Gene therapy for sulfatase deficiency

Abstract

This invention relates to methods and compositions for the diagnosis and treatment of Multiple Sulfatase Deficiency (MSD) as well as other sulfatase deficiencies. More specifically, the invention relates to isolated molecules that modulate post-translational modifications on sulfatases. Such modifications are essential for proper sulfatase function.

1 .- 85 . (canceled) 
     
     
         86 . A gene therapy method of treating a sulfatase deficiency in a subject, the method comprising delivering to a cell of the subject a vector comprising a polynucleotide encoding a Formylglycine Generating Enzyme (FGE) comprising an amino acid sequence having at least 80% identity to the amino acid sequence of amino acids 34-374 of SEQ ID NO:2, wherein the FGE has C α -formylglycine generating activity. 
     
     
         87 . The gene therapy method of  claim 86 , wherein the FGE comprises an amino acid sequence having at least 95% identity to the amino acid sequence of amino acids 34-374 of SEQ ID NO:2. 
     
     
         88 . The gene therapy method of  claim 86 , wherein the FGE comprises the amino acid sequence of amino acids 34-374 of SEQ ID NO:2. 
     
     
         89 . The gene therapy method of  claim 86 , wherein the sulfatase deficiency is selected from Mucopolysaccharidosis II (MPS II; Hunter Syndrome), Mucopolysaccharidosis IIIA (MPS IIIA; Sanfilippo Syndrome A), Mucopolysaccharidosis VIII (MPS VIII), Mucopolysaccharidosis IVA (MPS IVA; Morquio Syndrome A), Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy Syndrome), Metachromatic Leukodystrophy (MLD), X-linked Recessive Chondrodysplasia Punctata 1, or X-linked Ichthyosis (Steroid Sulfatase Deficiency). 
     
     
         90 . The gene therapy method of  claim 89 , wherein the sulfatase deficiency is Mucopolysaccharidosis IIIA (MPS IIIA; Sanfilippo Syndrome A). 
     
     
         91 . The gene therapy method of  claim 89 , wherein the sulfatase deficiency is Mucopolysaccharidosis II (MPS II; Hunter Syndrome). 
     
     
         92 . The gene therapy method of  claim 89 , wherein the sulfatase deficiency is Metachromatic Leukodystrophy (MLD). 
     
     
         93 . The gene therapy method of  claim 86 , wherein the method further comprises delivering to the cell a polynucleotide encoding a cysteine-type sulfatase. 
     
     
         94 . The gene therapy method of  claim 93 , wherein the polynucleotide encoding the cysteine-type sulfatase is delivered on a separate vector. 
     
     
         95 . The gene therapy method of  claim 93 , wherein the cysteine-type sulfatase is selected from the group consisting of Iduronate 2-Sulfatase, Sulfamidase, N-Acetylgalactosamine 6-Sulfatase, N-Acetylglucosamine 6-Sulfatase, Arylsulfatase A, Arylsulfatase B, Arylsulfatase C, Arylsulfatase D, Arylsulfatase E, Arylsulfatase F, Arylsulfatase G, HSulf-1, HSulf-2, HSulf-3, HSulf-4, HSulf-5, and HSulf-6. 
     
     
         96 . The gene therapy method of  claim 86 , wherein the vector is a viral vector. 
     
     
         97 . The gene therapy method of  claim 96 , wherein the viral vector comprises nucleic acid sequences from adenovirus, adeno-associated virus, or retrovirus. 
     
     
         98 . The gene therapy method of  claim 97 , wherein the viral vector comprises nucleic acid sequences from adeno-associated virus. 
     
     
         99 . The gene therapy method of  claim 86 , wherein the delivering step comprises in vivo transduction of the cell of the subject. 
     
     
         100 . The gene therapy method of  claim 99 , wherein the cell is selected from the group consisting of fibroblasts, keratinocytes, epithelial cells, endothelial cells, glial cells, neural cells, blood cells, lymphocytes, bone marrow cells, muscle cells, and precursors thereof. 
     
     
         101 . The gene therapy method of  claim 99 , wherein the cell is a neuron. 
     
     
         102 . The gene therapy method of  claim 86 , wherein the delivering step comprises in vitro transduction of the cell of the subject. 
     
     
         103 . The gene therapy method of  claim 102 , wherein the cell is a primary cell isolated from the subject. 
     
     
         104 . The gene therapy method of  claim 86 , wherein the polynucleotide encoding the FGE is operably linked to an gene expression regulatory sequence. 
     
     
         105 . The gene therapy method of  claim 86 , wherein the gene expression regulatory sequence is a mammalian or viral promoter. 
     
     
         106 . A composition for gene therapy for a sulfatase deficiency comprising a vector comprising a polynucleotide encoding a Formylglycine Generating Enzyme (FGE) comprising an amino acid sequence having at least 80% identity to the amino acid sequence of amino acids 34-374 of SEQ ID NO:2, wherein the FGE has C α -formylglycine generating activity. 
     
