US 2004/0072170 A1 · Novel target genes for diseases of the heart

Abstract

The present invention relates to a variety of genes abnormally expressed in heart tissue as well as to fragments of such genes. Assessment of the expression level of these genes may be used for testing the predisposition of mammals and preferably humans for a heart disease or for an acute state of such a disease. Preferred diseases in accordance with the invention are congestive heart failure, dilative cardiomyopathy, hypertrophic cardiomyopathy and ischemic cardiomyopathy. The present invention further relates to methods of identifying compounds capable of normalizing the expression level of the aforementioned genes and of further genes affected by the abnormal expression. The identified compounds may be used for formulating compositions, preferably pharmaceutical compositions for preventing or treating diseases. They may also be used as lead compounds for the development of medicaments having an improved efficiency, a longer half-life, a decreased toxicity etc. and to be employed in the treatment of heart diseases. Included in the invention are also somatic gene therapy methods comprising the introduction of at least one functional copy of any of the above-mentioned genes into a suitable cell. Finally, the invention relates to non-human transgenic animals comprising at least one of the aforementioned genes in their germ line. The transgenic animals of the invention may be used for the development of medicaments for the treatment of heart diseases.

Claims47

Dependent claims

A method for identifying a subject at risk for a disease of the heart, comprising the step of quantitating the amount of at least one RNA encoding an amino acid sequence selected from the group consisting of:

(a) the amino acid sequence of SEQ ID NO:
1 [NP—003961], the amino acid sequence of SEQ ID NO:
2 [41441pep], the amino acid sequence of SEQ ID NO:
3 [56461pep], the amino acid sequence of SEQ ID NO:
4 [AAA52025], the amino acid sequence of SEQ ID NO:
5 [61166pep], the amino acid sequence of SEQ ID NO:
6 [AAD45360], the amino acid sequence of SEQ ID NO:
7 [AAF63623], the amino acid sequence of SEQ ID NO:
8 [66214pep] or the amino acid sequence AAF19343, or the amino acid sequence of SEQ ID NO:
9 [CAA58676];
(b) an amino acid sequence that is at least 60%, preferably at least 80%, especially at least 90%, advantageously at least 99% identical to the amino acid sequence of (a);
(c) the amino acid sequence of (a) with at least one conservative amino acid substitution;
(d) an amino acid sequence that is an isoform of the amino acid sequence of any of (a) to (c);
(e) the RNA transcribed from the DNA sequence of SEQ ID NO:
10 [NM—003970], the DNA sequence of SEQ ID NO:
11 [AW755252], the DNA sequence of SEQ ID NO:
12 [EST clone 52706], the DNA sequence of SEQ ID NO:
13 [EST clone 56461], the DNA sequence of SEQ ID NO:
14 [M14780], the DNA sequence of SEQ ID NO:
15 [61166contig], the DNA sequence of SEQ ID NO:
16 [AF161698], the DNA sequence of SEQ ID NO:
17 [65330contig], the DNA sequence of SEQ ID NO:
18 [66214cds] or the DNA sequence AF129505, or the DNA sequence of SEQ ID NO:
19 [X83703] or a degenerate variant thereof;
and
(f) an amino acid that is encoded by a DNA molecule the complementary strand of which hybridizes in 4×SSC, 0.1% SDS at 65° C. to the DNA molecule encoding the amino acid sequence of (a), (c) or (d), in the heart tissue of the subject.

23 more elements

A method for identifying a subject at risk for a disease of the heart, comprising the step of quantitating the amount of a polypeptide selected from the group consisting of:

(a) the polypeptide having amino acid sequence SEQ ID NO:
1 [NP—003961], the amino acid sequence of SEQ ID NO:
2 [41441pep], the amino acid sequence of SEQ ID NO:
3 [56461pep], the amino acid sequence of SEQ ID NO:
4 [AAA52025], the amino acid sequence of SEQ ID NO:
5 [61166pep], the amino acid sequence of SEQ ID NO:
6 [AAD45360], the amino acid sequence of SEQ ID NO:
7 [AAF63623], the amino acid sequence of SEQ ID NO:
8 [66214pep] or the amino acid sequence AAF19343, or the amino acid sequence of SEQ ID NO:
9 [CAA58676];
(b) a polypeptide having an amino acid sequence that is at least 60%, preferably at least 80%, especially at least 90%, advantageously at least 99% identical to the amino acid sequence of (a);
and
(c) a polypeptide having the amino acid sequence of (a) with at least one conservative amino acid substitution,
in the heart tissue of the subject.

