Mitochondrial proteins constructs and uses thereof
AssigneeBioBlast Pharma Ltd.
InventorsHaya LORBERBOUM-GALSKI, Hagar GREIF
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Abstract
Disclosed are novel fusion protein constructs comprising a functional mitochondrial protein, that can enter mitochondria within intact cells. Further disclosed are methods of treating mitochondrial disorders by the disclosed fusion proteins and compositions therefor.
Claims28
A fusion protein comprising a HIV-1 transactivator of transcription (TAT) domain, a functional human mitochondrial protein and a human mitochondria targeting sequence (MTS) situated between said TAT domain and said functional human mitochondrial protein and wherein said human MTS is heterologous to said functional human mitochondrial protein.
A fusion protein according to any one of the preceding claims, wherein said functional human mitochondrial protein is any one of frataxin and ornithine transcarbamoylase (OTC).
A fusion protein according to any one of the preceding claims, wherein said MTS comprises from about 15 to about 40 amino acid residues, including from about 3 to about 5 nonconsecutive basic amino acid residues, and optionally from about 1 to about 3 or 4 or 5 serine/threonine residues.
A fusion protein according to any one of the preceding claims, wherein said MTS is any one of human mitochondrial citrate synthase MTS having the amino acid sequence denoted by SEQ ID NO. 23, the human lipoamide dehydrogenase MTS having the amino acid sequence denoted by SEQ ID NO. 24, the MTS of the human C6ORF66 gene product having the amino acid sequence denoted by SEQ ID NO. 25 and the MTS of human mitochondrial GLUD2 encoded by the nucleic acid denoted by SEQ ID NO. 16.
A fusion protein according to any one of the preceding claims, further comprising a linker covalently linking said TAT domain to said MTS sequence.
A fusion protein having the amino acid sequence denoted by SEQ ID NO. 28, comprising a HIV-1 transactivator of transcription (TAT) domain having the amino acid sequence denoted by SEQ ID NO. 27 fused to human frataxin having the amino acid sequence denoted by SEQ ID NO. 26 and a mitochondria targeting sequence (MTS) of human citrate synthase having the amino acid sequence denoted by SEQ ID NO. 23, said MTS situated between said TAT domain and said frataxin, and is linked to said TAT domain via a linker having the amino acid sequence denoted by SEQ ID NO. 32, and wherein said frataxin is C-terminal to said MTS of human citrate synthase.
A fusion protein having the amino acid sequence denoted by SEQ ID NO. 30, comprising a HIV-1 transactivator of transcription (TAT) domain having the amino acid sequence denoted by SEQ ID NO. 27 fused to human frataxin having the amino acid sequence denoted by SEQ ID NO. 26 and a mitochondria targeting sequence (MTS) of human lipoamide dehydrogenase having the amino acid sequence denoted by SEQ ID NO. 24, said MTS situated between said TAT domain and said frataxin and is linked to said TAT domain via a linker having the amino acid sequence denoted by SEQ ID NO. 32, and wherein said frataxin is C-terminal to said MTS of human lipoamide dehydrogenase.
Dependencies are inferred from the claim text.