VARIANTS OF THE HUMAN ATM PROTEIN FOR THE TREATMENT OF DISEASES RELATED TO AT LEAST ONE MUTATION OF THE ATM GENE
The present invention relates to variants of the human ATM protein or derivatives thereof, said variant and/or derivatives for use in the treatment or in the prevention of diseases related to at least one mutation of the ATM gene, i.e. diseases caused or induced by said mutation/s, mRNAs and cDNAs, expression vectors coding for said variant of the ATM protein or derivatives thereof and composition or associations comprising them.
1 . A variant of the human ATM protein having SEQ ID NO 1, or a derivative thereof.
2 . The derivative of the variant according to claim 1 , wherein said derivative is characterized in that it further comprises from 3 to 170, or 3 to 135, or 3 to 110, or 3 to 80, or 3 to 65 or 3 to 40 additional amino acids between the amino acids in position 205 and 206 of SEQ ID NO 1.
3 . The derivative according to claim 2 , wherein said additional amino acids code for one or more phosphorylation domain and are selected from the human ATM protein having SEQ ID NO 5.
4 . The derivative according to claim 3 , wherein said additional one or more phosphorylation domain is a domain comprising Serine (S) in position 1981 of SEQ ID NO 5, or is a domain comprising Serine (S) in position 1893 of SEQ ID NO 5, or is a domain comprising Serine (S) in position 367 of SEQ ID NO 5, or is a domain comprising Serine (S) in position 794 of SEQ ID NO 5, or is a domain comprising Serine (S) in position 1403 of SEQ ID NO 5.
5 . The derivative according to claim 3 , wherein said phosphorylation domain is selected from SEQ ID Nos 6-10.
6 . A medicament comprising the variant or derivative thereof according to claim 1 .
7 . A method for preventing, treating or adjuvating the treatment of a disease related to at least one mutation of the ATM gene/s in a subject comprising administering to the subject the medicament of claim 6 .
8 . The method according to claim 7 , wherein said disease related to at least one mutation of the ATM gene/s is Ataxia Telangiectasia or cancer.
9 . The method of claim 7 , wherein said variant and/or derivative thereof is administered in a therapeutically effective amount to a patient in need thereof, optionally in combination with at least one variant of the human ATM protein having SEQ ID NO 2, SEQ ID NO 3 or SEQ ID NO 4 and/or further therapeutically active compound or drug or drug cocktail or in association to a chemical, radiological or immunological cancer therapy.
10 . A nucleotide sequence coding for the variant of the human ATM protein having SEQ ID NO 1 or a derivative thereof, as defined claim 1 .
11 . The nucleotide sequence according to claim 10 wherein said sequence comprises optimised codons.
12 . The nucleotide sequence according to claim 11 , wherein said nucleotide sequence is a cDNA or an mRNA.
13 . The mRNA according to claim 12 wherein said mRNA comprises a 3′ and a 5′ UTR element flanking the coding sequence, a 5′ Cap and a polyA tail.
14 . The mRNA according to claim 12 wherein said mRNA comprises one or more modified nucleosides.
15 . The mRNA according to claim 12 , wherein said mRNA is complexed with one or more carrier molecules.
16 . The mRNA according to claim 15 wherein said mRNA is complexed in a cationic nanoemulsion, in a nanoparticle, in a liposome, in a cationic polymer liposome, in a polysaccharide particle, in a cationic lipid nanoparticle, in a cationic lipid cholesterol nanoparticle, in a cationic lipid cholesterol PEG nanoparticle.
17 . A medicament comprising the nucleotide sequence according to claim 10 .
18 . A method for preventing or treating or adjuvating the treatment of a disease related to at least one mutation of the ATM gene/s in a subject comprising administering to the subject the medicament of claim 17 .
19 . The method claim 18 , wherein said disease related to at least one mutation of the ATM gene is Ataxia Telangiectasia or cancer.
20 . An expression vector, comprising a nucleotide sequence according to claim 10 operably linked to a promoter.
21 . The expression vector of claim 20 wherein said nucleotide sequence is a cDNA or an RNA.
22 . The expression vector of claim 20 , wherein said expression vector is selected from a plasmid, a yeast vector, a mammalian vector, a viral vector, a gene therapy expression vector, a single-stranded phage, a double-stranded phage, artificial chromosome.
23 . The expression vector according to claim 22 , wherein said expression vector is selected from the following list: adenovirus, adeno-associated virus (AAV), lentivirus, retrovirus, cytomegalovirus (CMV), Herpes Simplex Virus (HSV).
24 . A medicament comprising the expression vector according to claim 20 .
25 . A method for preventing or treating or in adjuvating the treatment of a disease related to at least one mutation of the ATM gene/s in a subject comprising administering the medicament of claim 24 .
26 . The method according to claim 25 , wherein said disease related to at least one mutation of the ATM gene is Ataxia Telangiectasia or cancer.
27 . A pharmaceutical composition comprising the variant of the human ATM protein or a derivative thereof according to claim 1 , and a pharmaceutically acceptable carrier and/or excipient.
28 . The pharmaceutical composition according to claim 27 further comprising one or more variant of the human ATM protein having SEQ ID NO 2, 3 or 4, or a nucleotide sequence, a mRNA or an expression vector coding for said one or more variant having SEQ ID NO 2, 3 or 4.
29 . The pharmaceutical composition according to claim 27 in a form suitable for administration by systemic injection, central nervous system delivery, aerosol/nasal delivery, topical delivery, RBCs or vesicles.
30 . The pharmaceutical composition according to claim 29 , for intravenous injection administration, intraparenchymal administration in particular areas of the brain such as intracerebroventricular, cisternal, lumbar or intrathecal administration, or intra-arterial injection administration, or for direct administration into the cerebrospinal fluid.
31 . A combination of the variant of the human ATM protein or a derivative thereof according to claim 1 and a drug cocktail or at least one additional therapeutically active compound or drug.
32 . A pharmaceutical composition comprising the combination according to claim 31 .
33 . A method for preventing or treating, or adjuvating the treatment of a disease related to at least one mutation of the ATM gene/s in a subject comprising administering to the subject the pharmaceutical composition of claim 32 .
34 . The method of claim 33 , wherein said disease related to at least one mutation of the ATM gene is Ataxia Telangiectasia or cancer.