Gene therapy

Abstract

The present invention relates generally to polypeptides or nucleic acids for use in the treatment, management, retardation of progression or normalisation of development of an iduronate-2-sulfatase (IDS) deficiency and/or Mucopolysaccharidosis type II (MPS II) in an individual, wherein the polypeptides comprise iduronate-2-sulfatase (IDS) tethered to a tandem repeat of Apolipoprotein E (ApoEII) or the nucleic acids comprise an iduronate-2-sulfatase (IDS) gene sequence tethered to a tandem repeat of the Apolipoprotein E (ApoEII) gene sequence. The invention also relates to haematopoietic stem and progenitor cells (HSPCs) transduced by such nucleic acids for use in therapies.

1 . A nucleic acid comprising an iduronate-2-sulfatase (IDS) gene sequence and a repeat of the Apolipoprotein E (ApoEII) gene sequence. 
     
     
         2 . The nucleic acid as claimed in  claim 1 , further comprising an intervening linker sequence located between the IDS sequence and the ApoEII sequence. 
     
     
         3 . The nucleic acid of  claim 1 , wherein the IDS sequence comprises a codon-optimised sequence of the wild-type IDS sequence. 
     
     
         4 . The nucleic acid of  claim 1 , wherein the repeat of the ApoEII sequence is in the form of a tandem repeat. 
     
     
         5 . The nucleic acid of  claim 1 , wherein the IDS sequence comprises the sequence according to SEQ ID NO: 1 or SEQ ID NO: 2 or a derivative sequence having at least 90% homology thereof, or the ApoEII sequence comprises one or more sequences according to SEO ID NO: 3 or a derivative sequence having at least 95% homology thereof. 
     
     
         6 . (canceled) 
     
     
         7 . The nucleic acid of  claim 2 , wherein the intervening linker sequence comprises the sequence according to SEQ ID NO: 4 or a derivative sequence having at least 95% homology thereof. 
     
     
         8 . The nucleic acid of  claim 2 , wherein the nucleic acid is incorporated in a gene therapy vector. 
     
     
         9 . The nucleic acid of  claim 8 , wherein the vector is a lentiviral vector. 
     
     
         10 . The nucleic acid of  claim 1 , wherein the nucleic acid is transduced in one or more haematopoietic stem and progenitor cells (HSPCs). 
     
     
         11 . The nucleic acid of  claim 1 , for use in the treatment, management, retardation of progression or normalisation of development of a disease or condition attributable to iduronate-2-sulfatase (IDS) deficiency. 
     
     
         12 . The nucleic acid of  claim 11 , wherein the disease or condition comprises mucopolysaccharidosis type 11 (MPS 11) or Hunters syndrome. 
     
     
         13 . A composition comprising:
 a) a first moiety comprising iduronate-2-sulfatase (IDS); and   b) a second moiety comprising a repeat of Apolipoprotein E (ApoE11).   
     
     
         14 . The composition of  claim 13 , wherein the repeat of Apolipoprotein ApoEII is in the form of a tandem repeat. 
     
     
         15 . The composition of  claim 13 , wherein the first and second moiety have an intervening linker moiety located there between. 
     
     
         16 . The composition of  claim 13 , wherein the amino acid sequence of the first moiety comprises the sequence according to SEQ ID NO: 5 or a derivative sequence having at least 90% homology thereof, or the amino acid sequence of the second moiety comprise one or more sequences according to SEO ID NO: 7 or a derivative sequence having at least 95% homology thereof. 
     
     
         17 . (canceled) 
     
     
         18 . The composition of  claim 15 , wherein the amino acid sequence of the intervening linker moiety comprise the sequence according to SEQ ID NO: 8 or a derivative sequence having at least 95% homology thereof. 
     
     
         19 . The composition of  claim 1 , for use in the treatment, management, retardation of progression or normalisation of development of a disease or condition attributable to iduronate-2-sulfatase (IDS) deficiency. 
     
     
         20 . The composition of  claim 19 , wherein the disease or condition comprises mucopolysaccharidosis type II (MPS II) or Hunters syndrome. 
     
     
         21 . Haematopoietic stem and progenitor cells (HSPCs) for use in the treatment, management, retardation of progression or normalisation of development of an iduronate-2-sulfatase (IDS) deficiency and/or Mucopolysaccharidosis type II (MPS II) in an individual, wherein the HSPCs have been removed from the patient, transduced ex vivo with the nucleic acid claimed in  claim 1 , and the transduced HSPCs administered to the individual. 
     
     
         22 . A method for delivering a deficient iduronate-2-sulfatase (IDS) protein into the brain across the blood brain barrier in an individual suffering from a condition resulting from the deficiency in the protein, the composition comprising a viral vector comprising the gene sequence coding for the deficient protein tethered to a tandem repeat of the Apolipoprotein E (ApoEII) gene sequence, wherein the vector is transduced, ex vivo, with a population of haematopoietic stem and progenitor cells (HSPCs) and the transduced HSPCs administered to the individual where they express higher physiological levels of the deficient protein which are sufficient to cross the blood brain barrier. 
     
     
         23 . The method of  claim 22 , wherein vector comprises a sequence for a flexible linker between the gene sequence coding for the deficient protein and the tandem repeat of the Apolipoprotein E (ApoEII) gene sequence, or the ApoEII tandem repeat gene sequence comprises the sequence according to SEO ID NO: 3 or variant sequences having up to 95% homology thereof, or the flexible linker sequence comprises the sequence according to SEO ID NO: 4 or variant sequences having up to 95% homology thereof. 
     
     
         24 .- 25 . (canceled) 
     
     
         26 . The method of  claim 23 , wherein the HSPCs are autologous. 
     
     
         27 . A combination of a nucleic acid comprising an iduronate-2-sulfatase (IDS) gene sequence and a repeat of the Apolipoprotein E (ApoEII) gene sequence and one or more haematopoietic stem and progenitor cells (HSPCs), wherein the nucleic acid is capable of transducing the HSPCs.