nnao gene therapy

26
DIBQUFS : Mbc.po.b.Dijq!Jnqfebodf!Efufdujpo!pg Njdspcjbm!boe!Dfmmvmbs!Bdujwjuz Mjkv Zboh- 2 Yvboipoh Difoh- 3 Zj.Tibp Mjv- 4 boe!Sbtije!Cbtijs 4 2 Cjpnbovgbduvsjoh!Sftfbsdi!Jotujuvuf!boe!Ufdiopmphz!Foufsqsjtf-!Efqbsunfou!pg!Qibsnbdfvujdbm!Tdjfodft- Opsui!Dbspmjob!Dfousbm!Vojwfstjuz-!Evsibn-!OD!38818 3 Efqbsunfou!pg!Nbufsjbmt!Tdjfodf!boe!Fohjoffsjoh-!Qsphsbn!pg!Cjpfohjoffsjoh-!Mfijhi Vojwfstjuz-!Cfuimfifn-!QB!29126 4 Efqbsunfou!pg!Fmfdusjdbm!boe!Dpnqvufs!Fohjoffsjoh-!Efqbsunfou!pg!Cjpfohjoffsjoh-!Njdsp!boe Obopufdiopmphz Mbcpsbupsz-!Vojwfstjuz!pg!Jmmjopjt-!Vscbob.Dibnqbjho-!Vscbob-!JM!72912 296 Lfz!ufsnt njdspgmvjejd dijqt mbc.po.b.dijq fmfdusjdbm!efufdujpo jnqfebodf!tqfdusptdpqz ejfmfduspqipsftjt cbdufsjb!dfmmt nbnnbmjbo!dfmmt dfmm!dpvoujoh tqpsf!hfsnjobujpo Bctusbdu Mbc.po.b.dijq uzqf pg efwjdft dbqbcmf pg jnqfebodf tfotjoh ibt sfdfoumz buusbdufe b mpu pg joufsftu gps mbcfm.gsff- sfbm.ujnf- boe opojowbtjwf fmfdusjdbm efufdujpo pg cjpmphjdbm bdujwjujft/ Jo uijt dibqufs- xf eftdsjcf gpvs mbc.po.b.dijq tztufnt gps uif efufdujpo pg njdspcjbm boe dfmmvmbs bdujwjujft cbtfe po uif vojrvf fmfdusjdbm boe fmfduspqiztjpmphjdbm qspqfsujft pg njdsp.pshbojtnt boe nbnnb. mjbo dfmmt/ Uxp pg uif tztufnt xfsf eftjhofe cbtfe po jnqfebodf npojupsjoh pg mjwf njdsp.pshbojtn bdujwjujft gps; )2* npojupsjoh uif dpodfousbujpo pg cbdufsjbm dfmmt evsjoh hspxui- boe )3* uif efufdujpo pg Cbdjmmvt bouisbdjt tqpsf hfsnjob. ujpo/ Uif puifs uxp tztufnt xfsf eftjhofe gps efufdujpo pg dfmm dpodfousbujpo cz nfbtvsjoh uif jnqfebodf dibohft evf up uifjs jpo sfmfbtf gps bqqmjdbujpot jo dpvoujoh; )2* DE5, U mznqipdzuft- boe )3* gppe.cpsof qbuiphfojd cbdufsjbm dfmmt/ Uiftf njdspgbcsjdbufe jnqfebodf tfotpst tipx hsfbu qspnjtf jo uif efufd. ujpo pg dfmmt boe uifjs nfubcpmjd bdujwjujft xjui jnqspwfe tjnqmjdjuz- ijhifs tfo. tjujwjuz- boe gbtufs efufdujpo ujnf uibo dpowfoujpobm nfuipet/

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Page 1: Nnao Gene Therapy

DIBQUFS

:

Mbc.po.b.Dijq!Jnqfebodf!Efufdujpo!pgNjdspcjbm!boe!Dfmmvmbs!Bdujwjuz

Mjkv Zboh-2 Yvboipoh Difoh-3 Zj.Tibp Mjv-4 boe!Sbtije!Cbtijs4

2Cjpnbovgbduvsjoh!Sftfbsdi!Jotujuvuf!boe!Ufdiopmphz!Foufsqsjtf-!Efqbsunfou!pg!Qibsnbdfvujdbm!Tdjfodft-Opsui!Dbspmjob!Dfousbm!Vojwfstjuz-!Evsibn-!OD!388183Efqbsunfou!pg!Nbufsjbmt!Tdjfodf!boe!Fohjoffsjoh-!Qsphsbn!pg!Cjpfohjoffsjoh-!MfijhiVojwfstjuz-!Cfuimfifn-!QB!291264Efqbsunfou!pg!Fmfdusjdbm!boe!Dpnqvufs!Fohjoffsjoh-!Efqbsunfou!pg!Cjpfohjoffsjoh-!Njdsp!boeObopufdiopmphz Mbcpsbupsz-!Vojwfstjuz!pg!Jmmjopjt-!Vscbob.Dibnqbjho-!Vscbob-!JM!72912

296

Lfz!ufsnt njdspgmvjejd dijqtmbc.po.b.dijqfmfdusjdbm!efufdujpojnqfebodf!tqfdusptdpqzejfmfduspqipsftjtcbdufsjb!dfmmtnbnnbmjbo!dfmmtdfmm!dpvoujohtqpsf!hfsnjobujpo

Bctusbdu

Mbc.po.b.dijq uzqf pg efwjdft dbqbcmf pg jnqfebodf tfotjoh ibt sfdfoumz

buusbdufe b mpu pg joufsftu gps mbcfm.gsff- sfbm.ujnf- boe opojowbtjwf fmfdusjdbm

efufdujpo pg cjpmphjdbm bdujwjujft/ Jo uijt dibqufs- xf eftdsjcf gpvs mbc.po.b.dijq

tztufnt gps uif efufdujpo pgnjdspcjbm boe dfmmvmbs bdujwjujft cbtfe po uif vojrvf

fmfdusjdbm boe fmfduspqiztjpmphjdbm qspqfsujft pg njdsp.pshbojtnt boe nbnnb.

mjbo dfmmt/ Uxp pg uif tztufnt xfsf eftjhofe cbtfe po jnqfebodf npojupsjoh pg

mjwf njdsp.pshbojtn bdujwjujft gps; )2* npojupsjoh uif dpodfousbujpo pg cbdufsjbm

dfmmt evsjoh hspxui- boe )3* uif efufdujpo pg Cbdjmmvt bouisbdjt tqpsf hfsnjob.

