mucopolysaccharidoses ( mps ) are a group of lysosomal storage disorders ( lsds ) caused by deficiency of the lysosomal enzymes needed to degrade glycosaminoglycans ( gags ). 14 in mps , the undegraded gags are stored in lysosomes and / or secreted into the blood stream 15 , 16 , and excreted in urine . mps involve the deficiency of one of 11 enzymes needed for the stepwise degradation of ds , hs , ks , and / or cs . ert is an established means of treating mps . however , improving bone and brain pathology is still an unmet challenge because only a small fraction of enzyme is delivered to bone and brain . most of the enzyme - based drugs are delivered to major visceral organs like liver and spleen . although some of the enzyme reaches bone marrow , only small amounts of the enzyme go to bone or brain . the blood brain barrier provides a formidable obstacle for enzymes to reach brain . therefore , the improvement of bone and brain lesions is quite limited , even after long - term treatment with ert . we have tested an acidic oligopeptide - based targeting system for delivery of enzymes to tissues in murine mps iva and vii models . this strategy is based on tagging a short peptide consisting of acidic amino acids ( aaa ) to the mature enzyme . the aaa - tagged enzyme had five to ten times prolonged blood clearance compared with the untagged enzymes . the tagged enzyme was delivered effectively to bone , bone marrow , and brain in mps vii mice and was more effective in reversing the storage pathology than the untagged enzyme . others have shown therapeutic responses in brain of mouse models mps vii , aspartylglycosaminuria and β - mannosidosis when higher doses and longer treatment with enzyme is made possible . 17 , 18 , 19 these results indicate that when therapeutic enzyme is administered over a sufficient period , at doses higher than those used in conventional ert trials such a therapeutic dose has a beneficial effect in an adult mouse . the present invention allows such beneficial effects to be achieved with the administration of less therapeutic enzyme . therefore , the present invention discloses 1 ) an enzyme with therapeutic benefits for the cns whereby said benefits are enhanced by the attachment of an aaa sequence , 2 ) a method of attaching an acidic amino acid sequence to a therapeutic enzyme with benefits for the cns so as to allow said benefits to be delivered to the cns under conditions which would otherwise be ineffectual , 3 ) a method of treating a patient with an cns related disease using the aforementioned aaa - therapeutic enzyme . the inventors have previous disclosed aaa - galns which is hereby incorporated by reference . 20 this reference discloses a fusion protein for the treatment of disease , and a method of increasing the stability of a therapeutic protein in blood and transfer of said protein to bone . more specifically the therapeutic protein is galns and the disease is morquio disease . the inventors have also previously disclosed an aaa - gus , described in detail bellow , and herein incorporated by reference . 21 this reference discloses a fusion protein aaa - gus for the treatment of disease with improved in vivo stability and a method for treating a patient with mps vii . the term “ polypeptide therapeutic agent ” refereed to in the present invention means any polypeptide , oligopeptide or protein which will benefit a patient suffering from disease when administered to the patient . the term “ acidic amino acid ” or “ aaa ” referred to the present invention means glutamic acid or aspartic acid . as the employment of these acidic amino acids in the present invention is for the purpose of constructing an acidic short peptide , they may be used in any arbitrary combination including a simple use of one or the other of them alone for construction of such a short peptide . the number of the acidic amino acids forming a short peptide is