11 more elements

A method for identifying a compound that increases or decreases the level in heart tissue of a polypeptide selected from the group consisting of:

(a) the polypeptide having amino acid sequence SEQ ID NO:
1 [NP—003961], the amino acid sequence of SEQ ID NO:
2 [41441pep], the amino acid sequence of SEQ ID NO:
3 [56461pep], the amino acid sequence of SEQ ID NO:
4 [AAA52025], the amino acid sequence of SEQ ID NO:
5 [61166pep], the amino acid sequence of SEQ ID NO:
6 [AAD45360], the amino acid sequence of SEQ ID NO:
7 [AAF63623], the amino acid sequence of SEQ ID NO:
8 [66214pep] or the amino acid sequence AAF19343, or the amino acid sequence of SEQ ID NO:
9 [CAA58676];
(b) a polypeptide having an amino acid sequence that is at least 60%, preferably at least 80%, especially at least 90%, advantageously at least 99% identical to the amino acid sequence of (a);
and
(c) a polypeptide having the amino acid sequence of (a) with at least one conservative amino acid substitution,
said method comprising the steps of:
(1) contacting a DNA encoding said polypeptide under conditions that would permit the translation of said polypeptide with a test compound;
and
(2) detecting an increased or decreased level of the polypeptide relative to the level of translation obtained in the absence of the test compound.

14 more elements

A monoclonal antibody or derivative thereof that specifically binds to a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:

1 [NP—003961], the amino acid sequence of SEQ ID NO:
2 [41441pep], the amino acid sequence of SEQ ID NO:
3 [56461pep], the amino acid sequence of SEQ ID NO:
4 [AAA52025], the amino acid sequence of SEQ ID NO:
5 [61166pep], the amino acid sequence of SEQ ID NO:
6 [AAD45360], the amino acid sequence of SEQ ID NO:
7 [AAF63623], the amino acid sequence of SEQ ID NO:
8 [66214pep] or the amino acid sequence AAF19343, or the amino acid sequence of SEQ ID NO:
9 [CAA58676].

6 more elements

A method for identifying a compound that increases or decreases the level in heart tissue of an mRNA encoding a polypeptide selected from the group consisting of:

(a) the polypeptide having amino acid sequence SEQ ID NO:
1 [NP—003961], the amino acid sequence of SEQ ID NO:
2 [41441pep], the amino acid sequence of SEQ ID NO:
3 [56461pep], the amino acid sequence of SEQ ID NO:
4 [AAA52025], the amino acid sequence of SEQ ID NO:
5 [61166pep], the amino acid sequence of SEQ ID NO:
6 [AAD45360], the amino acid sequence of SEQ ID NO:
7 (AAF63623], the amino acid sequence of SEQ ID NO:
8 [66214pep] or the amino acid sequence AAF19343, or the amino acid sequence of SEQ ID NO:
9 [CAA58676];
(b) a polypeptide having an amino acid sequence that is at least 60%, preferably at least 80%, especially at least 90%, advantageously at least 99% identical to the amino acid sequence of (a);
and
(c) a polypeptide having the amino acid sequence of (a) with at least one conservative amino acid substitution,
said method comprising the steps of
(1) contacting a DNA giving rise to said mRNA under conditions that would permit transcription of said mRNA with a test compound;
and
(2) detecting an increased/decreased level of the mRNA relative to the level of transcription obtained in the absence of the test compound.