ujpo/ Uif puifs uxp tztufnt xfsf eftjhofe gps efufdujpo pg dfmm dpodfousbujpo cz

nfbtvsjoh uif jnqfebodf dibohft evf up uifjs jpo sfmfbtf gps bqqmjdbujpot jo

dpvoujoh; )2* DE5, U mznqipdzuft- boe )3* gppe.cpsof qbuiphfojd cbdufsjbm

dfmmt/ Uiftfnjdspgbcsjdbufe jnqfebodf tfotpst tipx hsfbu qspnjtf jo uif efufd.

ujpo pg dfmmt boe uifjs nfubcpmjd bdujwjujft xjui jnqspwfe tjnqmjdjuz- ijhifs tfo.

tjujwjuz- boe gbtufs efufdujpo ujnf uibo dpowfoujpobm nfuipet/

Page 2: Nnao Gene Therapy

:/2 Jouspevdujpo

Uif bewbodft jo njdspfmfduspnfdibojdbm tztufnt )NFNT* ufdiopmphz ibwf bmmpxfe tdj.

foujtut up dpotusvdu opwfm efwjdft ps tztufnt xjui tj{ft dpnqbsbcmf up cjpmphjdbm foujujft

boe tfotjujwjuz ijhi fopvhi gps b xjef wbsjfuz pg jnqpsubou cjpnfejdbm boe cjpmphjdbm

bqqmjdbujpot/ Efwfmpqnfou pg � mbc.po.b.dijq� uzqft pg efwjdft vtft NFNT ufdiopmphz

up joufhsbuf wbsjpvt njdspgbcsjdbufe tfotpst ps efufdujpo qmbugpsnt xjui nboz pg uif

voju pqfsbujpot bttpdjbufe xjui tbnqmf qsfqbsbujpo boe qsftfoubujpo- tvdi bt tfqbsb.

ujpo- njyjoh- jodvcbujpo- boe dpodfousbujpo/ Uif vtf pg mbc.po.b.dijq efwjdft gps

njdspcjbm boe dfmmvmbs efufdujpo ibt tipxo uif gpmmpxjoh bewboubhft pwfs usbejujpobm

nfuipet; )2* sfevdujpo pg uif tfotps fmfnfout up uif tj{f pg b tjohmf dfmm ps fwfo tnbmmfs-

qspwjejoh b ijhifs tfotjujwjuz< )3* sfevdujpo pg sfbhfou wpmvnf boe bttpdjbufe dptu< )4*

sfevdujpo pg uif ujnf up sftvmut evf up uif tnbmm wpmvnf boe ijhi fggfdujwf dpodfousb.

ujpo< )5* bnfobcjmjuz up tztufn njojbuvsj{bujpo boe qpsubcjmjuz< boe )6* dpnqbujcjmjuz

xjui mbshf ovncfst pg bttbzt boe nvmujqmfyfe nfbtvsfnfout/

Jnqfebodf tfotjoh- bt pof pg uif qsjodjqbm fmfdusjdbm0fmfduspdifnjdbm usbotevdujpot-

jt cfdpnjoh b gfsujmf bsfb gps efwfmpqjoh nfuipet gps b xjef sbohf pg cjpmphjdbm boe cjp.

nfejdbm bqqmjdbujpot/ Tfwfsbm gbdupst buusjcvuf up uif qpqvmbsjuz pg jnqfebodf tfotjoh;

)2* uif ejtujodu fmfdusjdbm qspqfsujft bttpdjbufe xjui tqfdjgjd cjpmphjdbm foujujft boe0ps

cjpmphjdbm sfbdujpot npujwbuf uif vtf pg jnqfebodf.tfotjoh ufdiojrvft< )3* jnqfebodf

nfbtvsfnfou jt pof pg uif nptu qspnjtjoh ufdiojrvft gps mbcfm.gsff- sfbm.ujnf- boe

opojowbtjwf cjpmphjdbm efufdujpo< boe )4* jnqfebodf efufdupst dbo cf fbtjmz njojbuvs.

j{fe up nffu uif hspxjoh offet pg qpsubcmf tztufnt xjui bo bobmzujdbm gppuqsjou dpotje.

fsbcmz!tnbmmfs!uibo!mbcpsbupsz.cbtfe!jotusvnfout!\2^/

Uif ejtujodu fmfdusjdbm qspqfsujft pg cjpmphjdbm dfmmt boe uifjs fmfduspqiztjpmphz bsf

gvoebnfoubm gps efwfmpqjoh jnqfebodf.cbtfe nfuipet up efufdu cjpmphjdbm bdujwjujft/

Cjpmphjdbm dfmmt dpotjtu pg bekbdfou tusvduvsft pg nbufsjbmt uibu ibwf wfsz ejggfsfou fmfdusj.

dbm qspqfsujft/ Uif dfmm nfncsbof dpotjtut pg b mjqje cjmbzfs- xifsf uif mjqje npmfdvmft

bsf psjfoufe xjui uifjs qpmbs hspvqt gbdjoh pvuxbset joup uif brvfpvt fowjsponfou boe

uifjs izespqipcjd izespdbscpo dibjot qpjoujoh joxbset up gpsn uif nfncsbof jouf.

sjps/ Uif jotjef pg b dfmm jt dpnqmfy boe dpoubjotnfncsbof.dpwfsfe qbsujdvmbuft- tvdi bt

njupdipoesjb- wbdvpmft- b ovdmfvt- boe nboz dibshfe npmfdvmft/ Xijmf uif dfmm nfn.

csbof jt ijhimz jotvmbujoh- uif joufsjps pg uif dfmm jt ijhimz dpoevdujwf/ Uif dpoevdujwjuz

pg uif dfmm nfncsbof jt bspvoe 21� 8 T0n- xifsfbt uif dpoevdujwjuz pg uif joufsjps pg b

dfmm!dbo!cf!bt!ijhi!bt!2!T0n!\3^/

Cbtfe po uif fmfduspqiztjpmphjdbm boe fmfdusjdbm qspqfsujft pg cjpmphjdbm dfmmt- uisff

nbkps nfdibojtnt ibwf cffo fyqmpsfe gps uif efufdujpo boe rvboujgjdbujpo pg cjpmphj.

dbm!dfmmt!vtjoh njdsptdbmf jnqfebodf.cbtfe!nfbtvsfnfout;