preferably 4 - 15 , more preferably 4 - 12 , and still more preferably 4 - 8 . a short peptide consisting of acidic amino acids may be directly attached to the n - terminus of physiologically active human gus via a peptide bond or like , or , instead , it may be attached via a linker peptide . in the present invention “ a linker peptide ” is not an indispensable component , for it is usable only for convenience in attaching a short peptide consisting of acidic amino acids to n - terminus of physiologically active gus . where it is used , a linker peptide may be a short peptide consisting e . g ., preferably of 15 or less , more preferably of 10 or less , and still more preferably of 6 or less amino acids . such a linker that consists of a single amino acid molecule and linking between the acidic short peptide and physiologically active gus via peptide bonds is also included in the definition of a linker peptide . a linker peptide may be made of any one or more amino acids desired . in the present invention , though there is no specific limitation as to the method for attaching an acidic short peptide to physiologically active gus , it is of advantage , e . g ., to form and use a transformant cell expressing the fusion protein consisting of the short peptide and physiologically active gus . in the present invention “ attachment ” in reference to acidic amino acids or aaa and therapeutic proteins or peptides or enzymes refers to creation of a covalent bond either through the creation of a fusion protein or through the use of chemical agents or manipulation to achieve the same result . a fusion protein of the present invention may include a non - acidic amino acid or a sequence of several ( e . g ., 3 ) non - acidic amino acids at n - terminus of the short peptide consisting of acidic amino acids . a fusion protein of the present invention may be formulated into a pharmaceutical composition containing the fusion protein dissolved or dispersed in a pharmaceutically acceptable carrier well known to those skilled in the art , for parenteral administration by e . g ., intravenous , subcutaneous , or intramuscular injection or by intravenous drip infusion . for pharmaceutical compositions for parenteral administration , any conventional additives may be used such as excipients , binders , disintegrants , dispersing agent , lubricants , diluents , absorption enhancers , buffering agents , surfactants , solubilizing agents , preservatives , emulsifiers , isotonizers , stabilizers , solubilizers for injection , ph adjusting agents , etc . a fusion protein of the present invention may be used advantageously in place of the conventional native enzyme protein in a substitution therapy for the treatment of mps vii . in the treatment , the fusion protein may be administered intravenously , subcutaneously , or intramuscularly . doses and frequencies of administration are to be determined by the physician in charge in accordance with the condition of his or her patient . preferred embodiments of the invention are described in the following examples . other embodiments within the scope of the claims herein will be apparent to one skilled in the art from consideration of the specification or practice of the invention as disclosed herein . it is intended that the specification , together with the examples , be considered exemplary only , with the scope and spirit of the invention being indicated by the claims , which follow the examples . vector pcxn had been constructed in accordance with a literature ( 7 ) and was offered to us by prof . miyazaki at osaka university . an expression vector for native human gus , pcxn - gus , was constructed by using human gus cdna that had been reported by oshima et al . ( 8 )( accession no . of genbank for the amino acid and cdna sequence of human gus is bc014142 .). an expression vector for human gus to the n - terminus of which is attached ( via a