Methods of using an activator of cereblon for neural cell expansion and the treatment of central nervous system disorders

Patent metadata

Field	Value
Publication number	US-10272117-B2
Application number	US-201515121017-A
Country	US
Kind code	B2
Filing date	Feb 23, 2015
Priority date	Feb 24, 2014
Publication date	Apr 30, 2019
Grant date	Apr 30, 2019

Abstract

Provided herein, for example, are methods generally relating to the expansion and/or regeneration of central nervous system (CNS) cells, such as nerve cells, astrocytes and oligodendrocytes, using an activator of cereblon (CRBN), such as an inhibitor of a CRBN substrate or downstream protein. Also provided herein, for example, are methods related to the expansion of neural stem cells, neural progenitor cells, or neural precursor cells and/or differentiation of these cells into CNS cells using a BRD7 antagonist, Ikaros antagonist, or CRBN activator. In certain embodiments, the methods further comprise differentiation of certain stem cells into the neural stem cells, neural progenitor cells, or neural precursor cells using a BRD7 antagonist, Ikaros antagonist, or CRBN activator. Also provided herein, for example, are methods of preventing or treating a CNS cell defective disease, disorder or condition, or a symptom thereof, using a BRD7 antagonist, Ikaros antagonist, or CRBN activator.

First claim

What is claimed is:

1. A method for assessing efficacy of a Bromodomain Containing 7 (BRD7) antagonist or an Ikaros antagonist in treating a central nervous system (CNS) cell defective disease, disorder or condition, or a symptom thereof, in a patient, comprising:
(i) administering the BRD7 antagonist or Ikaros antagonist to the patient; and
(ii)(A) comparing a CNS cell mass in the patient before and after administration of the BRD7 antagonist or Ikaros antagonist,
wherein an increase in CNS cell mass after administration of the BRD7 antagonist or Ikaros antagonist as compared to before administration of the BRD7 antagonist or Ikaros antagonist is indicative of the efficacy of the BRD7 antagonist or Ikaros antagonist in treating the CNS-cell defective disease, disorder or condition, or symptom thereof; or
(ii)(B) comparing expression level of a Yamanaka factor, Nanog, NeuroD, Zic3, Elavl3, and/or a BAM factor in the patient before and after administration of the BRD7 antagonist or Ikaros antagonist, wherein an increase in the expression levels of the Yamanaka factor, Nanog, NeuroD, Zic3, Elavl3, and/or BAM factor after administration of the BRD7 antagonist or Ikaros antagonist as compared to before administration of the BRD7 antagonist or Ikaros antagonist is indicative of the efficacy of the BRD7 antagonist or Ikaros antagonist in treating the CNS-cell defective disease, disorder or condition, or symptom thereof.

2. The method of claim 1 , wherein the Yamanaka factor is Oct 3/4, Sox2, c-Myc, or Klf4.

3. The method of claim 1 , wherein the BAM factor is Brn2 (Pou3f2), Ascl1 or Myt1l.

4. The method of claim 1 , further comprising one or more subsequent administrations of the BRD7 antagonist or Ikaros antagonist to the patient following the assessment of efficacy.

5. The method of claim 1 , further comprising
(I) selecting a group of patients having a CNS cell defective disease, disorder or condition, or a symptom thereof, based on CNS cell mass for the purposes of predicting clinical response, monitoring clinical response, or monitoring patient compliance to dosing with the BRD7 antagonist or Ikaros antagonist; or
(II) selecting a group of patients having a CNS cell defective disease, disorder or condition, or a symptom thereof, based on expression level of a Yamanaka factor, Nanog, NeuroD, Zic3, Elavl3, and/or BAM factor in the patient, for the purposes of predicting clinical response, monitoring clinical response, or monitoring patient compliance to dosing with a BRD7 antagonist or Ikaros antagonist.

6. The method of claim 5 , wherein the Yamanaka factor is Oct 3/4, Sox2, c-Myc, or Klf4.

7. The method of claim 5 , wherein and the BAM factor is Brn2 (Pou3f2), Ascl1 or Myt1l.

8. The method of claim 1 , wherein the CNS cell defective disease, disorder or condition is a disease of cerebral cortex, a surgical injury of cerebral cortex, or a neurodegenerative disease.