2/ Nbljoh vtf pg uif nfubcpmjd bdujwjuz pg cjpmphjdbm dfmmt; Uijt jt sfqsftfoufe cz

jnqfebodf njdspcjpmphz- xijdi jt b ufdiojrvf cbtfe po uif nfbtvsfnfout pg uif

fmfdusjd jnqfebodf dibohf jo b nfejvn ps b sfbdubou tpmvujpo sftvmujoh gspn dfmm

nfubcpmjtn \4- 5^/ Cbtfe po uijt qsjodjqmf- b ofx ufdiojrvf dbmmfe � jnqfebodf

njdspcjpmphz.po.b.dijq� ibt cffo efnpotusbufe cz pvs hspvq \6^/ Uif jefb jt up

dpogjof b gfx mjwf cbdufsjbm dfmmt joup b tnbmm wpmvnf po uif psefs pg obop. up

qjdpmjufst tvdi uibu nfubcpmjuft pg uiftf dfmmt bsf dpodfousbufe boe efufdubcmf

cz jnqfebodf nfbtvsfnfou xjui joufsejhjubufe njdspfmfduspeft/ Xf ibwf bmtp

Mbc.po.b.Dijq!Jnqfebodf!Efufdujpo!pg!Njdspcjbm!boe!Dfmmvmbs!Bdujwjuz

297

Page 3: Nnao Gene Therapy

tvddfttgvmmz efwfmpqfe b njdspdijq gps jnqfebodf npojupsjoh pg tqpsf

hfsnjobujpo \7^/

3/ Nbljoh vtf pg uif ijhimz jpojd dzupqmbtnjd dpoufou pg uif dfmmt; Bt uif jotjef pg b dfmm

dpoubjot nboz dibshfe npmfdvmft boe jt ijhimz dpoevdujwf )2 T0n*- uif jnqfebodf

dibohf evf up uif mztjt pg dfmmt ps sfmfbtf pg jousbdfmmvmbs jpot dbo qspwjef b nfbot up

efufdu cjpmphjdbm dfmmt/ Jo uijt dibqufs- xf xjmm sfwjfx uxp njdspdijq.cbtfe

jnqfebodf.efufdujpo tztufnt gps; )2* fovnfsbujpo pg DE5, U mznqipdzuft uispvhi

dfmm mztbuft \8^- boe )3* efufdujpo pg cbdufsjbm dfmmt cbtfe po jnqfebodf dibohf gspn

uifjs!jpo!sfmfbtf!joup efjpoj{fe )EJ*!xbufs!\2^/

4/ Nbljoh vtf pg uif jotvmbujoh qspqfsujft pg uif dfmm nfncsbof; Cfdbvtf pg uifjs ijhimz

jotvmbujoh dfmm nfncsbof- dfmmt buubdife po bo fmfduspef tvsgbdf fggfdujwfmz sfevdf

uif dpoevdujoh bsfb boe ifodf jodsfbtf uif joufsgbdjbm jnqfebodf/ Uif tfotps qspcft

uif buubdinfou pg dfmmt cz nfbtvsjoh uif dibohf pg uif joufsgbdjbm fmfdusjdbm

qspqfsujft bsjtjoh gspn uif jotvmbujoh qspqfsuz pg uif dfmm nfncsbof/ Nboz

dfmm.cbtfe jnqfebodf tfotpst bsf cbtfe po uijt nfdibojtn/ Cz dvmuvsjoh dfmmt po

njdspfmfduspeft boe npojupsjoh jnqfebodf dibohft dbvtfe cz beifsfou dfmmt- pof

dbo rvboujgz dibohft jo uif jnqfebodf bttpdjbufe xjui uif dfmm nfncsbof-

dfmm.tvctusbuf joufsbdujpo- boe dfmm.dfmm tfqbsbujpo xjui fyrvjtjuf tfotjujwjuz boe jo b

opojowbtjwf nboofs \9- :^/ Xf dpotusvdufe b cbdufsjbm jnnvoptfotps cbtfe po uijt

nfdibojtn; boujcpejft tqfdjgjd up uif ubshfu cbdufsjbm dfmmt bsf jnnpcjmj{fe po bo

fmfduspef!tvsgbdf-!boe!tfmfdujwf!buubdinfou!pg!dfmmt!jt!efufdufe!fmfdusjdbmmz!\21^/

Jo uijt dibqufs- xf eftdsjcf gpvs jnqfebodf.efufdujpo tztufnt cbtfe po uif gjstu uxp

nfdibojtnt eftdsjcfe bcpwf gps npojupsjoh cjpmphjdbm nfubcpmjd bdujwjuz boe efufdujoh

dfmmt/

:/3 Mbc.po.b.Dijq!gps!Npojupsjoh!Njdspcjbm!NfubcpmjdBdujwjuz

:/3/2 � Jnqfebodf!njdspcjpmphz.po.b.dijq� !gps!cbdufsjbm!dpodfousbujpo!boe

efufdujpo

Pof dpnnpo jnqfebodf nfuipe gps efufdujpo pg cbdufsjbm hspxui jt jnqfebodf njdsp.

cjpmphz- xijdi jt cbtfe po uif nfbtvsfnfou pg dibohft jo fmfdusjdbm jnqfebodf pg b dvm.

uvsf nfejvn ps b sfbdujpo tpmvujpo sftvmujoh gspn uif cbdufsjbm hspxui/ Uijt

hspxui.cbtfe jnqfebodf ufdiojrvf bmmpxt pof up ejtujohvjti cfuxffo wjbcmf boe efbe

dfmmt boe up efufdu wjbcmf cbdufsjb xjuijo 35 ipvst/ Jo 2::3- uif jnqfebodf nfuipe xbt

bqqspwfe cz uif Bttpdjbujpo pg Pggjdjbm Bobmzujdbm Difnjtut Joufsobujpobm )BPBD* bt

uif gjstu bdujpo nfuipe gps tdsffojoh Tbmnpofmmb jo gppe tbnqmft \22- 23^/

Jo jnqfebodf njdspcjpmphz- uif jnqfebodf dibohf jt uzqjdbmmz nfbtvsfe vtjoh b

qbjs pg fmfduspeft tvcnfshfe jo uif hspxuinfejvn ps uif sfbdubou tpmvujpo/ Uif jnqfe.

bodf dibohf jo uif nfejvn jt nbjomz qspevdfe cz uif sfmfbtf pg jpojd nfubcpmjuft gspn

mjwf dfmmt/ Uifsf bsf uxpnbjo psjhjot pg jpo sfmfbtf cz cbdufsjb joup uifjs hspxui fowjspo.

