Pharmaceutical compositions for prevention or treatment of neurodegenerative diseases
Inventors
DUNIA, Daniel • SZELECHOWSKI, Marion • BETOURNE, Alexandre • HUNOT, Stephane
Assignees
Centre National de la Recherche Scientifique CNRS • Universite Pierre et Marie Curie • Institut National de la Sante et de la Recherche Medicale INSERM • Institut du Cerveau et de La Moelle Epiniere ICM • Universite de Toulouse
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Publication Number
US-10059748-B2
Publication Date
2018-08-28
Expiration Date
Abstract
The present invention relates to methods and compositions for the prevention or treatment of neurodegenerative diseases.
Core Innovation
The invention relates to neuroprotective agents derived from Borna disease virus (BDV) protein X (BDV X). It describes a BDV X-derived polypeptide segment defined by an amino acid range from glycine at position 59 to alanine at position 85 in SEQ ID NO:1, including variants having at least 90% identity, with the polypeptide consisting of 86 amino acids or less. It further describes fusion proteins that include at least one heterologous polypeptide fused to the BDV X-derived polypeptide.
In certain embodiments, the heterologous partner is a cell-penetrating peptide or a mitochondria-penetrating peptide, including TAT cell penetrating sequence (SEQ ID NO:2) and a mitochondria-penetrating peptide sequence (SEQ ID NO:3). The BDV X-derived fusion constructs protect neurons and axons against mitochondrial respiratory complex I toxins, including rotenone and MPP+/MPTP models, and protection is associated with preservation of mitochondrial function, including mitochondrial membrane potential.
The invention further states that neuroprotection includes reduced oxidative stress and ROS production, promotion of mitochondrial hyperfilamentation, selectively reducing Drp1 phosphorylation (Ser616), and limiting mitochondrial fission. It additionally reports microfluidic neuron culture chamber studies and in vivo mouse PD model data, along with therapeutic delivery concepts including intranasal delivery and intra-cerebroventricular (ICV) delivery, as well as PEGylation and formulation with pharmaceutically acceptable carrier(s).
Claims Coverage
The provided independent claims cover five core categories built around a BDV X-derived polypeptide segment from SEQ ID NO:1 (positions 59 to 85) with an identity and length limitation, and additional claims cover corresponding nucleic acids, vectors, host cells, and pharmaceutical compositions. Some claims further require at least one heterologous polypeptide fused to the BDV X-derived polypeptide.
A fusion protein with a BDV X-derived segment and a heterologous polypeptide
A fusion protein comprising a polypeptide with an amino acid sequence ranging from glycine at position 59 to alanine at position 85 in SEQ ID NO:1 or having at least 90% identity to that sequence, wherein the polypeptide consists of 86 amino acids or less, and at least one heterologous polypeptide fused to the polypeptide.
A nucleic acid encoding a fusion protein with the BDV X-derived segment and a heterologous polypeptide
A nucleic acid sequence encoding a fusion protein comprising a polypeptide with an amino acid sequence ranging from glycine at position 59 to alanine at position 85 in SEQ ID NO:1 or having at least 90% identity to that sequence, wherein the polypeptide consists of 86 amino acids or less, and at least one heterologous polypeptide.
A vector encoding a fusion protein with the BDV X-derived segment and a heterologous polypeptide
A vector comprising a nucleic acid sequence encoding a fusion protein comprising a polypeptide with an amino acid sequence ranging from glycine at position 59 to alanine at position 85 in SEQ ID NO:1 or having at least 90% identity to that sequence, wherein the polypeptide consists of 86 amino acids or less, and at least one heterologous polypeptide.
A transformed host cell for expressing a fusion protein with the BDV X-derived segment and a heterologous polypeptide
A prokaryotic or eukaryotic host cell genetically transformed with at least one nucleic acid molecule encoding a fusion protein comprising a polypeptide with an amino acid sequence ranging from glycine at position 59 to alanine at position 85 in SEQ ID NO:1 or having at least 90% identity to that sequence, wherein the polypeptide consists of 86 amino acids or less, and at least one heterologous polypeptide; or a vector comprising the nucleic acid.
A pharmaceutical composition with a fusion protein containing the BDV X-derived segment and a heterologous polypeptide
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a fusion protein comprising a polypeptide with an amino acid sequence ranging from glycine at position 59 to alanine at position 85 in SEQ ID NO:1 or having at least 90% identity to that sequence, wherein the polypeptide consists of 86 amino acids or less, and at least one heterologous polypeptide.
A recombinant polypeptide corresponding to the BDV X-derived segment
A recombinant polypeptide comprising an amino acid sequence ranging from glycine at position 59 to alanine at position 85 in SEQ ID NO:1 or having at least 90% identity with that sequence, wherein the polypeptide consists of 86 amino acids or less.
A vector encoding a recombinant polypeptide corresponding to the BDV X-derived segment
A vector comprising a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence ranging from glycine at position 59 to alanine at position 85 in SEQ ID NO:1 or having at least 90% identity with the amino acid sequence ranging from glycine at position 59 to alanine at position 85 in the amino acid sequence SEQ ID NO:1, wherein the polypeptide consists of 86 amino acids or less.
A transformed host cell for expressing a recombinant polypeptide corresponding to the BDV X-derived segment
A prokaryotic or eukaryotic host cell genetically transformed with at least one nucleic acid molecule encoding a recombinant polypeptide comprising an amino acid sequence ranging from glycine at position 59 to alanine at position 85 in SEQ ID NO:1 or having at least 90% identity with the amino acid sequence ranging from glycine at position 59 to alanine at position 85 in the amino acid sequence SEQ ID NO:1, wherein the polypeptide consists of 86 amino acids or less.
A pharmaceutical composition with a recombinant polypeptide corresponding to the BDV X-derived segment
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a recombinant polypeptide comprising an amino acid sequence ranging from glycine at position 59 to alanine at position 85 in SEQ ID NO:1 or having at least 90% identity with the amino acid sequence ranging from glycine at position 59 to alanine at position 85 in the amino acid sequence SEQ ID NO:1, wherein the polypeptide consists of 86 amino acids or less.
Overall, the independent claims consistently require a BDV X-derived polypeptide segment defined by SEQ ID NO:1 positions 59 to 85 with either the specified sequence or at least 90% identity, and a size constraint of 86 amino acids or less. The earlier claims additionally require fusion proteins with at least one heterologous polypeptide, while later claims cover recombinant polypeptides without that fusion requirement, together with corresponding nucleic acids, vectors, host cells, and pharmaceutical compositions.
Stated Advantages
Protection of neurons and axons against mitochondrial complex I toxins.
Preservation of mitochondrial function, including mitochondrial membrane potential.
Reduced oxidative stress and ROS production.
Promotion of mitochondrial hyperfilamentation.
Selective reduction of Drp1 phosphorylation (Ser616) and limitation of mitochondrial fission.
Documented Applications
Use in microfluidic neuron culture chambers and in vivo mouse PD models to assess neuroprotection.
Therapeutic administration concepts including intranasal delivery and intra-cerebroventricular (ICV) delivery.
Application to neurodegenerative disease contexts referenced in the partial content, including PD (Parkinson’s disease), and mention of neurodegenerative diseases such as AD and ALS.
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