Therapeutic or prophylactic composition for TDP-43 proteinopathy
The present invention aims to provide a composition for the prevention or treatment of TDP-43 proteinopathy using a microRNA targeting the TDP-43 gene. A prophylactic or therapeutic composition for TDP-43 proteinopathy, comprising: one or more nucleic adds selected from the group consisting of isolated RNAs and isolated nucleic acids encoding the RNAs, wherein the RNAs consist of human miR-33 represented by SEQ ID NO: 1, variants of the human miR-33 having one or more mutations, and precursors of the human miR-33 and the variants.
1. A therapeutic composition for TDP-43 proteinopathy, comprising:
one or more nucleic acids consisting of isolated nucleic acids encoding RNAs,
wherein the RNAs are one or more isolated RNAs of following:
(i) a variant of human miR-33 represented by SEQ ID NO: 6;
(ii) a variant of human miR-33 represented by SEQ ID NO: 5;
(iii) a variant of human miR-33 represented by SEQ ID NO: 4; and
(iv) one selected from a group consisting of a pre-miRNA of (i), a pre-miRNA of (ii) and a pre-miRNA of (iii),
wherein each of the pre-miRNA of (i), the pre-miRNA of (ii) and the pre-miRNA of (iii) is composed of 60 to 100 nucleotides,
wherein each of the pre-miRNA of (i), the pre-miRNA of (ii) and the pre-miRNA of (iii) is a hairpin RNA having a hairpin-shaped structure composed of imperfectly paired stem and loop moieties,
wherein the stem moiety of the pre-miRNA of (i) comprises the nucleotides represented by SEQ ID NO: 6, the stem moiety of the pre-miRNA of (ii) comprises the nucleotides represented by SEQ ID NO: 5, the stem moiety of the pre-miRNA of (iii) comprises the nucleotides represented by SEQ ID NO: 4, and
wherein each of the pre-miRNA of (i), the pre-miRNA of (ii) and the pre-miRNA of (iii) is configured to be cleaved by Dicer in a cell to generate a double-stranded miRNA derived from the stem moiety and finally generate one of (i) to (iii), when the each of pre-miRNA of (i), the pre-miRNA of (ii) and the pre-miRNA of (iii) is directly transferred as an RNA molecule to the cell or is expressed in the cell using an expression vector; and
(v) a double-stranded miRNA generated from (iv).
2. The therapeutic composition for TDP-43 proteinopathy according to claim 1 , wherein the isolated nucleic acids encoding the RNAs are functionally encoded by a virus vector.
3. The therapeutic composition for TDP-43 proteinopathy according to claim 2 , wherein the virus vector is a lentivirus vector or an adeno-associated virus vector.
4. The therapeutic composition for TDP-43 proteinopathy according to claim 1 , wherein the RNA comprises at least one or more modified nucleotides.
5. The therapeutic composition for TDP-43 proteinopathy according to claim 1 , wherein the one or more nucleic acids are encapsulated in nanoparticles.
6. The therapeutic composition for TDP-43 proteinopathy according to claim 1 , wherein the TDP-43 proteinopathy is SOD1-unrelated amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin inclusions.
7. The therapeutic composition for TDP-43 proteinopathy according to claim 1 , wherein the pre-miRNA of (i) is a variant of human pre-miR-33 represented by SEQ ID NO:10, in which nucleotides at positions 6 to 26 counted from the 5′ end have been substituted by nucleotides represented by SEQ ID NO: 6.
8. The therapeutic composition for TDP-43 proteinopathy according to claim 1 , wherein the pre-miRNA of (ii) is a variant of human pre-miR-33 represented by SEQ ID NO:10, in which nucleotides at positions 6 to 26 counted from the 5′ end have been substituted by nucleotides represented by SEQ ID NO: 5.
9. The therapeutic composition for TDP-43 proteinopathy according to claim 1 , wherein the pre-miRNA of (iii) is a variant of human pre-miR-33 represented by SEQ ID NO:10, in which nucleotides at positions 6 to 26 counted from the 5′ end have been substituted by nucleotides represented by SEQ ID NO: 4.