Ucl Business Plc

St. Jude Children's Research Hospital

Biomarin Pharmaceutical Inc.

University College London

Jenny McIntosh

Amit Nathwani

Edward Tuddenham

Andrew Davidoff

Peter Cameron Colosi

Nishil Patel

The invention provides improved adeno-associated virus (AAV) Factor VIII (FVIII) vectors, including AAV FVIII vectors that produce a functional Factor VIII polypeptide and AAV FVIII vectors with high expression activity.

Adeno-associated virus factor VIII vectors

The present invention relates to polynucleotides comprising a Factor IX nucleotide sequence, wherein the Factor IX nucleotide sequence comprises a coding sequence that encodes a Factor IX protein or fragment thereof and wherein a portion of the coding sequence is not wild type. The present invention further relates to viral particles comprising a recombinant genome comprising the polynucleotide of the invention, compositions comprising the polynucleotides or viral particles, and methods and uses of the polynucleotides, viral particles or compositions.

Factor IX encoding nucleotides

There is provided a nucleic acid molecule comprising a nucleotide sequence encoding a Factor VIII protein, wherein a B domain portion of the Factor VIII protein is encoded by a nucleotide sequence between 90 and 111 nucleotides in length and has an amino acid sequence that is at least 85% identical to SEQ ID NO: 4 which comprises six asparagine residues. Also provided is a Factor VIII protein, a vector comprising the above nucleic acid molecule, a host cell, a transgenic animal, a method of treating Haemophilia for example, Haemophilia A, and a method for the preparation of a parvoviral gene delivery vector.

Factor VIII sequences

The present disclosure provides methods of generating multiplexed genetically modified animals, for example, porcine endogenous retrovirus (PERV)-inactivated pigs. The disclosure also provides methods of improving the birth rate of multiplexed genetically modified animals. In some embodiments, the present closure is concerned with the generation and utilization of porcine cells in which porcine endogenous retroviral (PERV) elements have been inactivated. In sonic embodiments, the PERV-free or PERV-reduced porcine cells are cloned to produce porcine embryos. In some embodiments, the PERV-free or PERV-reduced embryos may be grown into adult swine from which organs and/or tissues may be extracted and used for such purposes as xenotransplantation into non-porcine animals such as humans.

The invention relates to a new, more potent, coagulation Factor IX (FIX) expression cassette for gene therapy of Haemophilia B (HB). Disclosed is a vector for expressing factor IX protein, the vector comprising a promoter, a nucleotide sequence encoding for a functional factor IX protein, and an intron sequence, wherein the intron sequence is positioned between exon 1 and exon 2 of the nucleotide sequence encoding for a functional factor IX protein, and wherein the intron sequence has at least 80% identity to the sequence of SEQ ID NO. 1 as disclosed herein.

Factor IX gene therapy

There is provided a nucleic acid molecule comprising a nucleotide sequence encoding a Factor VIII protein, wherein a B domain portion of the Factor VIII protein is encoded by a nucleotide sequence between 90 and 111 nucleotides in length and has an amino acid sequence that is at least 85% identical to SEQ ID NO: 4 which comprises six asparagine residues. Also provided is a Factor VIII protein, a vector comprising the above nucleic acid molecule, a host cell, a transgenic animal, a method of treating Haemophilia Haemophilia A, and a method for the preparation of a parvoviral gene delivery vector.

Method of treating hemophilia A

The invention relates to a new, more potent, coagulation factor IX (FIX) expression cassette for gene therapy of haemophilia B (HB). Disclosed is a vector for expressing factor IX protein, the vector comprising a promoter, a nucleotide sequence encoding for a functional factor IX protein and an intron sequence, wherein the intron sequence is positioned between exon 1 and exon 2 of the nucleotide sequence encoding for a functional factor IX protein, and wherein the intron sequence has at least 80% identity to the sequence of SEQ ID NO. 1 as disclosed herein.

There is provided a nucleic acid molecule comprising a nucleotide sequence encoding a factor VIII protein, wherein a B domain portion of the factor VIII protein is encoded by a nucleotides sequence between 90 and 111 nucleotides in length and has an amino acid sequence that is at least 85% identical to SEQ ID NO: 4 which comprises six asparagine residues. Also provided is a factor VIII protein, a vector comprising the above nucleic acid molecule, a host cell, a transgenic animal, a method of treating Haemophilia A, and a method for the preparation of a parvoviral gene delivery vector.

Methods of delivering factor VIII encoding nucleic acid sequences

There is provided a nucleic acid molecule comprising a nucleotide sequence encoding for a functional factor VIII protein, wherein the portion of the nucleotide sequence encoding for the B domain of the factor VIII protein is between 90 and 111 nucleotides in length and encodes for an amino acid sequence comprising a sequence having at least 85% identity to SEQ ID NO: 4 and which comprises six asparagine residues. Also provided is a functional factor VIII protein, a vector comprising the above nucleic acid molecule, a host cell, a transgenic animal, a method of treating hemophilia, e.g. hemophilia A, and a method for the preparation of a parvoviral gene delivery vector.

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London, United Kingdom

Jenny McIntosh