Methods of reducing FUS/TLS- or TDP-43-mediated neuronal cytotoxicity by UPF1

• US 11,332,504 B2
• Filed: 01/10/2020
• Issued: 05/17/2022
• Est. Priority Date: 10/11/2012
• Status: Active Grant

• Current Assignee: Brandeis University
• Original Assignee: Brandeis University
• Inventors: Petsko, Greg, Ringe, Dagmar, Ju, Shulin
• Primary Examiner(s): Wang, Chang-Yu
• Application Number:
  US16/739,561
• Publication Number:
  US 20200131236A1
• Time in Patent Office: 858 Days
• CPC Class Codes: A01K 2207/05 Animals modified by non-integrating nucleic acids, e.g. antisense, RNAi, morpholino, episomal vector, for non-therapeutic purpose
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• CPC Class Codes: A01K 2207/20 Animals treated with compounds which are neither proteins nor nucleic acids
• CPC Class Codes: A01K 2217/206 Animal model comprising tissue-specific expression system, e.g. tissue specific expression of transgene, of Cre recombinase
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• CPC Class Codes: A01K 2267/0318 Animal model for neurodegenerative disease, e.g. non- Alzheimer's
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• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 31/711 Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 31/7115 Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
• CPC Class Codes: A61K 31/7125 Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
• CPC Class Codes: A61K 35/12 Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells vaccines or medicinal preparations containing antigens or antibodies A61K39/00
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• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 48/005 : characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
• CPC Class Codes: A61K 48/0066 : Manipulation of the nucleic acid to modify its expression pattern, e.g. enhance its duration of expression, achieved by the presence of particular introns in the delivered nucleic acid
• CPC Class Codes: A61K 9/0019 : Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
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• CPC Class Codes: C12Q 1/6883 : for diseases caused by alterations of genetic material
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• CPC Class Codes: G01N 2500/10 : involving cells
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• CPC Class Codes: G01N 33/5023 : on expression patterns
• CPC Class Codes: G01N 33/5058 : Neurological cells

Abstract

Nonsense-mediated mRNA decay (NMD) polypeptides, nucleic acids encoding NMD polypeptides, and methods of using such polypeptides and nucleic acids in the treatment of ALS and in screening for agents for the treatment of ALS are described.

Claims

1. A method of reducing fused in sarcoma/translocated in sarcoma (FUS/TLS)- or TAR-DNA-binding protein 43 (TDP-43)-mediated neuronal cytotoxicity, the method comprising:

providing to a neuronal cell a composition comprising a UPF1 polypeptide or a nucleic acid encoding a UPF1 polypeptide, thereby reducing the FUS/TLS- or TDP-43-mediated neuronal cytotoxicity in the neuronal cell;

wherein the UPF1 polypeptide comprises the amino acid sequence of SEQ ID NO;

2.

2. The method of claim 1, wherein the composition comprises the nucleic acid encoding the UPF1 polypeptide.

3. The method of claim 1, wherein the composition comprises a vector comprising the nucleic acid encoding the UPF1 polypeptide.

4. The method of claim 3, wherein the vector is a viral vector.

5. The method of claim 4, wherein the viral vector is a retroviral vector, a lentiviral vector, an adenoviral vector, or an adeno-associated viral vector.

6. The method of claim 2, wherein the neuronal cytotoxicity is an FUS/TLS-mediated neuronal cytotoxicity.

7. The method of claim 2, wherein the neuronal cytotoxicity is a TDP-43-mediated neuronal cytotoxicity.