METHOD OF DIAGNOSIS, PROGNOSIS OR TREATMENT OF NEURODEGENERATIVE DISEASES
Methods for the diagnosis and prognosis of neurodegenerative diseases, such as a Tauopathy or Alzheimer's disease, are described. Compositions and methods for the treatment of neurodegenerative diseases are also described.
1 . A method of treating a neurodegenerative disease, advantageously a Tauopathy, in particular Alzheimer's disease, comprising administering to a subject in need an effective amount of a composition comprising at least one agent which directly or indirectly affects an activity and/or a level of:
a) at least one gene selected from the group consisting of the nucleotide sequences of SEQ ID NO: 1 and SEQ ID NO: 3 and coding for an heparin-glucosamine 3-O-sulfotransferase, and/or
b) at least one transcription product of a gene selected from the group consisting of the nucleotide sequences of SEQ ID NO: 1 and SEQ ID NO: 3 and coding for an heparin-glucosamine 3-O-sulfotransferase, and/or
c) at least one translation product of said at least one gene selected from the group consisting of the nucleotide sequences of SEQ ID NO: 1 and SEQ ID NO: 3, said translation product being of SEQ ID NO: 2 and SEQ ID NO: 4, respectively, and/or
d) a fragment or derivative or variant of said gene, transcription product or translation product, and/or
e) heparan sulfate, in particular the level of 3-O-sulfated heparan sulfate, notably the level of 3-O-sulfated heparan sulfate disaccharide, and/or
f) abnormal phosphorylation of the Tau protein and/or total Tau protein,
wherein said neurodegenerative disease is different from a prion disease, and
wherein when said agent directly or indirectly affects the activity and/or the level:
of heparan sulfate, or of abnormal phosphorylation of the Tau protein and/or total Tau protein,
both activities and/or levels of heparan sulfate and of abnormal phosphorylation of the Tau protein and/or total Tau protein are affected by said agent,
or of at least one other element chosen among said gene, said transcription product of said genes, said translation product of said genes, or said fragment or derivative or variant of said gene or said transcription product or translation product is also affected.
2 . The method according to claim 1 wherein said at least one agent is selected from the group consisting of:
a) a polysaccharide or an oligosaccharide having a molecular weight from about 2000 Daltons to about 20 000 Daltons, preferably of about 20 000 Daltons, and/or low molecular weight heparins, and/or ultralow molecular weight heparins and/or
b) an oligonucleotide and/or
c) a small molecule, inhibitor of heparin and heparan sulfate actions.
3 . The method according to claim 2 , wherein said polysaccharide or oligosaccharide is a heparan sulfate mimetic or a pentasaccharide.
4 . The method according to claim 3 , wherein said heparan sulfate mimetic is selected from F6 molecule, CR36, HM 100, and HM 2602.
5 . The method according to claim 3 , wherein said pentasaccharide is selected from Arixtra® (fondaparinux), fucoidan, and pentosan polysulfate.
6 . The method according to claim 2 , wherein said low molecular weight heparin is enoxaparin (Lovenox®).
7 . The method according to any one of claims 2 to 5 , wherein said agent is a polysaccharide or an oligosaccharide having a molecular weight of about 20 000 Daltons, and wherein said agent is administered by intravenous route at a dose comprised from about 1.5 mg/Kg to about 50 mg/Kg or by oral route at dose from about 50 mg/kg to about 500 mg/kg.
8 . The method according to claim 7 , wherein said polysaccharide or oligosaccharide having a molecular weight of about 20 000 Daltons is administered at a dose comprised from about 100 to 200 mg/kg by oral route.
9 . The method according to claim 2 , wherein said oligonucleotide is a siRNA or a morpholino antisense oligonucleotide.
10 . The method according to claim 9 , wherein said siRNA is selected from the list consisting of: sense siRNA of SEQ ID NO: 71 and antisense siRNA of SEQ ID NO: 72, sense siRNA of SEQ ID NO: 73 and antisense siRNA of SEQ ID NO: 74, sense siRNA of SEQ ID NO: 75 and antisense siRNA of SEQ ID NO: 76, sense siRNA of SEQ ID NO: 77 and antisense siRNA of SEQ ID NO: 78.
11 . The method according to claim 9 , wherein said morpholino antisense oligonucleotide is of SEQ ID NO: 5 or SEQ ID NO: 6.
12 . The method according to any one of claims 9 to 11 , wherein said agent is an oligonucleotide and wherein it is administered by intravenous route at a dose comprised from 0.1 to 1 mM.
13 . The method according to claim 2 , wherein said small molecule is an inhibitor of heparin and heparan sulfate actions.
14 . The method according to claim 13 , wherein said inhibitor is selected from protamine and protamine sulfate.
15 . The method according to claim 14 , wherein said agent is a small molecule and wherein it is administered by intravenous route at a dose comprised from 1.0 mg/Kg to about 50 mg/Kg by intravenous route, or by oral route at a dose comprised from about 50 mg/kg to about 500 mg/kg.
16 . The method according to claim 2 , wherein said agent is an oligonucleotide and wherein said level of at least one transcription product being decreased is equal to about at least 50% of the original value.
17 . The method according to claim 2 , wherein said agent is an oligonucleotide of SEQ ID NO: 5 and wherein said at least one gene is of SEQ ID NO: 1.
18 . The method according to claim 2 , wherein said agent is an oligonucleotide of SEQ ID NO: 6 and wherein said at least one gene of SEQ ID NO: 3.
19 . The method of treating according to claim 2 , wherein said agent is an oligonucleotide and wherein said at least one gene consists of the two genes of SEQ ID NO: 1 and SEQ ID NO: 3, said oligonucleotide for the gene of SEQ ID NO: 1 being of SEQ ID NO: 5 and said oligonucleotide for the gene of SEQ ID NO: 3 being of SEQ ID NO: 6.
20 . The method according to claim 2 , wherein said agent is an oligonucleotide and wherein it is administered by intravenous route at a dose comprised from 0.1 to 1 mM.
21 . The method according to claim 20 , wherein said agent is administered by intravenous route at a dose of 0.5 mM.
22 . The method according to claim 2 , wherein said polysaccharide affects directly or indirectly said activity and/or level of the translation product of the gene of SEQ ID NO: 2.