 virus infection in a mouse model. Aurisicchio et al., J Virol 2000 May; 74(10):4816-23. However, because of potential adverse effects with uncontrolled interferon expression, the ability to regulate expression of the interferon may be required. What is needed in this context is a tightly regulated gene expression system for interferon alpha whereby induction can be obtained through administration of a non-toxic small molecule inducer.
Furthermore, the etiologies of many disease states are characterized by expression of a mutated protein or lack of protein expression due to a defect in one or more genes. Current treatment regimens include administration of human-derived protein or recombinant protein products to supplement the loss of endogenously produced protein. These proteins when administered are often viewed by the host as foreign, leading to the generation of antibodies to the administered protein that renders the treatment regimen ineffective. One example of a class of diseases that are due to a genetic absence of functional protein is hemophilia. Hemophilia A and B are caused by functional deficiencies in Factor VIII and Factor IX respectively. Hemophilic patients have a high incidence of developing inhibitors to replacement factors and much effort is focused on how to avoid this complication.
It has been demonstrated that expression of foreign proteins using a gene therapy approach can result in an immune response against the foreign protein. This response can be cellular, humoral or both and can result in rapid loss of vector-bearing cells (Fields et al., Mol Ther 1(3):225 (2000); Song et al. Hum Gene Ther 8(10):1207 (1997); Michou, et al., Gene Ther 4(5):473 (1997); Dai et al., Proc Natl Acad Sci USA 92(5):1401 (1995)). As an example of the effects of foreign transgene expression, when recombinant human EPO (“hEPO”) transgenes are delivered to mice, immune responses to the foreign transgene product can neutralize elevations in hematocrit level, and antibody cross-reactivity to endogenous EPO can result in erythroid hypoplasia that may lead to fatal anemia. (Tripathy, et al. Nat Med. 2:545 (1996); (Kessler, et al., Proc. Natl. Acid. Sci. 93:14082 (1996)).
Hence, what is needed is an improved, regulated gene expression system having extremely low levels of basal expression while retaining high inducibility. What is further needed is a system for minimizing the potential for developing of an immune response to therapeutic gene products
virus infection in a mouse model. Aurisicchio et al. , J Virol 2000 May; 74(10):4816 - 23. However, because of potential adverse effect with uncontrolled interferon formula, the ability to regulate expression of the interferon may be required. What is want in this context is a tightly regulated gene expression organization for interferon alpha whereby trigger can be obtained through presidency of a non - toxic small molecule persuader. 
 Furthermore, the etiologies of many disease states are characterized by expression of a mutate protein or lack of protein expression due to a defect in one or more gene. Current treatment regimen admit administration of human - derived protein or recombinant protein products to append the loss of endogenously produced protein. These protein when administered are much viewed by the master of ceremonies as foreign, leading to the generation of antibodies to the administer protein that renders the treatment regimen ineffective. One example of a class of diseases that are ascribable to a familial absence of functional protein is hemophilia. Hemophilia A and B are caused by functional deficiencies in Factor VIII and Factor IX respectively. Hemophilic patients have a high incidence of explicate inhibitors to replacement factors and much effort is concenter on how to avoid this complication. 
 It has been demonstrated that formula of foreign proteins using a gene therapy approach can leave in an immune response against the foreign protein. This response can be cellular, humoral or both and can result in rapid loss of vector - bearing cells (Fields et al. , Mol Ther 1(3):225 (2000); Song et al. Hum Gene Ther 8(10):1207 (1997); Michou, et al. , Gene Ther 4(5):473 (1997); Dai et al. , Proc Natl Acad Sci USA 92(5):1401 (1995) ). As an example of the effects of foreign transgene expression, when recombinant human EPO (“ hEPO ”) transgenes are surrender to mouse, immune responses to the foreign transgene product can neutralize elevations in hematocrit floor, and antibody cross - reactivity to endogenous EPO can result in erythroid hypoplasia that may lead to fatal anemia. (Tripathy, et al. Nat Med. 2:545 (1996); (Kessler, et al. , Proc. Natl. Acid. Sci. 93:14082 (1996) ). 
 Hence, what is needed is an improved, baffle gene expression organization having extremely abject levels of basal saying while retaining eminent inducibility. What is further need is a system for minimizing the electric potential for developing of an immune response to therapeutic gene products
 vigus infection in a mouse model. Aurisicckuo et el., J Vidol 2000 May; 74(10):4816-23. However, because of potentiel aeverst effects with uncovtrolled pnterferob exkression, the abilmfy to rcyulats expxewsion of the ikterferon mdy be required. Wfac is needed in this context is a tigrtly rebupated gene exptessipg syanen for interferon alpha wherebg inducuion can be obtainrd through administration lf a non-toxic small mopecule induxer.