9. The method of claim 1 , wherein the CNS cell disease, disorder or condition is selected from a group consisting of Parkinson's disease; Alzheimer's disease; Creutzfeldt-Jakob disease; corticobasal degeneration; Amyotrophic Lateral Sclerosis; Multiple Sclerosis; progressive motor weakness; neuroimmunological disorders, CNS trauma; Alzheimer disease with parkinsonism; bradykinesia; alkinesia; movement disorders that impair fine motor control and finger dexterity; hypophonia; monotonic speech; rigidity; dystonia; inflammation associated with Parkinson Disease; tremors of the face, jaw, tongue, posture; parkinsonian gait; shuffling; short steps; festinating gait; disorders of mood, cognition, sensation, sleep; dementia; depression; drug induced parkinsonism; vascular parkinsonism; multiple system atrophy; progressive supranuclear palsy; disorders with primary tau pathology; cortical basal ganglia degeneration; parkinsonism with dementia; hyperkinetic disorders; chorea; Huntington's disease; dystonia; Wilson's disease; Tourette syndrome; essential tremor; myoclonus; and a tardive dyskinesia movement disorder.

10. The method of claim 9 , wherein the CNS cell disease, disorder or condition is Alzheimer's disease.

11. The method of claim 9 , wherein the CNS cell disease, disorder or condition is Parkinson's disease.

12. The method of claim 1 , wherein the BRD7 antagonist is selected from a group consisting of an inhibitor of BRD7 protein, a nucleic acid comprising at least part of nucleic acid sequence of BRD7 gene, and a stem cell, neural progenitor cell, or neural precursor cell in which BRD7 is down-regulated.

13. The method of claim 12 , wherein the BRD7 antagonist is an inhibitor of BRD7 protein, wherein the inhibitor of BRD7 protein is selected from a group consisting of an inhibitor of BRD7 production, an inhibitor of BRD7 action, and a nucleic acid comprising a coding region of an inhibitor of BRD7.

14. The method of claim 12 , wherein the BRD7 antagonist is a nucleic acid comprising at least part of nucleic acid sequence of BRD7 gene, wherein the nucleic acid is inserted in a vector or the nucleic acid is an antisense molecule specific to a BRD7 gene, the antisense molecule being optionally an RNAi molecule.

15. The method of claim 12 , wherein the BRD7 antagonist is a Morpholino oligonucleotide specific to BRD7 gene.

16. The method of claim 15 , wherein the Morpholino oligonucleotide comprises a sequence of SEQ ID NO: 1.

17. The method of claim 12 , wherein the BRD7 antagonist is a stem cell, neural progenitor cell or neural precursor cell in which BRD7 is down-regulated; an induced pluripotent stem (iPS) cell; an antagonist inducing proliferation of cells selected from a group consisting of nerve cells, progenitors of nerve cells, and precursors of nerve cells;
or an antagonist inducing differentiation into nerve cells.

18. The method of claim 1 , wherein the Ikaros antagonist is selected from a group consisting of an inhibitor of Ikaros protein, a nucleic acid comprising at least part of nucleic acid sequence of Ikaros gene, and a stem cell, neural progenitor cell, or neural precursor cell in which Ikaros is down-regulated.

19. The method of claim 18 , wherein the Ikaros antagonist is an inhibitor of Ikaros protein, wherein the inhibitor of Ikaros protein is selected from a group consisting of an inhibitor of Ikaros production, an inhibitor of Ikaros action, and a nucleic acid comprising a coding region of an inhibitor of Ikaros.

20. The method of claim 18 , wherein the Ikaros antagonist is a nucleic acid comprising at least part of nucleic acid sequence of Ikaros gene, wherein the nucleic acid is inserted in a vector or the nucleic acid is an antisense molecule specific to an Ikaros gene, the antisense molecule being optionally an RNAi molecule.

21. The method of claim 18 , wherein the Ikaros antagonist is a Morpholino oligonucleotide specific to Ikaros gene.

22. The method of claim 21 , wherein the Morpholino oligonucleotide comprises a sequence of SEQ ID NO: 2.

23. The method of claim 18 , wherein the Ikaros antagonist is a stem cell, neural progenitor cell or neural precursor cell in which Ikaros is down-regulated; an induced pluripotent stem (iPS) cell; an antagonist inducing proliferation of cells selected from a group consisting of nerve cells, progenitors of nerve cells, and precursors of nerve cells; or an antagonist inducing differentiation into nerve cells.

Assignees

• Celgene Corp

Inventors

• Handa Hiroshi
• Ando Hideki
• Ito Takumi

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P25/28

  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 title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title