linker peptide ) a short peptide ( n - terminal bone tag : nbt ) consisting of acidic amino acids ( nbt - gus ), was constructed starting with pcxn - gus in the following manner . fig1 and 2 schematically illustrate the process for construction . using pcxn - gus as a template , pcr was carried out using la - taq ( takara ) to amplify δsig gus cdna ( the sequence , nt 67 - 1956 , left behind after removal of the sequence of nt 1 - 66 corresponding to a secretion signal , from the orf region of the sequence set forth as seq id no : 1 ) ( for human gus without signal sequence , see seq id no : 2 ), to the 5 ′- terminus of which is attached an agei cleavage sequence . the pcr was carried out according to the instruction for use of la - taq , i . e ., through the cycles consisting of 30 seconds at 94 ° c ., ( 30 seconds at 94 ° c ., 30 seconds at 60 ° c ., and 2 minutes at 72 ° c . )× 25 , and then 3 minutes at 72 ° c ., with primer 1 ( seq id no : 3 ), and primer 2 ( seq id no : 4 ). the cdna thus amplified was inserted into pt7blue vector ( novagen ) to construct pt7 - δsig gus . the n - terminal bone tag ( nbt ) cdna to be attached to the 5 ′- terminus then was constructed by pcr using la - taq ( takara ). briefly , primer 3 ( seq id no : 5 ) and primer 4 ( seq id no : 6 ) were used for the construction of nbt - e6 cdna , primer 5 ( seq id no : 7 ) and primer 4 ( seq id no : 6 ) for the construction of nbt - e8 cdna , primer 6 ( seq id no : 8 ) and primer 4 ( seq id no : 6 ) for the construction of nbt - d6 cdna , and primer 7 ( seq id no : 9 ) and primer 4 ( seq id no : 6 ) for the construction of nbt - d8 cdna . in the names of the nbt cdnas , “ e6 ” or “ e8 ” indicate that the nbt is made up of 6 or 8 serially connected glutamic acid residues , respectively . likewise , “ d6 ” or “ d8 ” indicates that the nbt is made up of 6 or 8 connected aspartic acid residues , respectively . employing each pair of the above primers , which contained a portion complementary to each other , pcr was carried out through the cycles consisting of 30 seconds at 94 ° c ., ( 30 seconds at 94 ° c ., 30 seconds at 60 ° c ., 30 seconds at 72 ° c . )× 20 minutes , and then one minute at 72 ° c . the thus amplified dna fragments were inserted into pt7blue vector ( novagen ) to construct pt7 - nbts . a human gus cdna recovered as a fragment of pt7 pt7 - δsig gus cleaved with agei and xbai was inserted into the agei - xbai site of pt7 - nbts to construct pt7 - nbt - guss . then each of pt7 - nbt - guss was cleaved with bcli , blunt - ended with t4 dna polymerase , and cleaved with xbai to recover nbt - gus cdnas . pst - rap - gusb ( a vector comprising the p97 signal sequence , provided by tomatsu at saint louis university ) was cleaved with bamhi and xbai , into which then was inserted the nbt - gus cdnas recovered above to construct pst - p97 - nbt - guss . pst - p97 - nbt - guss were cleaved with ecori to recover respective p97 - nbt - gus cdnas , each of which then was inserted into the ecori site of pcxn to construct a nbt - gus expression vector , pcxn - p97 - nbt - gus . the dna sequence of the expression vectors &# 39 ; region corresponding to the p97 - nbt - d6 - gus , p97 - nbt - d8 - gus , p97 - nbt - e6 - gus and p97 - nbt - e8 - gus cdnas are shown in the sequence listing ( seq id no : 10 , seq id no : 12 , seq id no : 14 , seq id no : 16 ,) along with their corresponding amino acid sequences ( seq id no : 11 , seq id no : 13 , seq id no : 15 , seq id no : 17 ), respectively . seq id no : 10 shows part of the sequence containing the nbt - e6 - gus cdna of pcxn - p97 - nbt - e6 - gus . its nt 1 - 57 encode the p97 signal sequence , nt 61 - 78 a poly glu , nt 79 - 96 a linker sequence , and nt 97 - 1983 gus without the signal sequence . seq id no : 11 shows the nbt - e6 - gus amino acid sequence with the p97 signal sequence . aa 1 - 19 : p97 signal sequence , aa 21 - 26 : poly glu , aa 