# US 2023/0054101 A1 · Treatment of amyotrophic lateral sclerosis

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- Number: US 2023/0054101 A1
- Document ID: US20230054101A1
- Status: Published application
- Kind: A1
- Application number: 17/721,715
- Filed: 2022-04-15
- Published: 2023-02-23
- Earliest claimed: 2012-10-11
- Assignees: Brandeis University
- Applicants: Brandeis University
- Inventors: Greg Petsko; Dagmar Ringe; Shulin Ju
- Web page: https://patentgrep.com/patent/US20230054101A1

## CPC

- C07K 14/47: from mammals
- 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)}
- A61K 38/17: from animals; from humans {(enzyme inhibitors A61K38/005)}
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- 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
- C12Q 1/025: {for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics (antimicrobial activity C12Q1/18)}
- G01N 33/5058: {Neurological cells}
- A01K 67/0275: Genetically modified vertebrates, e.g. transgenic
- A01K 2207/05: Animals modified by non-integrating nucleic acids, e.g. antisense, RNAi, morpholino, episomal vector, for non-therapeutic purpose
- A01K 2207/10: Animals modified by protein administration, for non-therapeutic purpose
- A01K 2207/20: Animals treated with compounds which are neither proteins nor nucleic acids
- A01K 2217/206: Animal model comprising tissue-specific expression system, e.g. tissue specific expression of transgene, of Cre recombinase
- A01K 2267/03: Animal model, e.g. for test or diseases
- A01K 2267/0306: Animal model for genetic diseases
- A01K 2267/0318: Animal model for neurodegenerative disease, e.g. non- Alzheimer's
- A01K 2267/0393: Animal model comprising a reporter system for screening tests
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- 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
- A61K 31/7115: Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
- A61K 31/7125: Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
- 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)
- 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)
- A61K 38/1709: {from mammals}
- A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- 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}
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- C12N 15/85: for animal cells
- C12Q 1/6883: for diseases caused by alterations of genetic material
- C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
- G01N 33/5023: {on expression patterns}
- G01N 2333/47: Assays involving proteins of known structure or function as defined in the subgroups
- G01N 2500/10: involving cells
- G01N 2800/56: Staging of a disease; Further complications associated with the disease
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## 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

### Claim at position 1

1-52. (canceled)

### Claim 53

A method of reducing TAR-DNA-binding protein 43 (TDP-43)-mediated neuronal cytotoxicity in a human subject suffering from amyotrophic lateral sclerosis (ALS), wherein the subject does not have a mutation in a SOD1 gene, the method comprising:
administering to the subject a composition comprising a UPF2 polypeptide or a nucleic acid encoding the UPF2 polypeptide, thereby reducing the TDP-43 mediated neuronal cytotoxicity in the subject,
wherein the UPF2 polypeptide comprises the amino acid sequence of SEQ ID NO:4.

### Claim 54 (depends on 53)

The method of claim 53, wherein the composition is administered into the central nervous system of the subject.

### Claim 55 (depends on 53)

The method of claim 53, wherein the composition comprises the nucleic acid encoding the UPF2 polypeptide.

### Claim 56 (depends on 53)

The method of claim 53, wherein the composition comprises a vector comprising the nucleic acid encoding the UPF2 polypeptide.

### Claim 57 (depends on 56)

The method of claim 56, wherein the vector is a viral vector.

### Claim 58 (depends on 7)

The method of claim 07, wherein the viral vector is a retroviral vector, a lentiviral vector, an adenoviral vector, or an adeno-associated viral vector.

### Claim 59 (depends on 53)

The method of claim 53, wherein the composition is administered to the subject by intrathecal injection.

### Claim 60

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 or glial cell a composition comprising a UPF2 polypeptide or a nucleic acid encoding a UPF2 polypeptide, thereby reducing the FUS/TLS- or TDP-43-mediated neuronal cytotoxicity in the neuronal or glial cell;
wherein the UPF2 polypeptide comprises the amino acid sequence of SEQ ID NO:4.

### Claim 61 (depends on 60)

The method of claim 60, wherein the neuronal or glial cell is in a subject and wherein the composition is administered into the central nervous system of the subject.

### Claim 62 (depends on 60)

The method of claim 60, wherein the composition comprises the nucleic acid encoding the UPF2 polypeptide.

### Claim 63 (depends on 60)

The method of claim 60, wherein the composition comprises a vector comprising the nucleic acid encoding the UPF2 polypeptide.

### Claim 64 (depends on 63)

The method of claim 63, wherein the vector is a viral vector.

### Claim 65 (depends on 64)

The method of claim 64, wherein the viral vector is a retroviral vector, a lentiviral vector, an adenoviral vector, or an adeno-associated viral vector.

### Claim 66 (depends on 62)

The method of claim 62, wherein the neuronal cytotoxicity is an FUS/TLS-mediated neuronal cytotoxicity.

### Claim 67 (depends on 62)

The method of claim 62, wherein the neuronal cytotoxicity is a TDP-43-mediated neuronal cytotoxicity.

### Claim 68 (depends on 60)

The method of claim 60, wherein the neuronal or glial cell does not have a SOD1 mutation.

### Claim 69 (depends on 60)

The method of claim 60, wherein the composition is administered to a subject by intrathecal injection.