# US 2025/0085272 A1 · Methods and systems for modulating and modeling aging and neurodegeneration diseases

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- Number: US 2025/0085272 A1
- Document ID: US20250085272A1
- Status: Published application
- Kind: A1
- Application number: 18/960,311
- Filed: 2024-11-26
- Published: 2025-03-13
- Earliest claimed: 2022-05-26
- Assignees: Memorial Sloan Kettering Cancer Center
- Applicants: Memorial Sloan-Kettering Cancer Center
- Inventors: Nathalie SAURAT; Lorenz STUDER
- Web page: https://patentgrep.com/patent/US20250085272A1

## CPC

- G01N 33/5058: {Neurological cells}
- C12N 5/0619: {Neurons}
- G01N 33/5023: {on expression patterns}
- G01N 33/5038: {involving detection of metabolites per se}
- G01N 33/5073: {Stem cells}
- G01N 33/5091: {for testing the pathological state of an organism}
- G01N 33/6896: {Neurological disorders, e.g. Alzheimer's disease}
- C12N 2501/13: Nerve growth factor [NGF]; Brain-derived neurotrophic factor [BDNF]; Cilliary neurotrophic factor [CNTF]; Glial-derived neurotrophic factor [GDNF]; Neurotrophins [NT]; Neuregulins
- C12N 2501/15: Transforming growth factor beta (TGF-β)
- C12N 2501/155: Bone morphogenic proteins [BMP]; Osteogenins; Osteogenic factor; Bone inducing factor
- C12N 2501/727: Kinases (EC 2.7.)
- C12N 2501/998: Proteins not provided for elsewhere
- C12N 2503/02: Drug screening
- C12N 2506/02: from embryonic cells
- C12N 2510/00: Genetically modified cells
- C12N 2533/52: Fibronectin; Laminin
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present disclosure relates to methods for modulating cellular aging and/or progression of neurodegenerative diseases (e.g., AD). In certain embodiments, the methods induce cellular aging. In certain embodiments, the methods promote progression of neurodegenerative diseases (e.g., AD). The present disclosure also relates to methods and systems for modeling aging related neurodegenerative diseases (e.g., AD) in vitro. In certain embodiments, the methods disclosed herein comprise inhibiting protein neddylation pathway. In certain embodiments, inhibiting protein neddylation pathway comprises knocking out or knocking down genes (e.g., UBA3, NAE1) that regulate protein neddylation pathway. In certain embodiments, inhibiting protein neddylation pathway comprises administration a neddylation inhibitor (e.g., MLN4924) to cells.

## Claims

### Claim 1

A method of preparing an in vitro model of neurodegenerative disease comprising modulating protein neddylation in a population of neurons; wherein the population of neurons exhibit genetic mutation of at least one gene that is associated with neurodegenerative disease.

### Claim 2 (depends on 1)

The method of claim 1, wherein modulating protein neddylation comprises exposing the population of neurons to a compound that modulates protein neddylation.

### Claim 3 (depends on 2)

The method of claim 2, wherein the at least one compound that modulates protein neddylation is selected from the group consisting of MLN4924, TAS4464, CSN5i-3, ZM223, NACM-OPT, Keap1-Nrf2-IN-4, WS-383, VII-31, derivatives thereof, and combinations thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein modulating protein neddylation comprises modifying expression of at least one gene which regulates protein neddylation pathways.

### Claim 5 (depends on 4)

The method of claim 4, wherein the at least one gene which regulates protein neddylation pathways is selected from the group consisting of UBA3, NAE1, and combinations thereof.

### Claim 6 (depends on 1)

The method of claim 1, wherein the mutation of at least one gene that is associated with neurodegenerative disease results in increased production of amyloid-beta peptide.

### Claim 7 (depends on 1)

The method of claim 1, wherein the mutation of at least one gene that is associated with neurodegenerative disease results in a change in the ratio of Aβ40 to Aβ42 peptide.

### Claim 8 (depends on 1)

The method of claim 1, wherein the at least one gene that is associated with neurodegenerative disease comprises the Amyloid-beta precursor protein (APP) gene.

### Claim 9 (depends on 8)

The method of claim 8, wherein the mutation of the APP gene comprises K595N/M596L.

### Claim 10 (depends on 1)

The method of claim 1, wherein the at least one gene that is associated with neurodegenerative disease comprises the presenilin-1 (PSEN) gene.

### Claim 11 (depends on 10)

The method of claim 10, wherein the mutation of the PSEN gene comprises M146V.

### Claim 12 (depends on 1)

The method of claim 1, wherein the mutation of at least one gene that is associated with neurodegenerative disease results in increased production of N-ethylmaleimide sensitive factor (NSF) aggregates.

### Claim 13 (depends on 1)

The method of claim 1, wherein the at least one gene that is associated with neurodegenerative disease comprises the (LRRK2) gene.

### Claim 14 (depends on 13)

The method of claim 13, wherein the mutation of the LRRK2 gene comprises G2019S.

### Claim 15 (depends on 1)

The method of claim 1, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), or Huntington's disease.

### Claim 16 (depends on 1)

The method of claim 1, wherein the neurons are obtained from in vitro differentiation of stem cells.

### Claim 17 (depends on 16)

The method of claim 16, wherein the stem cells are human stem cells selected from the group consisting of human embryonic stem cells, human induced pluripotent stem cells, human parthenogenetic stem cells, human primordial germ cell-like pluripotent stem cells, human epiblast stem cells, human F-class pluripotent stem cells, and combinations thereof.

### Claim 18 (depends on 1)

The method of claim 1, wherein the neurons are cortical neurons.

### Claim 19

A method of identifying genes associated with cellular aging and/or progression of neurodegenerative disease comprising:
a) obtaining a first population of neurons;
b) obtaining a second population of neurons, and modifying expression of a test gene in the second population of neurons;
c) measuring functional activity of the second population of neurons relative to the first population of neurons;
wherein the first population of neurons and the second population of neurons exhibit genetic mutation of at least one gene that is associated with neurodegenerative disease;
wherein a difference in the functional activity between the first population of neurons and the second population of neurons indicates that the test gene is associated with cellular aging and/or progression of neurodegenerative disease.

### Claim 20

A composition for identifying genes associated with cellular aging and/or progression of neurodegenerative disease comprising a population of neurons, wherein the population of neurons exhibit genetic mutation at a test gene, wherein the population of neurons exhibit genetic mutation of at least one gene that is associated with neurodegenerative disease.