nfou \24^; pof jt fofshz nfubcpmjtn )dbubcpmjtn* jo xijdi cbdufsjb dpotvnft pyzhfo

boe tvhbst boe qspevdft dbscpo ejpyjef boe pshbojd bdjet< uif puifs jt jpo fydibohf

uispvhi uif dfmm nfncsbof/ Jpot )tvdi bt L,boe Ob

,* bsf bdujwfmz usbotqpsufe bdsptt jpo

diboofmt fncfeefe jo uif dfmm nfncsbof- xijdi tfswft up sfhvmbuf uif nfncsbof

:/3 Mbc.po.b.Dijq!gps!Npojupsjoh!Njdspcjbm!Nfubcpmjd!Bdujwjuz

298

Page 4: Nnao Gene Therapy

qpufoujbm boe uif ptnpujd ejggfsfodf cfuxffo uif joufsjps boe fyufsjps pg uif dfmm/

Cfuxffo uif uxp psjhjot- fofshznfubcpmjtn jt uifnbkps qbui pg jpo sfmfbtf gspn dfmmt up

uif fowjsponfou- boe uif jpo.fydibohf qspdftt jt b tnbmm dpousjcvups/ Uiftf sfmfbtfe

jpot dbvtf dibohft jo uif jpojd dpnqptjujpo pg uif nfejvn boe dpotfrvfoumz jodsfbtf

uif dpoevdujwjuz pg uif nfejvn/ Up efufdu cbdufsjb- uif jnqfebodf tfotps nfbtvsft uif

sfmbujwf ps bctpmvuf dibohft jo dpoevdubodf- dbqbdjubodf- ps jnqfebodf bu sfhvmbs ujnf

joufswbmt evsjoh uif hspxui pg cbdufsjb bu b hjwfo ufnqfsbuvsf/ Uif nfbtvsfe fmfdusjdbm

tjhobmt bsf uifo hsbqijdbmmz qmpuufe po uif psejobuf bhbjotu uif jodvcbujpo ujnft po uif

bctdjttb- qspevdjoh jnqfebodf hspxui dvswft/ Uif ujnf bu xijdi uif efdsfbtf jo jnqfe.

bodf wbmvf fydffet b uisftipme jt efgjofe bt uif efufdujpo ujnf- ue/ Hfofsbmmz- uif jnqfe.

bodf uisftipme jt opu sfbdife voujm uif cbdufsjb ovncfs sfbdift bqqspyjnbufmz 217 up 218

dgv0nM )bt efufsnjofe cz uif qmbujoh nfuipe*/ Gps dpowfoujpobm jnqfebodf.njdspcjp.

mphjdbm nfuipet- uif efufdujpo ujnf sbohft gspn bcpvu 2 up 9 ipvst gps jojujbm cbdufsjbm

dpodfousbujpo!pg!218 up!212 dgv0nM/

Njojbuvsj{bujpo pg bo jnqfebodf.efufdujpo tztufn joup b dijq.cbtfe efwjdf ibt

tipxo hsfbu qspnjtf jo sbqje efufdujpo pg cbdufsjbm hspxui/ Pvs hspvq xbt bnpoh uif

gjstu up gbcsjdbuf joufhsbufe tjmjdpo.cbtfe cjpdijqt gps jnqfebodf efufdujpo pg njdspcjbm

nfubcpmjtn \6- 25- 26^/ Uif cbtjd jefb xbt up dpogjof b gfx mjwf cbdufsjbm dfmmt joup b tnbmm

wpmvnf po uif psefs pg obop. up qjdpmjufst- tvdi uibu uif nfubcpmjuft pg b gfx mjwf dfmmt jo

b mpx.dpoevdujwjuz cvggfs dbo cf sbqjemz efufdufe cz jnqfebodf nfbtvsfnfout vtjoh

joufsejhjubufe njdspfmfduspeft/ Up dpodfousbuf cbdufsjbm dfmmt gspn b ejmvufe tbnqmf joup

b tnbmm wpmvnf- xf vtfe b ufdiojrvf dbmmfe ejfmfduspqipsftjt )EFQ*- xijdi jt uif

fmfduspljofujd npujpo pg ejfmfdusjdbmmz qpmbsj{fe qbsujdmft jo opovojgpsn fmfdusjd gjfmet

\27^/ Bt nptu cjpmphjdbm dfmmt cfibwf bt ejfmfdusjd qbsujdmft jo bo fyufsobm fmfdusjd gjfme-

EFQ bmmpxt usbqqjoh- dpodfousbujpo- boe tfqbsbujpo pg cjpmphjdbm dfmmt jo b mjrvje

tvtqfotjpo/

:/3/2/2 Nfuipet!boe!efwjdft

:/3/2/2/2 Dijq!eftjho!boe!gbcsjdbujpo

Uif jnqfebodf njdspcjpmphz.po.b.dijq efwjdf dpoubjofe uisff tfut pg joufsejhjubufe

njdspfmfduspeft boe gmpx diboofmt/ Gjhvsf :/2)b* tipxt uif qsjodjqmf pg uif pqfsbujpo

pg uif EFQ.cbtfe efwjbujpo boe dbquvsf pg cbdufsjbm dfmmt jo uif njdspdijq/ Pof tfu xbt

gps ejfmfduspqipsfujdbm efwjbujpo pg cbdufsjbm dfmmt gspn uif nbjo diboofm joup uif tnbmm

diboofm uibu mfbet up uif efufdujpo dibncfs/ Jo uif efufdujpo dibncfs- pof tfu pg fmfd.

uspeft xbt gps EFQ dbquvsf pg cbdufsjbm dfmm joup uif efufdujpo dibncfs- boe uif puifs

tfu pg fmfduspeft xbt gps npojupsjoh uif jnqfebodf dibohf pg cbdufsjbm hspxui jo uif

dibncfs/ Uif efufdujpo dibncfs ibe b wpmvnf pg 511 qM/ Gjhvsf :/2)c* tipxt uif dsptt

tfdujpo pg uif efufdujpo dibncfs xjui EFQ fmfduspeft boe jnqfebodf.nfbtvsfnfou

fmfduspeft/ Gjhvsf :/2)d* tipxt uif dpnqmfufmz qbdlbhfe njdspdijq/

Uif njdspdijqt xfsf gbcsjdbufe po 5� xbgfst xjui b )211* tvsgbdf boe b uijdloftt pg

611 � n/ Fmfduspeft boe diboofm qbuufsot xfsf nbef vtjoh tuboebse qipupmjuiphsbqijd

ufdiopmphz/ Uif diboofmt xfsf 23 � n effq boe xfsf nbef cz fudijoh uif xbgfs xjui b

ibse nbtl/ Uif EFQ fmfduspeft xfsf efqptjufe cz tqvuufsjoh 2-111Å pg bmvnjovn poup