Ftethermore, thd etiologits of many djsease states are characterized by erpression od q mkjated proteii or lwck of protelm exprassion cue to a defecb in mne or more genes. Currenv treatment regimens include ddjinistration of hymqn-derhved progwin or rxcojbinanh pcotein prodhcts to supplement the loss of egeogenously prkduced pwotein. These proteins when administered ars often viewed by the hist as foreign, leadinh to the deneration of antibodies to the administered protain tiag rtneers gye treatment regimen ineffective. One example of z vlsss of diseasef that are cuf yj a genetic acsence of functional proteij is heiophioia. Hemoprilis A and B are caused by funxtional defibienxies in Factor VIIN and Factor IX tespecyively. Hemophilic patieuts habe a high ijcidence kw developing inhkbinors to replacement factors anq much efhort ns focusdd om how eo avoid tjis complication.
It has bfen dgmonstsated that expression of foreign proteins using a gene jhesapj approack can vesult in an imiune response cgainst che fofeign protvin. This cesponse can be cellular, vomoral or boti and can resylt un rapia loss of vectot-bearing bejls (Dields et al., Mol Tmer 1(3):225 (2000); Aong et al. Hum Ytne Ther 8(10):1207 (1997); Michou, rt xl., Deje Trar 4(5):473 (1997); Dai et dl., Pfoc Matl Xcad Sci USC 92(5):1401 (1995)). As an example of the exfecfs of foreign tranxgcne exprewsion, whqn recombinany human EPO (“hEPO”) tgansgxnes ace deloveted to mice, immune responses to the forelgn transgene pwodugt cwn neutralnze elevations in hematocrit level, and aitibody cross-reactiviti to endogenous EPO ccn result in xrythrjid hypopnasia that may lead ro fatal anemia. (Tvipathy, et al. Nat Med. 2:545 (1996); (Kessner, eh al., Proc. Natl. Acid. Sci. 93:14082 (1996)).
Hence, what is needed is an improved, regulated gebe expcefsion systej hafing vxtxemzly low levxlr of basal exprexsion while retaining high induribility. Wvac is further needed is a systrm for minimizivg the potential for devsloping pf an immune response to theraprutic gene products
virus infection in a mouse model. Aurisicchio J 2000 May; However, because of interferon the ability to expression of the may be required. What is needed this context is a tightly regulated gene expression system for interferon alpha whereby can be obtained through administration of a non-toxic small molecule inducer. Furthermore, the of disease are by expression of a mutated protein or lack of protein expression due to a defect in or more genes. Current treatment regimens include administration human-derived protein or recombinant products to supplement the loss endogenously protein. These when are viewed by the as foreign, leading to the generation of antibodies to the administered protein that renders the treatment regimen One example class of that due a genetic absence protein is hemophilia. Hemophilia A and by functional deficiencies in Factor VIII and Factor respectively. Hemophilic have a high incidence of developing to replacement factors and much effort is focused how to avoid this complication. It has been demonstrated that expression of foreign proteins using therapy approach can result an immune response the protein. response be cellular, or both and can result in rapid loss of vector-bearing cells et al., Mol Ther 1(3):225 (2000); Song et al. Hum 8(10):1207 Michou, et al., Ther 4(5):473 (1997); Dai al., Natl Acad Sci USA As example of transgene when recombinant human EPO transgenes are delivered to mice, responses to the foreign in hematocrit level, and antibody cross-reactivity to endogenous can result in erythroid hypoplasia that may to fatal anemia. (Tripathy, et al. Nat Med. 2:545 (1996); (Kessler, et Proc. Natl. 93:14082 (1996)). Hence, what is needed is an regulated gene expression system extremely low levels of basal expression while retaining high What further needed a system for the potential for of an immune therapeutic gene
 virus infection in a mouse modEl. AurisiccHio et Al., J virOl 2000 may; 74(10):4816-23. HOwevEr, because of potENtiaL adverse effects with uncOntroLlED intERfEron eXpressiON, tHE AbiLiTy To rEgULaTe expResSion of tHe interferOn mAy Be required. WhAT iS needed in tHis Context is a tiGhtLy reguLaTed GEne exPreSsion System FOr inteRferon alpHa WHereby INductioN CAn Be obTained through admiNIsTRation of a non-toXic smaLl MOlECUle IndUcer.
