Methods for diagnosing and treating heart disease

• US 20050064416A1
• Filed: 10/01/2002
• Published: 03/24/2005
• Est. Priority Date: 10/01/2001
• Status: Abandoned Application

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Rottbauer, Wolfgang, Fishman, Mark C.
• Application Number:
  US10/491,452
• Publication Number:
  US 20050064416A1
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/4716 Muscle proteins, e.g. myosin, actin
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers

Abstract

The invention provides methods of diagnosing and treating heart diseases and conditions, methods for identifying compounds that can be used to treat or to prevent such diseases and conditions, and methods of using these compounds to treat or to prevent such diseases and conditions. Also provided in the invention are animal model systems that can be used in screening methods.

Claims

1. A method of determining whether a test subject has, or is at risk of developing, a disease or condition related to Myosin Light Chain 2a, said method comprising analyzing a nucleic acid molecule of a sample from the test subject to determine whether the test subject has a mutation in a gene encoding said Myosin Light Chain 2a, wherein the presence of a mutation indicates that said test subject has, or is at risk of developing, a disease or condition related to Myosin Light Chain 2a.

2. The method of claim 1, wherein said test subject is a mammal.

3. The method of claim 1, wherein said test subject is a human.

4. The method of claim 1, wherein said disease or condition is a disease or condition of the heart.

5. The method of claim 4, wherein said disease or condition is heart failure.

6. A method for identifying a compound that can be used to treat or to prevent a disease or condition of the heart of associated with Myosin Light Chain 2a, said method comprising contacting an organism comprising a mutation in a gene encoding Myosin Light Chain 2a and having a phenotype characteristic of a disease or condition associated with Myosin Light Chain 2a with said compound, and determining the effect of said compound on said phenotype, wherein detection of an improvement in said phenotype indicates the identification of a compound that can be used to treat or to prevent said disease or condition of the heart.

7. The method of claim 6, wherein said disease or condition of the heart is heart failure.

8. The method of claim 6, wherein said organism is a zebrafish.

9. The method of claim 6, wherein said mutation in the gene encoding Myosin Light Chain 2a is the tell tale heart mutation.

10. A method of treating or preventing a disease or condition of the heart associated with Myosin Light Chain 2a in a patient, said method comprising administering to said patient a compound identified using the method of claim 6.

11. The method of claim 10, wherein said patient has a mutation in a gene encoding Myosin Light Chain 2a.

12. A method of treating or preventing a disease or condition associated with Myosin Light Chain 2a in a patient, said method comprising administering to said patient a functional Myosin Light Chain 2a protein or an expression vector comprising a nucleic acid molecule encoding said protein.

13. A substantially pure zebrafish Myosin Light Chain 2a polypeptide.

14. The polypeptide of claim 13, wherein said polypeptide comprises an amino acid sequence that is substantially identical to the amino acid sequence of SEQ ID NO:

2.

15. The polypeptide of claim 13, wherein said polypeptide comprises the amino acid sequence of SEQ ID NO:

2.

16. A substantially pure polypeptide comprising the sequence of SEQ ID NO:

2 and variants thereof comprising sequences that are at least 95% identical to that of SEQ ID NO;

2, and which have Myosin Light Chain 2a activity.

17. An isolated nucleic acid molecule comprising a sequence encoding a zebrafish Myosin Light Chain 2a polypeptide.

18. The nucleic acid molecule of claim 17, wherein said nucleic acid molecule encodes a polypeptide comprising an amino sequence that is substantially identical to the amino acid sequence of SEQ ID NO:

2.

19. The nucleic acid molecule of claim 17, wherein said nucleic acid molecule encodes a polypeptide comprising the amino acid sequence of SEQ ID NO:

2.

21. A vector comprising the nucleic acid molecule of claim 17.

22. A cell comprising the vector of claim 21.

23. A non-human transgenic animal comprising the nucleic acid molecule of claim 17.

24. The non-human transgenic animal of claim 23, wherein said animal is a zebrafish.

20. An isolated nucleic acid molecule that specifically hybridizes under high stringency conditions to the complement of the sequence set forth in SEQ ID NO:

1, wherein said nucleic acid molecule encodes a protein that has Myosin Light Chain 2a activity.

25. A non-human animal having a knockout mutation in one or both alleles encoding a Myosin Light Chain 2a polypeptide.

26. A cell from the non-human knockout animal of claim 25.

27. A non-human transgenic animal comprising a nucleic acid molecule encoding a mutant Myosin Light Chain 2a polypeptide.

28. The non-human transgenic animal of claim 27, wherein the non-human transgenic animal is a zebrafish.

29. The non-human transgenic animal of claim 27, wherein the non-human transgenic animal comprises the tell tale heart mutation.

30. An antibody that specifically binds to a Myosin Light Chain 2a polypeptide.

31. A method of modulating the activity of a Myosin Light Chain 2a polypeptide in a patient, said method comprising administering to the patient an RNA that stimulates or inhibits this activity.