TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS

• US 20200131236A1
• Filed: 01/10/2020
• Published: 04/30/2020
• Est. Priority Date: 10/11/2012
• Status: Active Grant

• Current Assignee: Brandeis University
• Original Assignee: Brandeis University
• Inventors: Petsko, Greg, Ringe, Dagmar, Ju, Shulin
• Granted Patent: US 11,332,504 B2
• Time in Patent Office: 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
• CPC Class Codes: A01K 2207/10 Animals modified by protein administration, for non-therapeutic purpose
• 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
• CPC Class Codes: A01K 2267/03 Animal model, e.g. for test or diseases
• CPC Class Codes: A01K 2267/0306 Animal model for genetic diseases
• CPC Class Codes: A01K 2267/0318 Animal model for neurodegenerative disease, e.g. non- Alzheimer's
• CPC Class Codes: A01K 2267/0393 Animal model comprising a reporter system for screening tests
• CPC Class Codes: A01K 67/0275 Genetically modified vertebrates, e.g. transgenic
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• 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
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/17 from animals; from humans enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 38/1709 from mammals
• 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
• CPC Class Codes: A61P 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: C07K 14/47 : from mammals
• CPC Class Codes: C12N 15/85 : for animal cells
• CPC Class Codes: C12Q 1/025 : for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics antimicrobial activity C12Q1/18
• CPC Class Codes: C12Q 1/6883 : for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/106 : Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: G01N 2333/47 : Assays involving proteins of known structure or function as defined in the subgroups
• CPC Class Codes: G01N 2500/10 : involving cells
• CPC Class Codes: G01N 2800/56 : Staging of a disease; Further complications associated with the disease
• 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. (canceled)

2. A method of treating amyotrophic lateral sclerosis (ALS) in a human subject in need thereof, the method comprising:

administering to the human subject a therapeutically effective amount of a UPF1 polypeptide or a nucleic acid encoding a UPF1 polypeptide;

wherein the human subject does not have a mutation in a SOD1 gene and wherein the UPF1 polypeptide comprises the amino acid sequence of SEQ ID NO;

2.

3. The method of claim 2, wherein the step of administering comprises administering to the human subject a composition comprising the UPF1 polypeptide or the nucleic acid encoding the UPF1 polypeptide.

4. The method of claim 3, wherein the step of administering comprises administering to the human subject a vector comprising the nucleic acid encoding the UPF1 polypeptide.

7. The method of claim 2, wherein the UPF1 polypeptide or the nucleic acid encoding the UPF1 polypeptide is administered into the CNS of the human subject.

8. The method of claim 2, wherein the UPF1 polypeptide or the nucleic acid encoding the UPF1 polypeptide is administered to the subject by intrathecal injection, intraventricular injection, paraspinal injection, and/or epidural injection.

17. The method of claim 2, wherein the UPF1 polypeptide or the nucleic acid encoding the UPF1 polypeptide is administered as part of a combination therapy comprising riluzole, baclofen, diazepam, trihexyphenidyl, or amitriptyline.

18. The method of claim 2, wherein the UPF1 polypeptide or the nucleic acid encoding the UPF1 polypeptide is administered as part of a combination therapy comprising an immunosuppressant.

19. The method of claim 18, wherein the immunosuppressant is selected from the group consisting of cyclosporine, FK506, rapamycin, daclizumab, CTLA4-Ig, an anti-TNF agent, an anti-CD2 agent, an anti-CD4 agent, and an anti-CD40 agent.

5. The method of claim 5, wherein the vector is a viral vector.

6. The method of claim 6, wherein the viral vector is a retroviral vector, a lentiviral vector, an adenoviral vector, or an adeno-associated viral vector.

9. A method of reducing FUS/TLS-mediated neuronal cytotoxicity in a human subject in need thereof, the method comprising:

administering to the human subject a therapeutically effective amount of a UPF1 polypeptide or a nucleic acid encoding a UPF1 polypeptide, thereby reducing the FUS/TLS-mediated neuronal cytotoxicity in the human subject;

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

2.

10. The method of claim 9, wherein the human subject is suffering from ALS.

11. The method of claim 9, wherein the step of administering comprises administering to the human subject a composition comprising the UPF1 polypeptide or the nucleic acid encoding the UPF1 polypeptide.

12. The method of claim 9, wherein the step of administering comprises administering to the subject a vector comprising the nucleic acid encoding the UPF1 polypeptide.

13. The method of claim 12, wherein the vector is a viral vector.

14. The method of claim 13, wherein the viral vector is a retroviral vector, a lentiviral vector, an adenoviral vector, or an adeno-associated viral vector.

15. The method of claim 9, wherein the UPF1 polypeptide or the nucleic acid encoding the UPF1 polypeptide is administered into the CNS of the human subject.

16. The method of claim 9, wherein the UPF1 polypeptide or the nucleic acid encoding the UPF1 polypeptide is administered to the human subject by intrathecal injection.