Mutations in PDGFRB and NOTCH3 as causes of autosomal dominant infantile myofibromatosis

Patent metadata

Field	Value
Publication number	US-9822418-B2
Application number	US-201414786425-A
Country	US
Kind code	B2
Filing date	Apr 22, 2014
Priority date	Apr 22, 2013
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

This invention relates to a method of diagnosing a subject as having and/or being a carrier for infantile myofibromatosis. This method involves providing an isolated biological sample from a subject; contacting the sample with one or more reagents suitable for detecting the presence or absence of one or more mutations in PDGFRB and/or NOTCH3; detecting, in the sample, the presence or absence of the one or more mutations in PDGFRB and/or NOTCH3 based on said contacting; and diagnosing the subject as having and/or being a carrier for infantile myofibromatosis based on said detecting, where the presence of the one or more mutations in PDGFRB and/or NOTCH3 indicates the subject has a mutation that causes infantile myofibromatosis. Also disclosed is a method of treating a subject having infantile myofibromatosis and a method of preventing or treating symptoms associated with infantile myofibromatosis.

First claim

What is claimed:

1. A method of treating a subject having one or more missense mutations in PDGFRB and/or NOTCH, said method comprising:
providing an isolated biological sample from a subject;
contacting the sample with one or more reagents suitable for detecting the presence of one or more missense mutations in PDGFRB and/or NOTCH3;
detecting, in the sample, the presence of the one or more mutations in PDGFRB and/or NOTCH3 based on said contacting; and
administering a therapy suitable for treatment of infantile myofibromatosis to a subject identified as having one or more mutations in PDGFRB and/or NOTCH3.

2. The method according to claim 1 , wherein the biological sample comprises a blood sample.

3. The method according to claim 1 , wherein the one or more mutations is in PDGFRB and encode an amino acid substitution at one or more amino acid residues corresponding to amino acid position 561 and/or 660 of SEQ ID NO:2, and the one or more mutations in NOTCH3 encode an amino acid substitution at an amino acid residue corresponding to amino acid position 1519 of SEQ ID NO:4.

4. The method according to claim 3 , wherein the amino acid substitution in NOTCH3 comprises a leucine to proline substitution at the amino acid position corresponding to Leu1519 of SEQ ID NO:4.

5. The method according to claim 1 , wherein said detecting comprises sequencing at least a portion of a nucleotide sequence in the sample corresponding to PDGFRB and/or NOTCH3.

6. The method according to claim 1 , wherein said detecting comprises:
carrying out a hybridization assay with one or more oligonucleotide probes having a nucleotide sequence that is complementary to a nucleotide sequence of a nucleic acid molecule in a sample comprising the one or more mutations in PDGFRB and/or NOTCH3.

7. The method according to claim 1 , wherein said detecting comprises carrying out an amplification-based assay with one or more oligonucleotide primers suitable for hybridization to and amplification of a nucleic acid molecule comprising the one or more mutations in PDGFRB and/or NOTCH3.

8. A method of treating a subject having infantile myofibromatosis, said method comprising:
selecting a subject having one or more missense mutations in PDGFRB and/or NOTCH3 and
administering an agent that modulates mutant PDGFRB and/or NOTCH3 gene expression and/or mutant PDGFRB and/or NOTCH3 encoded protein activity to the selected subject thereby treating infantile myofibromatosis.

9. The method according to claim 8 , wherein the one or more mutation in PDGFRB encodes an amino acid substitution at one or more amino acid residue corresponding to amino acid position 561 and/or 660 of SEQ ID NO:2, and the one or more mutation in NOTCH3 encodes an amino acid substitution at an amino acid residue corresponding to amino acid position 1519 of SEQ ID NO:4.

10. The method according to claim 9 , wherein the amino acid substitution in NOTCH3 comprises a leucine to proline substitution at the amino acid position corresponding to Leu1519 of SEQ ID NO:4.

11. A method of preventing or treating symptoms associated with infantile myofibromatosis comprising:
(i) selecting a subject having decreased levels of PDGFRB and/or NOTCH3 RNA and/or protein compared to a subject having normal levels of PDGFRB and/or NOTCH3 RNA and/or protein, or selecting a subject having one or more mutations in PDGFRB and/or NOTCH3; and
(ii) administering to the selected subject an agent that modulates PDGFRB and/or NOTCH3 gene expression and/or PDGFRB and/or NOTCH3 encoded protein activity under conditions effective to prevent or treat symptoms associated with infantile myofibromatosis in the subject.

12. The method according to claim 11 , wherein the agent modulates mutant PDGFRB and/or NOTCH3 gene expression and/or mutant PDGFRB and/or NOTCH3 encoded protein activity.

13. The method according to claim 11 , wherein the one or more mutation in PDGFRB encodes an amino acid substitution at one or more amino acid residues corresponding to amino acid position 561 and/or 660 of SEQ ID NO:2, and wherein the one or more mutation in NOTCH3 encodes an amino acid substitution at an amino acid residue corresponding to amino acid position 1519 of SEQ ID NO:4.

14. The method according to claim 13 , wherein the amino acid substitution in NOTCH3 comprises a leucine to proline substitution at the amino acid position corresponding to Leu1519 of SEQ ID NO:4.

15. The method according to claim 1 , wherein the one or more reagents suitable for detecting the presence of one or more mutations in PDGFRB and/or NOTCH3 comprise an antibody.

16. The method of claim 8 , wherein the agent is imatinib.

17. The method of claim 1 , wherein the therapy is selected from the group consisting of removal of a tumor, administering radiation therapy, and modulating PDGFRB and/or NOTCH3 gene expression and/or PDGFRB and/or NOTCH3 encoded protein activity.

18. The method of claim 11 , wherein the agent is Imatinib, Covitinib (TKI-258), Linifanib (ABT-869), and Motesanib Diphosphate (AMG-706).

19. The method of claim 11 , wherein the method comprises treating symptoms.

20. The method according to claim 3 , wherein the amino acid substitution in PDGFRB comprises an arginine to cysteine substitution at the amino acid position corresponding to Arg561 of SEQ ID NO: 2.

21. The method according to claim 3 , wherein the amino acid substitution in PDGFRB comprises a proline to threonine substitution at the amino acid position corresponding to Pro660 of SEQ ID NO: 2.

22. The method according to claim 9 , wherein the amino acid substitution in PDGFRB comprises an arginine to cysteine substitution at the amino acid position corresponding to Arg561 of SEQ ID NO: 2.

23. The method according to claim 9 , wherein the amino acid substitution in PDGFRB comprises a proline to threonine substitution at the amino acid position corresponding to Pro660 of SEQ ID NO: 2.

Assignees

• Icahn School Med Mount Sinai
• Children'S Hospital Of Philadelphia
• The Children'S Hospital Of Philadelphia

Inventors

• Martignetti John A
• Hakonarson Hakon
• Tian Lifeng

Classifications

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61N5/00

  Radiation therapy (ultrasound therapy A61N7/00; devices or apparatus applicable to both therapy and diagnosis A61B6/00) · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C12Q1/6886 Primary

  for cancer (immunoassay for cancer G01N33/575) · CPC title

• C12Q2600/156

  Polymorphic or mutational markers · CPC title