27 - 32 : linker sequence , aa 33 - 661 : gus without signal sequence . seq id no : 12 shows part of the sequence containing the nbt - e8 - gus cdna of pcxn - p97 - nbt - e8 - gus . its nt 1 - 57 encode the p97 signal sequence , nt 61 - 84 a poly glu , nt 85 - 102 a linker sequence , and nt 103 - 1989 gus without the signal sequence . seq id no : 13 shows the nbt - e8 - gus amino acid sequence with attached p97 signal sequence . aa 1 - 19 : p97 signal sequence , aa 21 - 28 : poly glu , aa 29 - 34 : linker sequence , aa 35 - 663 : gus without signal sequence . seq id no : 14 shows part of the sequence containing the nbt - d6 - gus cdna of pcxn - p97 - nbt - d6 - gus . its nt 1 - 57 encode the p97 signal sequence , nt 61 - 78 a poly asp , nt 79 - 96 a linker sequence , and nt 97 - 1983 gus without the signal sequence . seq id no : 15 shows the nbt - d6 - gus amino acid sequence with attached p97 signal sequence . aa 1 - 19 : p97 signal sequence , aa 21 - 26 : poly asp , aa 27 - 32 : linker sequence , aa 33 - 661 : gus without signal sequence . seq id no : 16 shows part of the sequence containing the nbt - d8 - gus cdna of pcxn - p97 - nbt - d8 - gus . its nt 1 - 57 encode the p97 signal sequence , nt 61 - 84 a poly asp , nt 85 - 102 a linker sequence , and nt 103 - 1989 gus without the signal sequence . seq id no : 17 shows the nbt - d8 - gus amino acid sequence with attached p97 signal sequence . aa 1 - 19 : p97 signal sequence , aa 21 - 28 : poly asp , aa 29 - 34 : linker sequence , aa 35 - 663 : gus without signal sequence . the proteins set forth as seq id no : 11 , seq id no : 13 , seq id no : 15 and seq id no : 17 contain the p97 secretion signal sequence . the signal sequence is removed during secretion process from the cell and the fusion proteins are thus recovered as nbt - gus in the medium . p97 is a cell - surface glycoprotein occurring in most human melanomas and its signal sequence consists of 19 amino acids ( 9 ). the aforementioned pcxn - p97 - nbt - guss containing the cdna encoding this signal sequence may also be constructed by the following method . briefly , a cdna containing the p97 signal sequence is synthesized through the process of primers annealing and pcr amplification . la - taq is used as an enzyme for pcr . as primers having mutually complementary portions , primer 8 ( seq id no : 18 ) and primer 9 ( seq id no : 19 ) are used . pcr is performed through the cycles of 30 seconds at 94 ° c ., ( 30 seconds at 94 ° c ., 30 seconds at 60 ° c ., 30 seconds at 72 ° c . )× 20 , and one minute at 72 ° c . the amplified cdna containing the p97 signal sequence is cleaved with bamhi and ecori . into the pcxn vector , after cleaved with ecori , are simultaneously incorporated the aforementioned nbt - guss cdna recovered after the enzyme treatment and cdna for the p97 signal sequence , giving pcxn - p97 - nbt - guss . seq id no : 18 is a forward primer , in which nt 1 - 5 comprise a random synthetic sequence , and nt 6 - 52 comprise part of the sequence encoding the p97 signal . seq id no : 19 is a reverse primer , in which nt 1 - 6 comprise a random synthetic sequence , and nt 7 - 52 comprise part of the sequence encoding the p97 signal . nunclon delta - multidish 6 well was inoculated with cho - k1 cells . after an overnight culture in dmem / f12 / fbs medium [ dmem / f12 medium ( gibco ) supplemented with 10 % fetal bovine serum ( thermo trace )], each of the expression vector constructed above was introduced into the cells using lipofectamine 2000 reagent . for experimental procedures , the instruction manual attached to the lipofectamine 2000 reagent was followed . after a two - day incubation at 37 ° c . in 5 % co 2 , the cells were added to 75 - cm 2 tissue culture flasks ( iwaki ) and incubated until colonies of resistant cells were formed with genetcin ( gibco ) added to the dmem / f12 / fbs medium at the final concentration of 1 mg / ml . after formation of colonies was confirmed under a microscope , cells which exhibited stable expression were cloned by the limiting dilution - culture method . screening for expression cells were performed by gus - specific enzyme activity assay of the culture supernatants . cell lines thus established were subcultured in dmem / f12 / fbs medium supplemented with 0 . 