Nuclear stress response in motor neuron disease and other neurological diseases

Patent metadata

Field	Value
Publication number	US-10359436-B2
Application number	US-201815967489-A
Country	US
Kind code	B2
Filing date	Apr 30, 2018
Priority date	Nov 7, 2013
Publication date	Jul 23, 2019
Grant date	Jul 23, 2019

Abstract

The invention relates to diagnosis, prognosis and treatment of neurological diseases. In one embodiment, the present invention provides methods and kits that diagnose whether a subject has a neurological disease or susceptibility to a neurological disease by evaluating nuclear stress body (NSB) levels. Further described are methods and kits that prognose a neurological disease in a subject by monitoring changes in NSB levels. Also described are methods and kits that treat neurological diseases by administering one or more inhibitors of NSB signaling to a patient, as well as compositions containing one or more NSB signaling inhibitors. Medical conditions suitable with various embodiments of the invention include but are not limited to ALS, FTLD, dementia and AD.

First claim

What is claimed is:

1. A method of detecting a neurodegenerative disease or susceptibility to a neurodegenerative disease, comprising:
obtaining a biological sample from a subject;
determining a level of nuclear stress bodies (NSBs) comprising RNA binding motif protein 45 (RBM45), heat shock transcription factor 1 (HSF1), or both in the biological sample using an image-based approach selected from the group consisting of: fluorescence microscopy, digital deconvolution, speckle analysis, colocalization analysis, and combinations thereof; and
diagnosing the subject as having a neurodegenerative disease or having susceptibility to a neurodegenerative disease if the level of NSBs comprising RBM45, HSF1, or both in the biological sample is determined to be higher than a normal control or subject.

2. The method of claim 1 , wherein the subject is a human.

3. The method of claim 1 , wherein the neurodegenerative disease is amyotrophic lateral sclerosis (ALD), frontotemporal lobar degeneration (FTLD), dementia, or Alzheimer's disease (AD).

4. The method of claim 1 , wherein the biological sample comprises a cell, neuron, glia, brain cell, spinal cord cell, brain neuron, brain glia, spinal cord neuron, spinal cord glia, motor neuron, or a combination thereof.

5. The method of claim 1 , wherein said determining is performed by:
contacting the biological sample with a detection agent that specifically binds to NSBs comprising RBM45, HSF1, or both; and
using the image-based approach for detecting the level of binding between NSBs comprising RBM45, HSF1, or both and the detection agent.

6. The method of claim 5 , where the detection agent is nucleic acid, DNA, RNA, an aptamer, or a combination thereof.

7. The method of claim 5 , wherein the detection agent is an antibody, an aptamer, or a combination thereof.

8. A method of diagnosing whether a subject has a neurodegenerative disease or has a susceptibility to a neurodegenerative disease, comprising:
obtaining a biological sample from the subject;
determining a level of nuclear stress bodies (NSBs) comprising RNA binding motif protein 45 (RBM45), heat shock transcription factor 1 (HSF1), or both in the biological sample using an image-based approach selected from the group consisting of: fluorescence microscopy, digital deconvolution, speckle analysis, colocalization analysis, and combinations thereof; and
diagnosing the subject as having a neurodegenerative disease or having susceptibility to a neurodegenerative disease if the level of NSBs comprising RBM45, HSF1, or both in the biological sample determined to be higher than a normal control or subject.

9. The method of claim 8 , wherein said determining is performed by:
contacting the biological sample with a detection agent that specifically binds to NSBs comprising RBM45, HSF1, or both; and
using the image-based approach for detecting the level of binding between NSBs comprising RBM45, HSF1, or both and the detection agent.

10. The method of claim 8 , wherein the neurodegenerative disease is amyotrophic lateral sclerosis (ALD), frontotemporal lobar degeneration (FTLD), dementia, or Alzheimer's disease (AD).

11. A method of prognosing a neurodegenerative disease in a subject, comprising:
obtaining a biological sample from the subject;
determining a level of nuclear stress bodies (NSBs) comprising RNA binding motif protein 45 (RBM45), heat shock transcription factor 1 (HSF1), or both in the biological sample using an image-based approach selected from the group consisting of: fluorescence microscopy, digital deconvolution, speckle analysis, colocalization analysis, and combinations thereof; and
prognosing the subject as having a poor prognosis if the level of NSBs comprising RBM45, HSF1, or both in the biological sample is increased in comparison to an earlier time point, or prognosing the subject as having a good prognosis if the level of NSBs comprising RBM45, HSF1, or both in the biological sample is decreased in comparison to an earlier time point.

12. The method of claim 11 , wherein the poor prognosis comprises susceptibility to a neurodegenerative disease, increased probability of developing a neurodegenerative disease, increased behavior deficit, decreased motor function, decreased cognitive function, decreased survival likelihood, shortened life expectancy, or a combination thereof.

13. The method of claim 11 , said determining is performed by:
contacting the biological sample with a detection agent that specifically binds to NSBs comprising RBM45, HSF1, or both; and
using the image-based approach for detecting the level of binding between NSBs comprising RBM45, HSF1, or both and the detection agent.

14. The method of claim 11 , wherein the subject received, is receiving, or will receive a neurodegenerative disease treatment.

15. The method of claim 11 , wherein the biological sample is obtained before, during, or after a neurodegenerative disease treatment.

16. The method of claim 11 , wherein the neurodegenerative disease is amyotrophic lateral sclerosis (ALD), frontotemporal lobar degeneration (FTLD), dementia, or Alzheimer's disease (AD).

Assignees

• Dignity Health

Inventors

• Bowser Robert
• Collins Mahlon

Classifications

• G01N2800/28

  Neurological disorders · CPC title

• G01N33/6875

  Nucleoproteins · CPC title

• G01N2800/52

  Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• G01N2800/50

  Determining the risk of developing a disease · CPC title