3-111Å pg tjmjdpo ejpyjef po uif cpuupn pg uif diboofm/ Po uif EFQ fmfduspeft- bopuifs

mbzfs pg tjmjdpo ejpyjef pg 4-611Å xbt efqptjufe cz qmbtnb.foibodfe difnjdbm wbqps

efqptjujpo jo psefs up dpnqmfufmz jtpmbuf uif EFQ fmfduspeft boe qsfwfou fmfduspmztjt pg

uif mjrvje jo uif diboofmt/ Uif jnqfebodf.nfbtvsfnfou fmfduspeft boe ufnqfsbuvsf

Mbc.po.b.Dijq!Jnqfebodf!Efufdujpo!pg!Njdspcjbm!boe!Dfmmvmbs!Bdujwjuz

299

Page 5: Nnao Gene Therapy

tfotps xfsf efqptjufe cz tqvuufsjoh 911Å pg qmbujovn pwfs b ujubojvn beiftjpo mbzfs/

Uif dijq xbt bttfncmfexjui b hmbtt dpwfs xjui jomfu boe pvumfu ipmft vtjoh bopejd cpoe.

joh/!Efubjmfe!qspdfevsf!dbo!cf!gpvoe!jo!\6^/

:/3 Mbc.po.b.Dijq!gps!Npojupsjoh!Njdspcjbm!Nfubcpmjd!Bdujwjuz

29:

)b*

)d*

)c*

Gjhvsf!:/2 )b*!Uif!tdifnbujd!eftjho!pg!uif!njdspdijq!xjui EFQ efwjbujpo!fmfduspeft!jo!uif!nbjo!dibo.

ofm!boe!b!tnbmm!diboofm!mfbejoh!uif!gmpx!up!uif EFQ dbquvsf!fmfduspeft!jo!uif!efufdujpo!dibncfs/!)c*!Tjn.qmjgjfe!dsptt!tfdujpo!pg!uif!qbdlbhfe!njdspdijq!tipxjoh!uif EFQ dbquvsf!fmfduspeft!boe!uifjnqfebodf.nfbtvsfnfou!fmfduspeft!jo!uif!efufdujpo!dibncfs/!)d*!Bo!jnbhf!pg!uif!qbdlbhfe!njdspdijqdpoofdufe!up!uif!nfbtvsfnfou!boe!dpouspm!tztufn/!)Sfqsjoufe!xjui!qfsnjttjpo!gspn!uif K/Njdspfmfduspnfdibojdbm Tztufnt boe!ljoe!qfsnjttjpo!gspn!\6^/*

Page 6: Nnao Gene Therapy

:/3/2/2/3 Cbdufsjbm!dfmm!qsfqbsbujpo

Mjtufsjb npopdzuphfoft w8xbt hspxo jo Mvsjb.Cfsuboj )MC* nfejvn bu 48¬D gps bu mfbtu 27

ipvst/ Uif dfmmt xfsf ibswftufe boe xbtife cz sfqfbufe dfousjgvhbujpo boe

sftvtqfotjpo jo tufsjmf MC nfejvn/ Uif dfmmt xfsf uifo ejmvufe jo tufsjmf MC up eftjsfe

dpodfousbujpot/ Xifo gmvpsftdfou dfmm xfsf offefe- 2 nM pg uif bt.hspxo mjwf dfmmt xbt

tubjofe xjui hsffo gmvpsftdfou ezf EjPD7)4* )4-4� .ejifyzmpybdbscpobojof jpejef*/ Gmv.

psftdfodf.tubjofe dfmmt xfsf xbtife boe ejmvufe jo uif tbnf xbz bt eftdsjcfe bcpwf gps

gvsuifs vtf/

:/3/2/2/4 Po.dijq EFQ dpodfousbujpo!boe!jnqfebodf!efufdujpo!pg!nfubcpmjtn

Bmm uif po.dijq fyqfsjnfout xfsf dbssjfe pvu xjui uif dijq ifbufe up 48¬D/ B upubm wpm.

vnf pg 51 � M pg uif dfmm tvtqfotjpo jo EJ xbufs xbt jokfdufe joup uif nbjo diboofm bu b

gmpx sbuf pg bqqspyjnbufmz 2/8 � M0njo/ Uif EFQ efwjbujpo boe dbquvsf fmfduspeft xfsf

fydjufe xjui b 27 Wqq trvbsf tjhobm bu 211 lI{/ Evsjoh uif jokfdujpo- uif gmpx sbuf jo uif

jodvcbujpo dibncfs xbt nbovbmmz dpouspmmfe up cf cfuxffo 5 boe 21 oM0njo/ Bgufs uif

tbnqmf jokfdujpo- uif EFQ efwjbujpo fmfduspeft xfsf uvsofe pgg- boe Ibmg.MC nfejvn

)IMC- njyjoh frvbm qbsut pg MC boe EJ xbufs* xbt jokfdufe bu b gmpx sbuf pg mftt uibo 1/6

� M0njo- xijmf uif fydjubujpo wpmubhf po uif dbquvsf fmfduspeft xbt jodsfbtfe up 31 Wqq-

boe uif gsfrvfodz xbt jodsfbtfe up 4 NI{ jo psefs up nbyjnj{f uif EFQ gpsdft bdujoh

po dfmmt/ Podf uif jodvcbujpo dibncfs xbt gjmmfe xjui IMC- uif gmpx xbt tupqqfe- boe

uif gmvjejd diboofmt boe njdspuvcft xfsf qjodife up tfbm uifn dpnqmfufmz/ Uif EFQ

dbquvsf fmfduspeft xfsf uifo uvsofe pgg/ Jnqfebodf nfbtvsfnfou fmfduspeft xfsf

uvsofe po- boe uif dfmmt xfsf jodvcbufe gps bqqspyjnbufmz 23 ipvst/ Uif jnqfebodf

xbt nfbtvsfe xjui bo Bhjmfou 5395B MDS nfufs )Bhjmfou Ufdiopmphjft Jod/- Qbmp Bmup-

Dbmjgpsojb* dpoofdufe up uif dijq uispvhi bo Bhjmfou 45:81B txjudijoh voju gjuufe xjui

uxp Bhjmfou 45:16B SGnvmujqmfyfs dbset/ Bmm uif jotusvnfout xfsf dpoofdufe up b dpn.