2 mg / ml geneticin . after intravenous administration of native - or nbt - gus to mice , gus activity in the blood was determined as follows . briefly , 12 . 5 ul of plasma sample from the mice was added to 50 ul of a solution of 10 mm 4 - methylumbelliferyl - β - d - glucuronide ( sigma chemical co ., st . louis , mo ., cat # m9130 ) which had been prepared using determination buffer ( 0 . 1m sodium acetate buffer ph 4 . 8 ), and reaction was allowed for 1 hr at 37 ° c . then , 950 ul of stop buffer ( 1 m glycine - hcl , ph 10 . 5 ) was added and mixed to stop the enzyme reaction . samples of the reaction mixture were transferred to a fluorometer for measurement with excitation 366 nm / emission 450 nm . native gus and gus fusion proteins were produced in overexpressing cho cells , which were grown to confluency and fed with low - serum medium ( waymouth &# 39 ; s mb 752 / 1 medium , supplemented with 2 % fbs / 1 . 2 mm glutamine / 1 mm pyruvate ) ( gibco ) for purification every 24 hr . the media of the culture were pooled , centrifuged at 5 , 000 × g for 20 min at 4 ° c ., and frozen at − 20 ° c . purification was performed using affinity chromatography ( 10 ). briefly , the conditioned medium from cells overexpressing the native gus or a gus fusion protein was filtered , and nacl was added to the medium at the final concentration of 0 . 5 m . the medium was applied to a 5 ml column of affi - gel 10 ( biorad ) which carried an anti - human gus monoclonal antibody and had been pre - equilibrated with wash buffer . the column was washed at 36 ml / hour with 20 - column volumes of wash buffer . the column was eluted at 36 ml / hour with 50 ml of 10 mm sodium phosphate ( ph 5 . 0 ) containing 3 . 5 m mgcl 2 . fractions were collected and subjected to gus activity assay . fractions containing the enzyme activity were pooled for each of the native or fusion proteins , diluted with an equal volume of p6 buffer ( 25 mm tris , ph 7 . 5 / 1 mm β - glycerol phosphate / 0 . 15 mm nacl / 0 . 025 % sodium azide ), and desalted over a biogel p6 column ( biorad ) pre - equilibrated with p6 buffer . fractions containing gus activity were pooled , and the finally purified active protein was stored at − 80 ° c . per 1 g of body weight , 1 , 000 u of native gus or one of the nbt - guss , both purified , were administered to male , 4 - month old c57bl mice ( 3 animals / group ) in the tail vein . samples of venous blood were collected at 2 min , 5 min , 10 min , 20 min , 30 min , 1 hr , 2 hr , 6 hr , 24 hr after the administration , and gus activity in the serum was measured . the results are shown in fig3 . comparison between the nbt - guss - administered groups and the native gus - administered group reveales that , at 2 min after the administration , the enzyme activity in the blood was 2 - fold higher in the nbt - guss - administered groups as compared with the native gus - administered group . while the enzyme activity in the blood at 30 min after the administration was almost disappeared in the native gus - administered group , the nbt - guss - administered groups retained activity levels , which were even higher than the activity level found at 2 min in the native gus - administered group . afterwards , the nbt - guss - administered groups continued to show remarkably slower reduction in the enzyme activity levels in the blood as compared with those found in the native gus - administered group . even 24 hr ( 1440 min ) after the administration , the residual enzyme activity was detectable in the nbt - guss - administered group . a half - life time of the enzyme activity in blood in the native gus - administered group was 4 . 