     
         107 . The composition of  claim 106 , wherein the FGE comprises an amino acid sequence having at least 95% identity to the amino acid sequence of amino acids 34-374 of SEQ ID NO:2. 
     
     
         108 . The composition of  claim 106 , wherein the FGE comprises the amino acid sequence of amino acids 34-374 of SEQ ID NO:2. 
     
     
         109 . The composition of  claim 106 , wherein the composition further comprises a polynucleotide encoding a cysteine-type sulfatase. 
     
     
         110 . The composition of  claim 109 , wherein the polynucleotide encoding the cysteine-type sulfatase is encoded by a separate vector. 
     
     
         111 . The composition of  claim 109 , wherein the cysteine-type sulfatase is selected from the group consisting of Iduronate 2-Sulfatase, Sulfamidase, N-Acetylgalactosamine 6-Sulfatase, N-Acetylglucosamine 6-Sulfatase, Arylsulfatase A, Arylsulfatase B, Arylsulfatase C, Arylsulfatase D, Arylsulfatase E, Arylsulfatase F, Arylsulfatase G, HSulf-1, HSulf-2, HSulf-3, HSulf-4, HSulf-5, and HSulf-6 
     
     
         112 . The composition of  claim 106 , wherein the vector is a viral vector. 
     
     
         113 . The composition of  claim 112 , wherein the viral vector comprises nucleic acid sequences from adenovirus, adeno-associated virus, or retrovirus. 
     
     
         114 . The composition of  claim 113 , wherein the viral vector comprises nucleic acid sequences from adeno-associated virus. 
     
     
         115 . The composition of  claim 106 , wherein the polynucleotide encoding the FGE is operably linked to an gene expression regulatory sequence. 
     
     
         116 . The composition of  claim 115 , wherein the gene expression regulatory sequence is a mammalian or viral promoter. 
     
     
         117 . The composition of  claim 106 , wherein the sulfatase deficiency is selected from Mucopolysaccharidosis II (MPS II; Hunter Syndrome), Mucopolysaccharidosis IIIA (MPS IIIA; Sanfilippo Syndrome A), Mucopolysaccharidosis VIII (MPS VIII), Mucopolysaccharidosis IVA (MPS IVA; Morquio Syndrome A), Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy Syndrome), Metachromatic Leukodystrophy (MLD), X-linked Recessive Chondrodysplasia Punctata 1, or X-linked Ichthyosis (Steroid Sulfatase Deficiency). 
     
     
         118 . The composition of  claim 117 , wherein the sulfatase deficiency is Mucopolysaccharidosis IIIA (MPS IIIA; Sanfilippo Syndrome A). 
     
     
         119 . The composition of  claim 117 , wherein the sulfatase deficiency is Mucopolysaccharidosis II (MPS II; Hunter Syndrome). 
     
     
         120 . The composition of  claim 117 , wherein the sulfatase deficiency is Metachromatic Leukodystrophy (MLD). 
     
     
         121 . A gene therapy vector comprising a polynucleotide encoding a Formylglycine Generating Enzyme (FGE) comprising an amino acid sequence having at least 80% identity to the amino acid sequence of amino acids 34-374 of SEQ ID NO:2, wherein the FGE has C α -formylglycine generating activity. 
     
     
         122 . The gene therapy vector of  claim 121 , wherein the FGE comprises an amino acid sequence having at least 95% identity to the amino acid sequence of amino acids 34-374 of SEQ ID NO:2. 
     
     
         123 . The gene therapy vector of  claim 121 , wherein the polynucleotide encoding the FGE is operably linked to an gene expression regulatory sequence. 
     
     
         124 . The gene therapy vector of  claim 123 , wherein the gene expression regulatory sequence is a mammalian or viral promoter. 
     
     
         125 . A cell transduced with a gene therapy vector comprising a polynucleotide encoding a Formylglycine Generating Enzyme (FGE) comprising an amino acid sequence having at least 80% identity to the amino acid sequence of amino acids 34-374 of SEQ ID NO:2, wherein the FGE has C α -formylglycine generating activity. 
     
     
         126 . The cell of  claim 125 , wherein the cell is a primary cell. 
     
     
         127 . The cell of  claim 125 , wherein the cell is a secondary cell. 
     
     
         128 . The cell of  claim 125 , wherein the cell is selected from the group consisting of fibroblasts, keratinocytes, epithelial cells, endothelial cells, glial cells, neural cells, blood cells, lymphocytes, bone marrow cells, muscle cells, and precursors thereof. 
     
     
         129 . The cell of  claim 125 , wherein the vector is integrated into the genome of the cell. 
     
     
         130 . The cell of  claim 125 , wherein the vector functions in an extrachromosomal fashion. 
     
     
         131 . The cell of  claim 125 , wherein the polynucleotide encoding the FGE is operably linked to an gene expression regulatory sequence. 
     
     
         132 . The cell of  claim 131 , wherein the gene expression regulatory sequence is a mammalian or viral promoter. 
     
     
         133 . The cell of  claim 132 , wherein the mammalian promoter is an endogenous promoter of the cell.