Nuclear stress response in motor neuron disease and other neurological diseases

Patent metadata

Field	Value
Publication number	US-9983217-B2
Application number	US-201415028680-A
Country	US
Kind code	B2
Filing date	Nov 7, 2014
Priority date	Nov 7, 2013
Publication date	May 29, 2018
Grant date	May 29, 2018

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 for diagnosing whether a subject has amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), dementia, or Alzheimer's disease (AD), comprising:
obtaining a biological sample from the subject;
determining a level of nuclear stress bodies (NSBs) comprising RBM45 and/or HSF1 or determining the presence of nuclear stress bodies (NSBs) comprising RBM45 and/or HSF1 in the biological sample using an image-based approach comprising fluorescence microscopy, digital deconvolution, speckle analysis, colocalization analysis, or a combination thereof; and
diagnosing the subject as having amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), dementia, or Alzheimer's disease (AD) if the level of NSBs comprising RBM45 and/or HSF1 in the biological sample is determined to be higher than a normal subject or if NSBs comprising RBM45 and/or HSF1 are determined to be present in the biological sample.

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

3. 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.

4. 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 and/or HSF1, and
using the image-based approach for detecting the level of binding between NSBs comprising RBM45 and/or HSF1 and the detection agent.

5. The method of claim 4 , where the detection agent is an antibody, nucleic acid, DNA, RNA, aptamer, or a combination thereof.

6. 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 and/or HSF1; and
using the image-based approach for detecting whether binding occurs between NSBs comprising RBM45 and/or HSF1 and the detection agent.

7. The method of claim 1 , wherein determining the level of NSBs comprising RBM45 and/or HSF1 or the presence of NSBs comprising RBM45 and/or HSF1 comprises:
contacting the biological sample with a detection agent;
using the image-based approach for imaging the detection agent in the biological sample;
performing digital deconvolution and/or automated imaging analysis on the image obtained from the biological sample; and
assessing redistribution and/or colocalization of the detection agent in the biological sample imaged.

8. A method for diagnosing whether a subject has susceptibility to amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), dementia, or Alzheimer's disease (AD), comprising:
obtaining a biological sample from the subject,
determining a level of nuclear stress bodies (NSBs) comprising RBM45 and/or HSF1 or determining the presence of nuclear stress bodies (NSBs) comprising RBM45 and/or HSF1 in the biological sample using an image-based approach comprising fluorescence microscopy, digital deconvolution, speckle analysis, colocalization analysis, or a combination thereof; and
diagnosing the subject as having susceptibility to amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), dementia, or Alzheimer's disease (AD) if the level of NSBs comprising RBM45 and/or HSF1 in the biological sample is determined to be higher than a normal subject or if NSBs comprising RBM45 and/or HSF1 are determined to be present in the biological sample.

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 and/or HSF1; and
using the image-based approach for detecting the level of binding between NSBs comprising RBM45 and/or HSF1 and the detection agent.

10. 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 and/or HSF1; and
using the image-based approach for detecting whether binding occurs between NSBs comprising RBM45 and/or HSF1 and the detection agent.

11. The method of claim 8 , wherein determining the level of NSBs comprising RBM45 and/or HSF1 or the presence of NSBs comprising RBM45 and/or HSF1 comprises:
contacting the biological sample with a detection agent;
using the image-based approach for imaging the detection agent in the biological sample;
performing digital deconvolution and/or automated imaging analysis on the image obtained from the biological sample; and
assessing redistribution and/or colocalization of the detection agent in the biological sample imaged.

12. A method for prognosing amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), dementia, or Alzheimer's disease (AD) in a subject, comprising:
obtaining a biological sample from the subject,
determining a level of nuclear stress bodies (NSBs) comprising RBM45 and/or HSF1 in the biological sample using an image-based approach comprising fluorescence microscopy, digital deconvolution, speckle analysis, colocalization analysis, or a combination thereof; and
prognosing the subject as having a poor prognosis if the level of NSBs comprising RBM45 and/or HSF1 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 and/or HSF1 in the biological sample is decreased in comparison to an earlier time point.

13. The method of claim 12 , wherein the poor prognosis comprises susceptibility to amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), dementia, or Alzheimer's disease (AD), increased probability of developing amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), dementia, or Alzheimer's disease (AD), increased behavior deficit, decreased motor function, decreased cognitive function, decreased survival likelihood, or shortened life expectancy, or a combination thereof.

14. The method of claim 12 , wherein said determining is performed by:
contacting the biological sample with a detection agent that specifically binds to NSBs comprising RBM45 and/or HSF1; and
using the image-based approach for detecting the level of binding between NSBs comprising RBM45 and/or HSF1 and the detection agent.

15. The method of claim 12 , wherein the subject received, is receiving, or will receive a treatment for amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), dementia, or Alzheimer's disease (AD).

16. The method of claim 15 , wherein the biological sample is obtained before, during, or after the treatment for amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), dementia, or Alzheimer's disease (AD).

17. The method of claim 12 , wherein determining the level of NSBs comprising RBM45 and/or HSF1 or the presence of NSBs comprising RBM45 and/or HSF1 comprises:
contacting the biological sample with a detection agent;
using the image-based approach for imaging the detection agent in the biological sample;
performing digital deconvolution and/or automated imaging analysis on the image obtained from the biological sample; and
assessing redistribution and/or colocalization of the detection agent in the biological sample imaged.

Assignees

• Dignity Health

Inventors

• Bowser Robert
• Collins Mahlon

Classifications

• G01N33/6896 Primary

  Neurological disorders, e.g. Alzheimer's disease · CPC title

• G01N2800/50

  Determining the risk of developing a disease · CPC title

• G01N33/6875

  Nucleoproteins · CPC title

• G01N2800/28

  Neurological disorders · CPC title

• C07K16/18

  against material from animals or humans · CPC title