14 more elements

A transgenic non-human mammal whose somatic and germ cells comprise at least one gene encoding a functional or disrupted polypeptide selected from the group consisting of:

(a) the polypeptide having amino acid sequence SEQ ID NO:
1 [NP—003961], the amino acid sequence of SEQ ID NO:
2 [41441pep], the amino acid sequence of SEQ ID NO:
3 [56461pep], the amino acid sequence of SEQ ID NO:
4 [AAA52025], the amino acid sequence of SEQ ID NO:
5 [61166pep], the amino acid sequence of SEQ ID NO:
6 [AAD45360], the amino acid sequence of SEQ ID NO:
7 [AAF63623], the amino acid sequence of SEQ ID NO:
8 [66214pep] or the amino acid sequence AAF19343, or the amino acid sequence of SEQ ID NO:
9 [CAA58676];
(b) a polypeptide having an amino acid sequence that is at least 60%, preferably at least 80%, especially at least 90%, advantageously at least 99% identical to the amino acid sequence of (a);
and
(c) a polypeptide having the amino acid sequence of (a) with at least one conservative amino acid substitution,
that said functional or disrupted polypeptide has been modified, said modification being sufficient to decrease or increase the amount of said functional polypeptide expressed in the heart tissue of said transgenic non-human mammal, wherein said transgenic non-human mammal exhibits a disease of the heart.

11 more elements

A method for identifying one or a plurality of genes whose expression in heart tissue is modulated by inhibiting, decreasing or increasing the expression of a polypeptide selected from the group consisting of:

(a) the polypeptide having amino acid sequence SEQ ID NO:
1 [NP—003961], the amino acid sequence of SEQ ID NO:
2 [41441pep], the amino acid sequence of SEQ ID NO:
3 [56461pep], the amino acid sequence of SEQ ID NO:
4 [AAA52025], the amino acid sequence of SEQ ID NO:
5 [61166pep], the amino acid sequence of SEQ ID NO:
6 [AAD45360], the amino acid sequence of SEQ ID NO:
7 [AAF63623], the amino acid sequence of SEQ ID NO:
8 [66214pep] or the amino acid sequence AAF19343, or the amino acid sequence of SEQ ID NO:
9 [CAA58676];
(b) a polypeptide having an amino acid sequence that is at least 60%, preferably at least 80%, especially at least 90%, advantageously at least 99% identical to the amino acid sequence of (a);
and
(c) a polypeptide having the amino acid sequence of (a) with at least one conservative amino acid substitution,
or of an mRNA encoding said polypeptide,
said modulation being indicative of a disease of the heart, said method comprising the steps of:
(1) contacting a plurality of heart tissue cells with a compound that inhibits, decreases or increases the expression of said polypeptide under conditions that permit the expression of said polypeptide in the absence of a test compound, and
(2) comparing a gene expression profile of said heart cell in the presence and in the absence of said compound.

14 more elements

A method for identifying one or a plurality of genes whose expression in heart tissue is modulated by the inhibition, decrease or increase of the expression of a polypeptide selected from the group consisting of:

(a) the polypeptide having amino acid sequence SEQ ID NO:
1 [NP—003961], the amino acid sequence of SEQ ID NO:
2 [41441pep], the amino acid sequence of SEQ ID NO:
3 [56461pep], the amino acid sequence of SEQ ID NO:
4 [AAA52025], the amino acid sequence of SEQ ID NO:
5 [61166pep], the amino acid sequence of SEQ ID NO:
6 [AAD45360], the amino acid sequence of SEQ ID NO:
7 [AAF63623], the amino acid sequence of SEQ ID NO:
8 [66214pep] or the amino acid sequence AAF19343, or the amino acid sequence of SEQ ID NO:
9 [CAA58676];
(b) a polypeptide having an amino acid sequence that is at least 60%, preferably at least 80%, especially at least 90%, advantageously at least 99% identical to the amino acid sequence of (a);
and
(c) a polypeptide having the amino acid sequence of (a) with at least one conservative amino acid substitution,
or of an mRNA encoding said polypeptide, said modulation being indicative of a disease of the heart, said method comprising the steps of:
(1) providing expression profiles of
(i) a plurality of heart tissue cells from or derived from a heart of a subject suffering from a disease of the heart;
and
(ii) a plurality of heart tissue cells from or derived from a subject not suffering from a disease of the heart;
and
(2) comparing the expression profiles (i) and (ii).

17 more elements

Dependencies are inferred from the claim text.

Novel target genes for diseases of the heart

Life of this patent

Novel target genes for diseases of the heart

Life of this patent

Abstract

Claims47