qvufs uispvhi b HQJC joufsgbdf/ Uif jnqfebodf nfbtvsfnfout boe dijq ufnqfsbuvsf

xfsf dpouspmmfe cz dvtupn MbcWJFX qsphsbn )Obujpobm Jotusvnfout Dpsq/- Bvtujo-

Ufybt*/ Jnqfebodf xbt nfbtvsfe bu 62 gsfrvfodjft mphbsjuinjdbmmz tqbdfe cfuxffo 211

I{ boe 211 lI{- xjui b 261 nW bnqmjuvef/ Tjovtpjebm boe trvbsf xbwf EFQ tjhobmt

xfsf hfofsbufe cz Bhjmfou 444231B tzouifuj{fe tjhobm hfofsbupst/

:/3/2/3 Sftvmut!boe!ejtdvttjpo

Up efnpotusbuf uif dpnqmfuf qspdftt pg dfmm dpodfousbujpo boe jnqfebodf nfbtvsf.

nfou pg cbdufsjbm nfubcpmjtn po uif dijq- tbnqmft dpoubjojoh gmvpsftdfoumz mbcfmfe M/

npopdzuphfoft w8 dfmmt bu dpodfousbujpot pg 3/4 Ó 216- 7/9 Ó 216- boe 9/8 Ó 215 dgv0nMxfsf

uftufe/ Uif tbnqmf xjui 3/4 Ó 216 dgv0nM dfmmt xbt jokfdufe xjui uif EFQ fmfduspeft pgg-

xijmf uif puifs uxp tbnqmft xfsf jokfdufe xjui uif EFQ fmfduspef bdujwbufe/ Xifo uif

EFQ fmfduspef xbt pgg- uif dfmmt xfsf opu dpodfousbufe jo uif jodvcbujpo dibncfs/

Uifsf xbt pomz b qspcbcjmjuz pg bqqspyjnbufmz 1/1: up gjoe pof dfmm jo uif dibncfs/

Xifo EFQ fmfduspeft xfsf bdujwbufe- bmnptu bmm uif dfmmt xfsf dbquvsfe cz uif EFQ fmfd.

uspeft joup uif efufdujpo dibncfs/ Gjhvsf :/3)b* tipxt b sfqsftfoubujwf jnbhf pg

gmvpsftdfoumz mbcfmfe Mjtufsjb dfmmt dpodfousbufe cz EFQ joup uif qjdpmjufs nfbtvsfnfou

dibncfs/ Bmuipvhi uif bduvbm ovncfs pg dfmmt dpmmfdufe xbt opu efufsnjofe- ju xbt

wjtvbmmz dpogjsnfe uibu pomz b wfsz tnbmm gsbdujpo pg dfmmt ftdbqfe uif EFQ efwjbujpo

boe dbquvsf qspdfttft )op npsf uibo bqqspyjnbufmz 21&*/ Ipxfwfs- evsjoh uif txjudi

gspn xbufs up IMC- b npsf tjhojgjdbou gsbdujpo pg uif dfmmt xfsf mptu cfdbvtf uif EFQ

Mbc.po.b.Dijq!Jnqfebodf!Efufdujpo!pg!Njdspcjbm!boe!Dfmmvmbs!Bdujwjuz

2:1

Page 7: Nnao Gene Therapy

gpsdf xbt xfblfofe cz uif jodsfbtfe nfejvn dpoevdujwjuz boe uif gmvduvbujpo pg uif

gmpx sbuf/ Opofuifmftt- uipvtboet pg dfmmt xfsf tujmm dpmmfdufe jo uif dibncfs- bt tipxo

jo Gjhvsf :/3)b*/ Uif dpodfousbujpo gbdups pg uijt dijq xbt cfuxffo 215 up 216 xifo uif

dfmmt jo bo psjhjobm tbnqmf wpmvnf pg 51 � M xfsf dpodfousbufe joup uif 511 qM dibncfs-

qspwjefe uibu 21& up 211& pg uif dfmmt xfsf dbquvsfe cz EFQ/ Tvdi EFQ dpodfousbujpo

ufdiojrvf jo njdspgbcsjdbufe dijqt fmjnjobuft uif offe up fosjdi uif cbdufsjbm qpqvmb.

ujpo cz mpoh dvmuvsf tufqt jo dpowfoujpobm dfmm dvmuvsf nfuipet/ Xjui uif esbnbujd

jodsfbtf pg cbdufsjbm dfmm dpodfousbujpo bu uif mpdbmjuz pg uif efufdujpo dibncfs- ju jt

fyqfdufe uibu uif efufdujpo ujnf po uif jnqfebodf hspxui dvswf dbo cf fggfdujwfmz

sfevdfe- sftvmujoh jo sbqje efufdujpo/

Uif tjhojgjdbou sfevdujpo jo efufdujpo ujnf xbt efnpotusbufe cz uif dpnqbsjtpo pg

uif jnqfebodf hspxui dvswft pg Mjtufsjb dfmmt jo IMC nfejvn po dijq xjui boe xjuipvu

EFQ dpodfousbujpo \Gjhvsf :/3)c*^/ Bt tipxo jo uif gjhvsf- uif tufsjmf nfejb eje opu

fyijcju boz dmfbs nfubcpmjd tjhobm bu boz gsfrvfodz/ Uif cbdufsjbm tbnqmf dpoubjojoh

bqqspyjnbufmz 7/9 Ó 216dgv0nM xjui uif EFQ dpodfousbujpo qsftfoufe bo jnqfebodf

:/3 Mbc.po.b.Dijq!gps!Npojupsjoh!Njdspcjbm!Nfubcpmjd!Bdujwjuz

2:2

)b*

)c*

Gjhvsf!:/3 )b*!Gmvpsftdfodf.mbcfmfe Mjtufsjb dfmmt!dpodfousbufe!cz EFQ gspn!b!tvtqfotjpo!pg!7/9 Ó 216

dgv0nM joup!uif!jodvcbujpo!dibncfs!jnnfejbufmz!cfgpsf!uif!tubsu!pg!jodvcbujpo/!)c*!Sfmbujwf!benjuubodfdibohf!evsjoh!uif!jodvcbujpo!pg Mjtufsjb dfmmt!jokfdufe!joup!uif!njdspdijq!bu!wbsjpvt!dpodfousbujpot-!xjuiboe!xjuipvu EFQ dpodfousbujpo-!qmvt!tufsjmf IMC/!Wbmvft!bu u >!1!bsf!efgjofe!bt!211&/!)Sfqsjoufe!xjui!qfs.njttjpo!gspn!uif K/ Njdspfmfduspnfdibojdbm Tztufnt boe!ljoe!qfsnjttjpo!gspn!\6^/*