9 min , while a half - life time in blood in the nbt - gus - administered group was prolonged 5 - 6 times . the results demonstrate that the stability of gus in the body is remarkably increased by attaching a short peptide of acidic amino acids to the n - terminus of native gus . to compare the effectiveness of aaa - tagged and untagged gus at clearing storage from affected tissues in the mps vii mouse , the inventors used a protocol in which enzyme was given in 12 weekly treatments with 1 mg / kg enzyme . there were notable differences in which the d 6 - gus appeared to be more effective in clearing the storage material . the parietal neocortical neurons and glia had less storage in the d 6 - gus - treated mps vii mice . in brain , the aaa - tagged enzyme showed improved clearance of storage from parietal neocortical neurons and glial cells , where as storage showed minimal or no clearance response to untagged enzyme at the same dose . fig4 shows light microscopy of tissues from native gus and d 6 - gus treated mps vii mice . the cortical neuron , hippocampus , and glia cell sections show a reduction of storage ( s ) in d 6 - gus treated compared to gus treated mice . in these studies , mps vii / e540a tg mice were used . 22 these mice carry a gus transgene that encodes an inactive enzyme , which confers immunotolerance to the human protein . to define the clearance from the blood circulation , 1 , 000 units per g of body weight of d6 - gus , d8 - gus or untagged gus were administered to 4 - month - old mps vii mice ( 3 animals / group ) via the tail vein . samples of venous blood were collected at 2 min , 5 min , 10 min , 20 min , 30 min , 1 h , 2 h , 6 h , and 24 h after administration , and gus activity in the serum was measured . to determine the effectiveness of d6 - gus , d8 - gus , and untagged enzyme at reversing storage pathology , three adult animals in each group received twelve weekly doses ( 5 , 000 units / g ) of d6 - gus , d8 - gus , untagged enzyme or pbs by injection in the lateral tail vein . animals were killed 1 week after the 12th injection , and the organs were removed for histopathology analysis with light or electron microscopy . for morphological evaluation , liver , spleen , kidney , brain , heart , femur , and bone marrow from 4 - 5 month old mps vii mice treated with d6 - gus ( n = 2 ), d8 - gus ( n = 3 ), and untagged enzyme ( n = 3 ), or buffer ( n = 2 ) were collected at necropsy , immersion - fixed in 4 % paraformaldehyde / 2 % glutaraldehyde in pbs , postfixed in osmium tetroxide , and embedded in spurr &# 39 ; s resin . for evaluation of lysosomal storage by light microscopy , toluidine blue - stained 0 . 5 - μm - thick sections were examined . one mouse treated by d6 - gus died immediately after the 12th weekly infusion and was not evaluated morphologically . tissues from the treated and untreated mice were evaluated for reduction in storage without knowledge of their treatment . two pathologists ( cv , bl ) independently evaluated the brain for lysosomal storage . some individual elements of the inventors &# 39 ; methodology are generally known or described in detail in numerous laboratory protocols , one of which is molecular cloning 2nd edition , ( 1989 ) sambrook , j ., fritsch , e . f . and maniatis , j ., cold spring harbor . as such detailed discussion of their composition and methodology is superfluous . applicants make no statement , inferred or direct , regarding the status of the following references as prior art . applicants reserve the right to challenge the veracity of any statements made in these references , which are incorporated herein by reference . 1 wraith , j . e . ( 2002 ) semin . neonatol . 7 , 75 - 83 . 2 barton , n . w ., furbish , f . s ., murray , g . j ., garfield , m . & amp ; brady , r . o . ( 1990 ) proc . natl . acad . sci . usa 87 , 1913 - 1916 . 