ABHD5 and partial HDAC4 fragments and variants as a therapeutic approach for the treatment of cardiovascular diseases
AssigneeRuprecht-Karls-UniversitäT Heidelberg
InventorsJohannes Backs, Zegeye Jebessa, Lorenz Lehmann, Hugo Katus, Oliver Müller
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Abstract
The present invention relates to Abhydrolase containing domain 5 (ABHD5) and N-terminal fragments of HDAC4 (HDAC4-NT) and variants of the aforementioned peptides for the treatment and prevention of heart failure. The present invention further provides vectors for the cardiomyocyte-specific expression of said peptides and a test system comprising ABHD5 for the identification of novel compounds which are useful for the treatment of heart failure.
Claims7
A vector comprising
- a nucleic acid sequence encoding ABHD5 or a variant thereof, operatively linked to a human troponin T promoter,
- wherein the ABHD5 has an amino acid sequence selected from the group consisting of the amino acid sequences of SEQ ID NOs:
- 1, 2, 3, 4, and 5;
- wherein the variant has at least 99% sequence identity with one or more of the amino acid sequences selected rom the group consisting of SEQ ID NOs:
- 1, 2, 3, 4, and 5;
- and
- wherein the variant is capable of cleaving histone deacetylase 4 (HDAC4) to produce HDAC-NT and has less affinity to lipid droplets than ABHD5.
A method of treating a patient exhibiting symptoms of ventricular heart failure comprising:
- administering an effective amount of a vector comprising a nucleic acid encoding ABHD5 or a variant thereof to the patient, wherein the nucleic acid is operably linked to a promotor, and wherein the nucleic acid is administered to the patient's heart;
- wherein the ABHD5 has an amino acid sequence selected from the group consisting of the amino acid sequences of SEQ ID NOs:
- 1, 2, 3, 4, and 5;
- wherein the variant has at least 99% sequence identity with one or more of the amino acid sequences selected from the group consisting of SEQ ID NOs:
- 1, 2, 3, 4, and 5;
- and
- wherein the variant is capable of cleaving histone deacetylase 4 (HDAC4) following amino acid 201 to produce HDAC-NT and has less affinity to lipid droplets than ABHD5.
A method of treating myocardial remodeling during heart failure, the method comprising
- administering an effective amount of a nucleic acid encoding ABHD5 or a variant thereof to a patient exhibiting the heart failure, wherein the nucleic acid is administered to the patient's heart;
- wherein the ABHD5 has an amino acid sequence selected from the group consisting of the amino acid sequences of SEQ ID NOs:
- 1, 2, 3, 4, and 5;
- wherein the variant has at least 99% sequence identity with one or more of the amino acid sequences selected from the group consisting of SEQ ID NOs:
- 1, 2, 3, 4, and 5 and wherein the variant is capable of cleaving histone deacetylase 4 (HDAC4) to produce HDAC-NT and has less affinity to lipid droplets than ABHD5;
- and
- wherein ABHD5 or a variant thereof is expressed from the nucleic acid and cleaves histone deacetylase 4 (HDAC4) following amino acid 201 to produce HDAC-NT which treats the myocardial remodeling in the patient exhibiting the heart failure.
Dependencies are inferred from the claim text.