METHOD TO PREDICT RESPONSE TO PHARMACOLOGICAL CHAPERONE TREATMENT OF DISEASES

摘要

The present invention provides methods to determine whether a patient with a lysosomal storage disorder will benefit from treatment with a specific pharmacological chaperone. The present invention exemplifies an in vitro method for determining a-galactosidase A responsiveness to a pharmacological chaperone such as 1-deoxygalactonojirimycin in a cell line expressing a mutant from of a galactosidase A. The invention also provides a method for diagnosing Fabry disease in patients suspected of having Fabry disease. Fig. 1A 1/36 Fabry Mutations Generated by Site-Directed Mutagenesis Milseense L45R W2R R112H G147R G183S R227P D264V A285P Q312R R356G P409S V390frX8 4011nsiaafi M1l H46L W2V R1128 S148N G183V R227Q 0264Y W287C D313G R356W P409T 401S MIK H46R A73V 'F113L S148R Y184C A230T P265L W287G D313Y Q357X T410OA deI20-24aa MIL H46Y W6R F113S Y152C M187T D231G P265R A288D V316E E358A T4101 del13-Oaa MIR W47G W6T 1117S DIS5H M187V D231N D266E A288P B17N E358G T410K del153aa MIT W47L W81C R118C A156T L191P D231V D266H 1289F 1317T E358K T410P del205-7aa MIV E48D W81S L120P A156V L191Q D234E D266N 1289S N3201 059T G411D del254aa A13P 548K G85D L120S A156Y T1941 0234Y D266V M2901 N320K G360C L414S dei358aa L14P R49C G85M A121P WjG2C V199M S235C D266Y A291T N320Y G360D L415P ins247-8aa L16H R49G Y86C A121T W162G S201F S235F M2671 A292P Q321E G360S L33Y L16P R49L Y860 V124D W162R -S201Y W236C M267R A292T Q321L G361R L166G F18S R49P Y88D H125P G163V C202W W236L L268S P293A 0321R P362L H46S L19P R49S L89P S126G D165H C202Y W236R V269A P293H G325D R363C 1124F A20P F50C LO9R G128E D165V P205L S238N V269M P293S G325S R363H A31V M5ll C90R L129P D165Y P205R 1239T 1270T P293T 0327E R363P L32P M5IK 191T L131P DISY P205S 1242F G271C F295C Q327K L372P Complex D33Y C52G D92G G132E L166V P205T 1242N G271S W2961 G328A L372R D55V/Q57L N34K C52R D92H G132R L167P L206P L243F G271V M296V G328E G3730 T N34S C52S D92N Y134H K168N Y207C L243W N72K S297C G328R G373R Sm all G35R C52Y 092Y Y134S K168R Y207H 0244N N272S S297F G328V G373S Ins/Del L36F L54P D93G A135V F169S Y207S D244H F273L N298H E338K A377D 1del5aa L36S D55V 093N D136H D170H N215D S247C L275F N298K V339E C378R 86del6aa A37V C56F D93V D136Y DI70V N215S S247P S276G N298S W340R C378Y 113del8aa 120del2aa/L P40L C56G C94S G13SE G171C Y216C Q250P S276N 0299G E341D C382W 120H 152inslaaY P40S C56Y C94Y G138R G171D Y216D 1253T 0279E L300F E341K C382Y 152D T411 Q57L W95L N139T G171R 1219N A257P Q279H L300H R342L 1384N 153delIaa M42L E59K V95S T1411 C172F C223G G258R 0279K L300P R342Q T385P 205del3aa M42R P60L A97P C142R C172G C223R G258V Q279R R301G L344P Q386P 205del7aa M42T C63Y A97V C142W C172R C223Y P259L Q280H R3O1P S345P P389R 254del18 281deliaa/V M42V S65T R1OOK C142Y C172S N224D P259R Q280K R301Q A348P F396Y 281A G43D E6G R100T A143P C172W N224S G260A T282A 1303N W349R E398K 358de l aa G43R EB6K E103Q A143T C172Y H2260 G261D T282N K308N A350P L4038 382deliaa G438 E56Q L106R G144V C174G H225R W262C Q283P A309P A352D 1407K 403dellaa L68F Q107L P146S G183A W226C N263S M284T L31OF 1354K 4o 247ins3aa W44C M721 R112C G147E G183D W2I6R D264A A286D Q312H N355K P409A 247ins8aa