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1. WO2020109314 - FIBROBLAST GROWTH FACTOR 21 (FGF21) GENE THERAPY

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Claims

1. A gene construct comprising a nucleotide sequence encoding a fibroblast growth factor 21 (FGF21 ), for use in the treatment and/or prevention of a metabolic disorder, wherein the therapy involves expression of the gene construct in the central nervous system (CNS), preferably in the brain, more preferably in the hypothalamus and/or the cortex and/or the hippocampus and/or the cerebellum and/or the olfactory bulb, most preferably in the hypothalamus.

2. A gene construct for use according to claim 1 , wherein the nucleotide sequence encoding FGF21 is operably linked to a ubiquitous promoter.

3. A gene construct for use according to claim 1 or claim 2, wherein the ubiquitous promoter is selected from the group consisting of a CAG promoter and a CMV promoter, preferably wherein the ubiquitous promoter is a CAG promoter.

4. A gene construct for use according to any one of claims 1-3, wherein the gene construct comprises at least one target sequence of a microRNA expressed in a tissue where the expression of FGF21 is wanted to be prevented.

5. A gene construct for use according to any one of claims 1-4, wherein the at least one target sequence of a microRNA is selected from those target sequences that bind to microRNAs expressed in the heart and/or the liver of a mammal.

6. A gene construct for use according to any one of claims 1 to 5, wherein the nucleotide sequence encoding FGF21 is operably linked to a ubiquitous promoter and at least one target sequence of a microRNA expressed in the liver and at least one target sequence of a microRNA expressed in the heart.

7. A gene construct for use according to claim 5 or 6, wherein a target sequence of a microRNA expressed in the heart is selected from SEQ ID NO’s: 13 and 21-25 and a target sequence of a microRNA expressed in the liver is selected from SEQ ID NO’s: 12 and 14-20.

8. A gene construct for use according to any one of claims 5 to 7, wherein the gene construct comprises a target sequence of microRNA- 122a and a target sequence of microRNA-1.

9. A gene construct for use according to any one of claims 1 to 8, wherein the nucleotide sequence encoding FGF21 is selected from the group consisting of:

(a) a nucleotide sequence encoding a polypeptide comprising an amino acid sequence that has at least 60% sequence identity with the amino acid sequence of SEQ ID NO: 1 , 2 or 3;

(b) a nucleotide sequence that has at least 60% sequence identity with the nucleotide sequence of SEQ ID NO: 4, 5, 6, 7, 8, 9, 10 or 1 1 ; and

(c) a nucleotide sequence the sequence of which differs from the sequence of a nucleotide sequence of (b) due to the degeneracy of the genetic code.

10. An expression vector comprising a gene construct as described in any one of claims 1 to 9, for use in the treatment and/or prevention of a metabolic disorder, wherein the therapy involves expression of the gene construct in the CNS, preferably in the brain, more preferably in the hypothalamus and/or the cortex and/or the hippocampus and/or the cerebellum and/or the olfactory bulb, most preferably in the hypothalamus.

1 1. An expression vector for use according to claim 10, wherein the expression vector is a viral vector.

12. An expression vector for use according to claim 10 or 1 1 , wherein the expression vector is selected from the group consisting of adenoviral vectors, adeno-associated viral vectors, retroviral vectors, and lentiviral vectors, preferably wherein the expression vector is an adeno-associated viral vector.

13. An expression vector for use according to any one of claims 10 to 12, wherein the expression vector is an adeno-associated viral vector of serotype 1 , 2, 3, 4, 5, 6, 7, 8, 9, rh 10, rh8, Cb4, rh74, DJ, 2/5, 2/1 , 1/2 or Anc80, preferably wherein the expression vector is an adeno-associated viral vector of serotype 1 , 2 or 9.

14. A pharmaceutical composition comprising a gene construct according to any one of claims 1-9 and/or an expression vector according to any one of claims 10-13, together with one or more pharmaceutically acceptable ingredients, for use in the treatment and/or prevention of a metabolic disorder, wherein the therapy involves expression of the gene construct in the CNS, preferably in the brain, more preferably in the hypothalamus and/or the cortex and/or the hippocampus and/or the cerebellum and/or the olfactory bulb, most preferably in the hypothalamus.

15. A gene construct for use according to any one of claims 1-9 and/or an expression vector for use according to any one of claims 10-13 and/or a pharmaceutical composition for use according to claim 14, wherein the gene construct and/or expression vector and/or pharmaceutical composition is administered by intra-CSF administration.

16. A gene construct for use according to any one of claims 1-9 and/or an expression vector for use according to any one of claims 10-13 and/or a pharmaceutical composition for use according to claim 14, wherein the metabolic disorder is a diabetes and/or obesity.