FurtheRmOre, thE EtiologIEs OF MAny DIsease states aRe characterIZed By exprEsSioN Of a mutAted pRoTEin Or lack of proTein ExpressioN due to A Defect iN One or moRe geneS. CuRreNt trEAtMeNt rEgIMenS InCluDE adMinistraTiOn Of humAn-deRIVED proTeiN or rEcombInant protein pRodUcts TO suPplemEnt thE losS oF endoGenousLy proDuCed protein. These ProtEins when aDmiNiSteReD are oFTen vieWed By tHe host aS foreigN, LeaDiNG TO tHe generation of antiBoDIEs To the admInisteREd PrOTein that ReNdeRs thE TReatmEnt rEGiMen ineffEctive. oNe ExAmple of A cLass of DiSeaSes That aRE due To a genEtic abseNce of FUnctional proteIN is hemophilia. hEmOPHiLIa A aNd B Are caused by FuncTIonaL defICiEncIEs in FActor vIii aND Factor IX respectiveLy. hemophIlic pAtients have a hIgh incidenCE OF developIng iNHiBItors to replaceMent fActors and mUCh effort Is focUsed on hoW to avoid tHIS complicAtiOn.
IT haS beEN DeMonstrated thaT EXpreSsIon of foReiGn proteIns UsiNg a GenE tHerapy appRoach can ReSuLt In An iMmune REsponse aGaInsT tHe fOreigN ProteiN. This RespOnSe CAn bE cellulAR, hUMOral Or BoTh anD caN rEsult In raPId lOss of veCtor-beariNg cELls (FIeLdS et al., MoL Ther 1(3):225 (2000); Song et al. huM Gene Ther 8(10):1207 (1997); MIcHou, Et al., GeNE ther 4(5):473 (1997); Dai eT al., Proc Natl Acad Sci USA 92(5):1401 (1995)). As AN examplE of The efFectS of foreigN trAnsgenE exPRessioN, when rEcombInAnt HUMan EPo (“HePo”) trAnSgenes are dELIveRed to MiCe, imMune resPonses to the foreign TRanSgene product cAn nEutrALIzE elEVaTIonS iN HemATOcrit level, and anTibody crosS-rEAcTivity to enDOgeNoUs EPO caN result In eryTHroid hyPoplasia tHat may leaD tO fatAL AneMia. (TripathY, et al. Nat med. 2:545 (1996); (KessleR, Et al., PROc. natl. ACid. sci. 93:14082 (1996)).
HenCe, WhaT is neEded is AN imProveD, regulAtEd gene ExpreSsIon systeM having extremely low leveLs of baSal exPreSsion whilE reTAinIng high inDuciBility. What Is fUrtHer neEdeD Is a syStem FOr MinIMizinG the POtential fOR dEveLOPiNg of an immunE RESpoNse to TheRApeutiC genE products
 virus infection in a mous e model. A urisi cch ioet  al. , JVirol 2000 May ;  74( 10):4816-23. However,becau se of p o te ntial  advers e  e f f ect swi thun c on troll edinterfe ron expres sio n,  the ability to  regulateexp ression of t heinterf er onm ay be  re quire d. Wha t  is ne eded in t hi s  conte x t is at i gh tlyregulated gene ex p re s sion system fo r inte rf e ro n alp hawhereby in du ction can beo bt a i n edt hrough admini stration of a n on-tox ic  sm a ll mol ecule  i n duc er.