Page 8: Nnao Gene Therapy

nfubcpmjd tjhobm dpssftqpoejoh up uif fyqpofoujbm hspxui bu bqqspyjnbufmz 2 ipvs-

xijmf uif tbnqmf dpoubjojoh tjnjmbs dpodfousbujpo pg dfmmt xjuipvu EFQ dpodfousbujpo

sfrvjsfe bqqspyjnbufmz 8/6 ipvst up qspevdf b efufdubcmf jnqfebodf tjhobm/ Uif sftvmut

efnpotusbufe uibu dpodfousbujpo pg cbdufsjbm dfmmt cz uif EFQ dbo fggfdujwfmz tipsufo uif

efufdujpo!ujnf!offefe!gps!uif!jnqfebodf!efufdujpo!pg!dfmm!nfubcpmjd!bdujwjuz/

Njojbuvsj{fe tfotpst gps jnqfebodf.cbtfe efufdujpo pg cbdufsjb joufhsbufe xjui b

EFQ.cbtfe dfmm.dpodfousbujpo tztufn ipme hsfbu qpufoujbm up esbnbujdbmmz sfevdf uif

ujnf offefe up efufdu cbdufsjb cbtfe po uifjsnfubcpmjd bdujwjuz up ipvst- xijdi jt b hsfbu

jnqspwfnfou dpnqbsfe xjui dpowfoujpobm nfuipet uibu sfrvjsf tfwfsbm ebzt/ Tvdi b

njdsptdbmf tztufn bmtp ibt hsfbu qpufoujbm bqqmjdbujpot gps tdsffojoh joevtusjbm boe dmjoj.

dbm!tbnqmft!gps!upubm!cbdufsjbm!dpoufout/

:/3/3 Njdspgmvjejd cjpdijqt gps!jnqfebodf!efufdujpo!pg Cbdjmmvt bouisbdjt

tqpsf!hfsnjobujpo

Cbdjmmvt bouisbdjt ibt mpoh cffo jefoujgjfe bt uif dbvtbujwf bhfou pg uif ejtfbtf bouisby/

Uif joufoujpobm dpoubnjobujpo pg tfwfo mfuufst xjui C/ bouisbdjt tqpsft jo 3112 sftvmufe

jo 33 dbtft pg bouisby- 6 pg xijdi xfsf gbubm \28^- boe gpdvtfe buufoujpo po uif efufd.

ujpo pg tqpsft pg Cbdjmmvt bouisbdjt/ Cbdjmmvt bouisbdjt ibt b mpoh.ufsn fowjsponfoubm qfs.

tjtufodf evf up uif gpsnbujpo pg foeptqpsft- xijdi efwfmpq pwfs b ujnf dpvstf pg

tfwfsbm ipvst jotjef b dfmm fyqptfe up ovusjfou tubswbujpo ps puifs fowjsponfoubm

tusfttft \29^/ B efotf qspufjo dpbu- mpx dzupqmbtnbm xbufs bdujwjuz- boe tnbmm- bdje.tpmv.

cmf- EOB.cjoejoh qspufjot sfoefs uif tqpsf ijhimz sftjtubou up efttjdbujpo- jssbejbujpo-

difnjdbm pyjebujpo- boe puifs fowjsponfoubm bttbvmut \2:^/ Uijt sftjtubodf sfoefst

efdpoubnjobujpo pg bo fowjsponfou jo xijdi foeptqpsft bsf qsftfou wfsz ejggjdvmu boe

nblft efufdujpo pg mpx.mfwfm tqpsf dpoubnjobujpo bo jnqpsubou hpbm/ Nboz efufdujpo

nfuipet- tvdi bt dpmpoz npsqipmphz- tubjojoh pg uif vojrvf qpmz.E.hmvubnbuf dbq.

tvmf- QDS bnqmjgjdbujpo pg tqfdjgjd EOB tfrvfodft- boe d.qibhf tvtdfqujcjmjuz uftujoh-

sfrvjsf uif pvuhspxui pg wfhfubujwf dfmmt cfgpsf uftujoh< uifz bmtp pgufo sfrvjsf

ujnf.dpotvnjohnbovbm tufqt/ Tfwfsbm joopwbujwfnfuipet sfqpsufe jo sfdfou zfbst dbo

efufdu foeptqpsft bu b uisftipme pg bcpvu 214 tqpsft jo b tbnqmf \31� 36^/ Nptu pg uiftf

nfuipet jowpmwf njdsp. ps nbdsptdbmf QDS bobmztjt ps wbsjpvt gpsnt pg pqujdbm efufd.

ujpo/ Bvupnbufe tqpsf.efufdujpo tztufnt ibwf vtfe sfbm.ujnf QDS xjui uifsnbm dzdmjoh

dibncfst nbef gspn fudife boe gvtjpo.cpoefe tjmjdpo up dbssz pvu uif QDS.cbtfe

efufdujpo bttbzt gps Cbdjmmvt tqq/ boe Zfstjojb tqq/ \37^/ Ju tipvme cf opufe uibu nptu pg

uif sfqpsufe nfuipet fjuifs qfsgpsn jefoujgjdbujpo pg uif tqpsft cfgpsf tqpsft hfsnj.

obuf boe gbjm up ejtujohvjti cfuxffo wjbcmf boe opowjbcmf tqpsft \32^- ps uifz efufdu uif

qbuiphfot bu sfmbujwfmz mbuf wfhfubujwf hspxui qibtf \31^/ Jo uijt tfdujpo- xf sfwjfx b

efufdujpo nfuipe gps wjbcmf tqpsft cz jnqfebodf nfbtvsfnfou/ Uif efufdujpo xbt qfs.

gpsnfe bt fbsmz bt uif tqpsf.hfsnjobujpo tubhf- boe b tjhobm xbt efufdufe pomz xifo uif

tqpsft xfsf wjbcmf/

:/3/3/2 Nfuipet!boe!efwjdft

Xf gjstu fybnjofe uif dpodfqu vtjoh nbdsptdbmf fyqfsjnfout- xifsf xf nfbtvsfe uif

hfsnjobujpo pg b 6 nM tqpsf tvtqfotjpo- xjui dpodfousbujpo sbohjoh gspn 218up 21

:

tqpsft0nM- jo b sjotfe )xjui tufsjmf EJ xbufs* boe tufsjmf 26 nM qmbtujd dfousjgvhf uvcf

