Abhd5 and partial hdac4 fragments and variants as a therapeutic approach for the treatment of cardiovascular diseases

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.

1 .- 17 . (canceled) 
     
     
         18 . An elongated and/or multimerized variant of the N-terminal fragment of histone deacetylase 4 (HDAC4-NT). 
     
     
         19 . The variant of HDAC4-NT of  claim 18 , which has at least 80% sequence identity over the entire length of the protein according to SEQ ID NO:13 or 14. 
     
     
         20 . The variant of HDAC4-NT of  claim 18 , which is an elongation variant comprising the amino acid positions 2 to 202, 1 to 220, 1 to 216, 1 to 212 or 1 to 208 of human HDAC4 as defined by SEQ NO: 11. 
     
     
         21 . The variant of HDAC4-NT of  claim 18 , wherein the variant is a multimerization variant comprising at least 2, at least 3, at least 4, or at least 5 repeats of HDAC4-NT. 
     
     
         22 . A vector comprising a nucleic acid encoding HDAC4-NT or a variant thereof. 
     
     
         23 . The vector of  claim 22 , selected from the group consisting of plasmids, cosmids, phages, viruses and artificial chromosomes. 
     
     
         24 . The vector of  claim 22 , selected from the group consisting of adenovirus vectors, adeno-associated virus (AAV) vectors, alphavirus vectors, herpes virus vectors, arena virus vectors, measles virus vectors, pox virus vectors, NYVAC, avipox vectors, vesicular stomatitis virus vectors, retrovirus vectors, lentivirus vectors, viral like particles, and bacterial spores. 
     
     
         25 . The vector of  claim 24 , which is an AAV vector. 
     
     
         26 . The vector of  claim 25 , selected from the group consisting of AAV type 6, type 1, type 5, type 9 and type 2. 
     
     
         27 . The vector of  claim 22  wherein HDAC4-NT or the variant thereof is expressed under control of the human troponin promoter and a recognition site for micro-RNA 122 between the promoter and the terminator sequence so that said recognition site becomes part of the transcript produced from this vector. 
     
     
         28 . A method of treating of preventing heart failure, the method comprising administering an effective amount of a nucleic acid encoding HDAC4-NT or a variant thereof or a vector comprising a nucleic acid encoding HDAC4-NT or a variant thereof, to a patient. 
     
     
         29 . A method of treating myocardial remodeling during heart failure, the method comprising administering an effective amount of a nucleic acid encoding HDAC4-NT or a variant thereof or a vector comprising a nucleic acid encoding HDAC4-NT or a variant thereof, to a patient.