3 barton , n . w ., brady , r . o ., dambrosia , j . m ., di bisceglie , a . m ., doppelt , s . h ., hill , s . c ., mankin , h . j ., murray , g . j ., parker , r . i ., argoff , c . e ., et al . ( 1991 ) n . engl . j . med . 324 , 1464 - 1470 . 4 murray , g . j . ( 1987 ) methods enzymol . 149 , 25 - 42 . 5 furbish , f . s ., steer , c . j ., krett , n . l . & amp ; barranger , j . a . ( 1981 ) biochim . biophys . acta 673 , 425 - 434 . 6 stahl , p . d ., rodman , j . s ., miller , m . j . & amp ; schlesinger , p . h . ( 1978 ) proc . natl . acad . sci . usa 75 , 1399 - 1403 . 7 achord , d . t ., brot , f . e ., bell , c . e . & amp ; sly , w . s . ( 1978 ) cell 15 , 269 - 278 . 8 barton , n . w ., brady , r . o ., dambrosia , j . m ., di bisceglie , a . m ., doppelt , s . h ., hill , s . c ., mankin , h . j ., murray , g . j ., parker , r . i . & amp ; argoff , c . e . ( 1991 ) n . engl . j . med . 324 , 464 - 470 . 9 barranger , j . a . & amp ; o &# 39 ; rourke , e . ( 2001 ) j . inherit . metab . dis . suppl 2 , 89 - 96 . 10 japanese patent no . 2852127 11 sly w s , quinton b a , mcalister w h , and rimoin d l ,. j pediatr . 82 : 249 - 257 ( 1973 ) 12 achord , d . t ., brot , f . e ., bell , c . e . & amp ; sly , w . s . ( 1978 ) cell 15 , 269 - 278 . 13 u . s . application ser . no . 11 / 484 , 870 , filed jul . 11 , 2006 14 neufeld e f , muenzer j . ( 2001 ) the mucopolysaccharidoses . in scriver , c . r ., beaudet , a ., valle , d ., and sly . w . s . ( eds . ), the metabolic and molecular bases of inherited diseases . 8th edition ed . mcgraw - hill professional , new york , vol . iii , pp . 3421 - 3452 . 15 tomatsu s , okamura k , taketani t , orii k o , nishioka t , gutierrez m a , velez - castrillon s , fachel a a , grubb j h , cooper a , thornley m , wraith e , barrera l a , giugliani r , schwartz i v , frenking g s , beck m , kircher s g , paschke e , yamaguchi s , ullrich k , isogai k , suzuki y , orii t , kondo n , creer m , noguchi a . ( 2005 ). j inherit metab dis . 28 : 187 - 202 . 16 tomatsu s , gutierrez m a , ishimaru t , pena o m , montano a m , maeda h , velez - castrillon s , nishioka t , fachel a a , cooper a , thornley m , wraith e , barrera l a , laybauer l s , giugliani r , schwartz i v , frenking g s , beck m , kircher s g , paschke e , yamaguchi s , ullrich k , isogai k , suzuki y , orii t , noguchi a . ( 2005 ). 28 : 743 - 57 17 vogler , c ., levy , b ., grubb , j . h ., galvin , n ., tan , y ., kakkis , e ., pavloff , n . & amp ; sly w . s . ( 2005 ), proc natl acad sci usa . 102 : 14777 - 14782 . 18 dunder , u ., kaartinen , v ., valtonen , p ., vaananen , e ., kosma , v . m ., heisterkamp , n ., groffen , j . & amp ; mononen , i . ( 2000 ), faseb j . 14 , 361 - 367 . 19 roces d p , lullmann - rauch r , peng j , balducci c , andersson c , tollersrud o , fogh j , orlacchio a , beccari t , saftig p , von figura k . ( 2004 ), 13 : 1979 - 1988 . 20 u . s . application ser . no . 10 / 864 , 758 , filed jun . 10 , 2004 21 u . s . application ser . no . 11 / 245 , 424 , filed oct . 7 , 2005 22 sly , w . s ., vogler , c ., grubb , j . h ., zhou , m ., jiang , j ., zhou , x . y ., tomatsu , s ., bi , y . & amp ; snella , e . m . ( 2001 ), proc . natl . acad . sci . usa 98 , 2205 - 2210 .
the present invention provides a polypeptide therapeutic agent , useful in enzyme replacement therapy , with increased therapeutic benefits for the central nervous system . the invention provides a method of enhancing the effect of a polypeptide or protein on the central nervous system by the attachment of a short acidic amino acid sequence . specifically the inventors disclose the attachment of a 4 - 15 acidic amino acid sequence to human β - glucuronidase by construction of a fusion protein . this molecule is useful in the treatment of type vii mucopolysaccharidosis when administered to a patient .