Diagnosis and treatment of multiple sulfatase deficiency and other sulfatase deficiencies

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 composition comprising a sulfatase produced by mammalian cells co-expressing the sulfatase and a formylglycine generating enzyme (FGE), wherein the sulfatase has increased ratio percentage of active sulfatase as compared to a control sulfatase produced by the same mammalian cells in the absence of the FGE. 
     
     
         87 . The composition of  claim 86 , wherein the ratio of active sulfatase to total sulfatase is increased by at least 5% as compared to the control sulfatase produced in the absence of the FGE. 
     
     
         88 . The composition of  claim 86 , wherein the mammalian cells over-express the FGE, over-express the FGE by activating the endogenous FGE, or over-express the FGE by over-expressing an exogenous FGE. 
     
     
         89 . A composition comprising a sulfatase produced by mammalian cells with enhanced Cα-formylglycine generating activity relative to wild-type cells, wherein the sulfatase has increased formation of formylglycine on the sulfatase as compared to a control sulfatase produced by the wild-type cells. 
     
     
         90 . The composition of  claim 89 , wherein the mammalian cells comprise an activated endogenous formylglycine generating enzyme (FGE). 
     
     
         91 . The composition of  claim 89 , wherein the mammalian cells comprise an exogenous formylglycine generating enzyme (FGE). 
     
     
         92 . The composition of  claim 89 , wherein the 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. 
     
     
         93 . A method of treating a sulfatase deficiency in a subject, comprising administering into the subject a pharmaceutical composition comprising a sulfatase produced by mammalian cells co-expressing the sulfatase and a formylglycine generating enzyme (FGE), wherein the sulfatase has increased ratio percentage of active sulfatase as compared to a control sulfatase produced by the same mammalian cells in the absence of the FGE. 
     
     
         94 . A method of treating a sulfatase deficiency in a subject, comprising administering into the subject a pharmaceutical composition comprising a sulfatase produced by mammalian cells with enhanced Ca-formylglycine generating activity relative to wild-type cells, wherein the sulfatase has increased formation of formylglycine on the sulfatase as compared to a control sulfatase produced by the wild-type cells. 
     
     
         95 . The method of  claim 93 , wherein the sulfatase deficiency is selected from the group consisting of 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, and X-linked Ichthyosis (Steroid Sulfatase Deficiency). 
     
     
         96 . A sulfatase-producing cell, the cell co-expresses:
 (i) a sulfatase, and   (ii) a Formylglycine Generating Enzyme (FGE);   wherein the cell has increased Cα-formylyglycine generating activity as compared to a wild-type cell resulting in an increased ratio of active sulfatase to total sulfatase produced by the cell.   
     
     
         97 . A sulfatase produced by the sulfatase-producing cell of  claim 96 . 
     
     
         98 . A pharmaceutical composition comprising a sulfatase of  claim 97 . 
     
     
         99 . A method of producing activated sulfatase, comprising cultivating the sulfatase-producing cell of  claim 96 . 
     
     
         100 . A polypeptide for preparing a medicament that is for use in treating a sulfatase deficiency, wherein the polypeptide has C α -formylglycine generating activity and:
 a) has a sequence selected from the group consisting of SEQ ID NO. 2, 5, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, or amino acids 34-374 of SEQ ID NO. 2; or   b) has at least 50% sequence identity with SEQ ID No 2; or   c) has one or more conservative amino acid mutations relative to a polypeptide as described   
       in a) or b) above; or
 d) is a fragment of a polypeptide as described in a) above; 
 e) is a fusion protein of any of a) to d) above. 
 
     
     
         101 . A nucleic acid encoding a polypeptide as described in  claim 100  or a vector comprising said nucleic acid. 
     
     
         102 . A composition or a kit comprising a polypeptide as described in  claim 100  and a sulfatase. 
     
     
         103 . A composition or a kit comprising a nucleic acid as described in  claim 101 . 
     
     
         104 . A method comprising modifying a substrate so as to introduce an aldehyde group using a formylglycine generating enzyme (FGE). 
     
     
         105 . The method of  claim 104 , wherein the substrate is a sulfatase comprising the sequence of X—X—X—P—S—R (SEQ ID NO:32).