Testing peptides in in vitro models of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Frontotemporal dementia, Amyotrophic lateral sclerosis, to evaluate systems and methods of treatment therefore.
Core Innovation
The invention describes the use of cell permeable peptides, specifically G3BP1 peptides comprising between 19-21 amino acids (such as SEQ ID NO: 2), to block stress granule aggregation in neurons. These peptides are shown to disassemble aggregates of stress granules and neurodegeneration-associated RNA binding proteins along axons, thereby reducing or preventing neurotoxicity and neurodegeneration. The method involves treating neuronal cells, including cortical neurons, with these peptides to prevent induced and mediated neurotoxicity, such as that caused by neurodegenerative disease-related insults.
The document addresses the problem that current therapeutic interventions targeting toxic cytoplasmic aggregates and aberrant stress granules have had limited success in preventing or reversing neurodegeneration. Neurodegenerative diseases like Parkinson's disease, Alzheimer's disease, Frontotemporal dementia, and Amyotrophic lateral sclerosis are characterized by increased protein aggregation and elevated stress granule levels, which contribute to disease progression. There is a need for modalities that directly target the assembly and disassembly of stress granules to provide neuroprotection.
This innovation demonstrates that the administration of a cell permeable G3BP1 peptide, particularly the 190-208 region, can trigger the disassembly of aberrant stress granules formed as a result of neurodegenerative insults or the expression of disease-causing mutant proteins (e.g., TDP-43, TIA-1). The inventors provide evidence that this approach prevents axon degeneration, protects neurons from the neurotoxic effects of agents such as MPP+ and beta-amyloid, and may represent a novel therapeutic strategy for neurodegenerative diseases by restoring stress granule dynamics. Treatment was shown to be effective across different models and disease-associated stressors.
Claims Coverage
There are two main independent inventive features claimed in the patent.
Prophylactic method for blocking stress granule aggregation using G3BP1 peptides
A method comprising: - Treating at least one cortical neuron cell with a cell permeable polypeptide to reduce neurodegeneration by blocking stress granule aggregation. - The cell permeable polypeptide is a G3BP1 peptide comprising between 19-21 amino acids. - The treatment with the peptide disassembles aggregates of stress granules and neurodegeneration-associated RNA binding proteins along axons. - This method prevents induced and mediated neurotoxicity via blocking stress granule aggregation.
Prophylactic method for blocking neurodegenerative disease associated with axon degeneration using G3BP1 peptides
A method comprising: - Administering a cell permeable polypeptide to at least one cortical neuron cell in a subject with or without a neurodegenerative disease. - The cell permeable polypeptide is a G3BP1 peptide comprising between 19-21 amino acids. - Administration of the peptide disassembles pathological protein aggregates in cortical neuron cells. - Administration of the peptide also prevents RNA binding protein aggregation in axons after exposure to neurotoxins.
The inventive features cover the prophylactic use of cell permeable G3BP1 peptides of specified length to block stress granule and pathological protein aggregation in neurons, thus preventing neurotoxicity and neurodegeneration.
Stated Advantages
The cell permeable G3BP1 190-208 peptide can disassemble aberrant stress granules and pathological protein aggregates, providing neuroprotection against various neurodegenerative disease models.
Treatment with the cell permeable peptide prevents axon degeneration and loss of neurons following neurodegenerative insults.
The peptide-mediated disassembly of stress granules increases axonal protein synthesis and accelerates nerve regeneration after injury.
The invention offers a direct modality to target and disassemble stress granules, which existing therapies have not achieved effectively.
Documented Applications
Treatment of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Frontotemporal dementia, and Amyotrophic lateral sclerosis by blocking stress granule aggregation.
Prophylactic and therapeutic intervention to prevent axon degeneration and protect neurons from neurotoxic insults in in vitro models.
Use of the G3BP1 peptide to accelerate nerve regeneration following traumatic injury.
Prevention of protein aggregation associated with neurodegeneration in cellular models expressing disease-causing mutant proteins.
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