Compositions and methods for treating protein aggregation-associated diseases
Inventors
Frydman, Judith • Radford, Sheena E. • Deuerling, Elke
Assignees
KONSTANZ, University of • University of Leeds • Leland Stanford Junior University
Publication Number
US-12338268-B2
Publication Date
2025-06-24
Expiration Date
2040-03-04
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Compositions and methods for treating aggregation-associated diseases are disclosed. In particular, compositions comprising the nascent polypeptide-associated complex (NAC) and the apical domain of CCT1 as well as peptide fragments thereof and fusion proteins containing NAC and CCT1 peptides can be used to suppress pathological protein aggregation and are useful for treatment of diseases associated with polyQ aggregation, amyloid beta aggregation, and alpha-synuclein aggregation.
Core Innovation
This invention discloses compositions and methods for treating aggregation-associated diseases by utilizing the nascent polypeptide-associated complex (NAC), the apical domain of CCT1, peptide fragments thereof, and fusion proteins containing NAC and CCT1 peptides. Notably, these compositions can suppress pathological protein aggregation, particularly polyQ, amyloid beta, and alpha-synuclein aggregation.
The problem addressed by the invention is the increasing frequency of late-onset neurodegenerative diseases linked to aging, many of which are caused by accumulation of toxic protein aggregation species like expanded polyglutamine (polyQ) repeats, amyloid beta, and alpha-synuclein. These aggregates result from a breakdown or overload of the body’s molecular chaperone machinery, which would normally facilitate folding or degradation of misfolded proteins. Over time, the efficiency of this machinery decreases, increasing the need for therapeutic interventions that enhance or replace the protein folding systems.
The core innovation involves using isolated peptides comprising at least a portion of the N-terminal domain of the beta subunit of NAC, peptide fragments thereof, and fusion proteins connecting NAC peptides to peptides from the apical domain of CCT1. These compositions suppress aggregation of proteins containing polyQ sequences (e.g., huntingtin exon1, Ataxin-3), amyloid beta, or alpha-synuclein, which underlies many neurodegenerative diseases such as Huntington's disease, Spinocerebellar ataxia, Alzheimer's disease, and synucleinopathies. Pharmaceutical compositions and administration methods are disclosed for delivering these agents to subjects in need.
Claims Coverage
The patent includes two independent claims covering two main inventive features: (1) isolated peptides from the N-terminal domain of the NAC beta subunit that suppress polyglutamine (polyQ) aggregation, and (2) fusion proteins comprising a NAC peptide connected to an apical domain of CCT1 to suppress polyQ aggregation.
Isolated peptide from the N-terminal domain of NAC beta subunit for polyQ aggregation suppression
An isolated peptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:2, or a sequence with at least 90% identity, wherein the peptide suppresses aggregation of a protein comprising a polyglutamine (polyQ) sequence.
Fusion protein comprising NAC peptide and apical domain of CCT1 for polyQ aggregation suppression
A fusion protein comprising: - A peptide with an amino acid sequence selected from SEQ ID NOS:1-3 linked to - A peptide comprising an apical domain of chaperonin containing TCP1 subunit 1 (CCT1). The apical domain of CCT1 can have an amino acid sequence of SEQ ID NO:7 or at least 90% identity to SEQ ID NO:7. The fusion protein, such as one having SEQ ID NO:8 or at least 90% identity thereto, is capable of suppressing aggregation of a protein comprising a polyQ sequence.
The claims establish protection for specific isolated NAC-derived peptides and fusion proteins that include NAC and CCT1 domains, for the purpose of suppressing polyQ protein aggregation.
Stated Advantages
The disclosed compositions and methods can suppress pathological protein aggregation, thereby reducing formation of toxic aggregates associated with neurodegenerative diseases.
Therapeutically effective doses of these compositions may result in improved neurological recovery, including restored neuronal function, improved cognition, improved memory, and increased survival.
The invention may retard loss of cerebellar Purkinje neurons and loss of brain cells.
Reduction in aggregation can decrease the formation of insoluble protein aggregates in neurons, amyloid plaques in the brain, or Lewy bodies.
Documented Applications
Treatment of polyQ aggregation-associated diseases, including Huntington's disease, dentatorubropallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17.
Treatment of amyloid beta aggregation-associated diseases such as Alzheimer's disease.
Treatment of synucleinopathies associated with alpha-synuclein aggregation, including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and neuroaxonal dystrophies.
Suppression of aggregation of polyQ-expanded huntingtin exon1 or Ataxin-3.
Interested in licensing this patent?