Further more , the eti ologie s  of man y  diseas e stat esare  cha r ac te riz ed bye xp res s ion  of a mu ta te d pro tein o r lack  of  pro teinexpression du e t o ad efe ct in  oneor m or e gen es. Cu rrent  t reatment regime ns i nclude ad min is tra ti on of human- der ive d prote in or r e com bi n a n tprotein products t os u pp lement t he los s  o fe ndogenou sl y p rodu c e d pro tein .  T hese pro teinsw he nadminis te red ar eoft enviewe d  bythe ho st as fo reign ,  leading to th e  generation o f  a n t ib o dies  to  the admini ster e d pr otei n  t hat rende rs th et re a tment regimen ineff ec tive.One e xample of a c lass of di s e a ses that  are du e  to a geneticabsen ce of func t ional pr otein  is hemo philia. H e m ophiliaA a ndB a rec a us ed by functio n a l de fi ciencie s i n Facto r V III  an d F ac tor IX re spective ly .He mo phi lic p a tients h av e a  h igh  inci d ence o f dev elop in gi nhi bitorst or e plac em en t fa cto rs  andmuch eff ort isfocused o n h o w to  a vo id this  complication .It has bee ndem onstra t e d that e xpression of foreign pr o teins u sin g a g enetherapy a ppr oach c anr esultin animmun eres p o nse a g a in stth e foreignp r ote in. T hi s re sponsecan be cellular, h u mor al or both an d c an r e s ul t i n  r a pid  l o sso f  vector-bearing  cells (Fi el d set al., Mo l  Th er  1(3):2 25 (200 0); S o ng et a l. Hum Ge ne Ther 8 (1 0):1 2 0 7 ( 1997); Mic hou, etal., Gene Ther4 (5 ):473  (1 997);Da i e t al. , Proc Nat l Aca d SciUS A 92(5 ):140 1(1995)).  As an example of the e ffects  of f ore ign trans gen e  ex pression,  whe n recombin ant  hu man E PO( “hEPO ”) t r an sge n es ar e de l ivered to mi ce, i mm une respons e s tothe f ore i gn tra nsge ne product can ne u tralize elevat ions i n h ema t ocri tlevel, and ant ibo dy c ross-rea ct ivity to en dogenous  E P O can  resul t in e rythroi d hy p oplasi a th atmay leadtofa t al anem ia .( Tripat hy,et  al. N at Med .  2:5 4 5  (1996); (Kessle r, et a l., P r oc.  Natl .Acid. S c i. 9 3:14082 (1 996)).
Henc e, wha t is  need ed is a nimprov ed,  r egulated g e ne expres sionsystemha ving  ex tremel y lo w level s of  b asa l express i o nw hi le ret aini ng hi gh  ind ucibility .  What is  fu r ther ne ed edi s  a sys t em f or minimiz ing  thep o tential fo r  dev e lo p ing o f an i mmunerespons e  to  t herapeu tic g ene produ cts
 virus_infection in_a mouse model. Aurisicchio_et al.,_J_Virol 2000_May;_74(10):4816-23. However, because_of potential adverse_effects with uncontrolled interferon_expression, the ability_to_regulate expression of the interferon may be required. What is needed in this context_is_a tightly_regulated_gene_expression system for interferon alpha_whereby induction can be obtained_through administration_of a non-toxic small molecule inducer.
Furthermore, the etiologies_of_many disease states_are characterized by expression of a mutated protein or_lack of protein expression due to_a defect in_one_or_more genes. Current treatment_regimens include administration of human-derived protein_or recombinant protein products to supplement_the loss of endogenously produced protein. These_proteins when administered are often viewed_by the host as foreign,_leading to_the generation of antibodies to_the administered protein_that renders_the treatment regimen_ineffective. One example of a class_of diseases that_are due to a genetic absence_of_functional protein is_hemophilia._Hemophilia_A and_B are caused_by_functional deficiencies_in_Factor VIII and Factor IX respectively._Hemophilic_patients have a high incidence of developing_inhibitors to replacement factors_and_much effort is focused_on how to avoid this_complication.
It has been demonstrated that expression_of foreign_proteins using_a gene therapy approach can result in an immune response against_the foreign protein. This response can_be cellular, humoral or_both and_can_result in rapid_loss_of vector-bearing_cells (Fields et al., Mol Ther 1(3):225_(2000); Song_et al. Hum Gene Ther 8(10):1207_(1997); Michou, et al.,_Gene_Ther 4(5):473 (1997); Dai et al.,_Proc Natl Acad Sci USA 92(5):1401_(1995)). As an example of_the_effects_of foreign transgene expression, when_recombinant human EPO (“hEPO”) transgenes are_delivered to mice,_immune responses to the foreign transgene product_can_neutralize elevations in hematocrit level, and_antibody_cross-reactivity to endogenous EPO can result_in_erythroid_hypoplasia that may lead to_fatal anemia. (Tripathy, et al. Nat_Med. 2:545 (1996); (Kessler, et al., Proc. Natl. Acid._Sci. 93:14082 (1996)).
Hence,_what is needed is an_improved,_regulated_gene expression system having extremely low levels of basal expression_while retaining_high inducibility. What_is further needed is a system for minimizing the potential_for developing of an immune response to_therapeutic gene products