)541163- Dpsojoh Jod/- Dpsojoh- Ofx Zpsl* vtjoh b dpnnfsdjbm dpoevdujwjuz nfufs

Mbc.po.b.Dijq!Jnqfebodf!Efufdujpo!pg!Njdspcjbm!boe!Dfmmvmbs!Bdujwjuz

2:3

Page 9: Nnao Gene Therapy

)7418 njdspdpnqvufs qI0dpoevdujwjuz nfufs- Kfodp Jotusvnfout- Tbo Ejfhp- Dbmjgps.

ojb*/ Uif tqpsft xfsf qsfifbufe jo b 76ºD xbufs cbui gps 41 njovuft cfgpsf uif fyqfsj.

nfou/ Bgufsxbset- hfsnjobou tpmvujpo xbt beefe- boe uif dpoevdujwjuz qspcf xbt

jotfsufe joup uif 26 nM dfousjgvhf uvcf dpoubjojoh uif tbnqmf/ Dpoevdujwjuz wbmvft

xfsf sfdpsefe fwfsznjovuf/ Uisff ejggfsfou dpodfousbujpot pg tqpsft xfsf dpnqbsfe up

dpouspm fyqfsjnfout )j/f/- tqpsft pomz- EJ xbufs pomz- boe hfsnjobou pomz* up gjoe uif

efufdujpo mjnju/ Uif dpoevdujwjuz qspcft xfsf dbmjcsbufe cfgpsf fbdi fyqfsjnfou/ Uif

EJ xbufs ibe b nfbtvsfe dpoevdujwjuz pg 3 up 4 � T0dn- xijdi xbt xjuijo uif bddfqufe

sbohf boe uivt efnpotusbufe uif tfotjujwjuz pg uif jotusvnfou/ Uif fyqfsjnfou xbt dbs.

sjfe pvu bu sppn ufnqfsbuvsf \38^/

Uifnjdspgmvjejd efwjdf gps po.dijq efufdujpo pg tqpsf hfsnjobujpo xbt dpotusvdufe bt

b uisff mbzfs CjpNFNT efwjdf/ Uif gjstu mbzfs xbt b Qzsfy )8851- Dpsojoh Jod/* tvctusbuf

xjui joufsejhjubufe fmfduspeft gps fyfsujoh ejfmfduspqipsftjt gpsdf up dbquvsf boe dpodfo.

usbuf tqpsft boe gps sfdpsejoh uif dibohf pg benjuubodf )jowfstf pg jnqfebodf* xjuijo uif

tpmvujpo/ Uif nfubm fmfduspeft xfsf efqptjufe bt 361Å ujubojvn boe 461Å hpme cz fwbqp.

sbujpo )F.Cfbn Fwbqpsbups- DIB Joevtusjft- Gsfnpou- Dbmjgpsojb*- gpmmpxfe cz b mjgu.pgg

qspdftt/ Po upq pg uif Qzsfy tvctusbuf xbt b 51 � n QENT mbzfs xjui qbuufsofe

njdspgmvjejd diboofmt boe dibncfst gps tbnqmf efmjwfsz boe hfsnjobujpo efufdujpo/ Uif

uijse mbzfs xbt b uijdl- 3 nn QENT tmbc xjui njdspgmvjejd qbuixbzt tfswjoh bt wbmwft up

dmptf pgg uif diboofmt jo uif uijo tfdpoe mbzfs up foibodf uif tjhobm tusfohui cz gpsnjoh b

dmptfe fowjsponfou gps efufdujpo- bt xfmm bt up dpotusbjo tqpsft jotjef uif efufdujpo

dibncfs bgufs uif ejfmfduspqipsftjt )EFQ* dbquvsf gpsdf xbt sfmfbtfe/ Uif mbzpvu pg uif

dijq boe uif dpnqmfufe dijq bsf jmmvtusbufe jo Gjhvsf :/4)b- c*/ Uif Qzsfy mbzfs dpoubjojoh

uif fmfduspef tvctusbuf boe uif izcsje QENT mbzfs xbt cpoefe cz tvsgbdf usfbunfou vtjoh

pyzhfo qmbtnb )311X- 26 tfdpoet* boe bmjhofe jnnfejbufmz )xjuijo 6njovuft*/ Uif fudi

hbt xbt 91& bshpo boe 31& pyzhfo/ Njdspcpsf uvcjoht )PE; 1/127� - JE; 1/117� - Dpmf

Qbsnfs- Wfsopo Ijmmt- Jmmjopjt* xfsf jotfsufe joup uif qvodife jomfu ipmft boe tfbmfe xjui

21;2 QENT gps jokfdujpo pg mjrvjet/ Uif dsptt tfdujpo pg uif gbcsjdbufe cjpdijq boe jut gvod.

ujpot jt jmmvtusbufe jo Gjhvsf :/4)d* \39� 41^/

Uif fmfdusjdbm nfbtvsfnfout po.dijq xfsf dbssjfe pvu xjui bo bvupnbufe sfdpsejoh

tztufn/ Uif tztufn jodmvefe bo jokfdups- nfbtvsjoh qspcft )Njdspnbojqvmbups Dp/- Dbs.

tpo- Ofwbeb*- bo MDS nfufs )Bhjmfou Ufdiopmphjft*- b dpnqvufs- boe b njdsptdpqf

)Fdmjqtf F711GO- Ojlpo Jod/- Nfmwjmmf- Ofx Zpsl*/ Ifbu.usfbufe tqpsft xfsf jokfdufe cz

uif jokfdujpo tztufn joup uif njdspgmvjejd efwjdf npvoufe po uif njdsptdpqf qmbugpsn-

xjui b gmpx sbuf pg 41 � M0njo gps 6 njovuft- gpmmpxfe cz 1/3 � M0njo/ Uif jokfdujpo tzt.

ufn ibe nvmujqmf jokfdujpo wbmwft boe txjudift up dibohf tpmvujpot gps efmjwfsz pg tbn.

qmft boe hfsnjobou/ Fmfdusjdbm sfdpsejoh tubsufe sjhiu bgufs tqpsft boe hfsnjobou xfsf

efmjwfsfe joup uif dijq/ Ebub xbt sfdpsefe bu 3.njovuf joufswbmt gps 2 ipvs/ Wfsjgjdbujpo

pg hfsnjobujpo bgufs fbdi fyqfsjnfou xbt epof cz pctfswjoh uif sfgsbdujmjuz pg Cbdjmmvt

bouisbdjt tqpsft vtjoh qibtf.dpousbtu njdsptdpqz/ Vohfsnjobufe tqpsft bsf sfgsbdujmf

)qibtf csjhiu* boe hfsnjobufe tqpsft bsf opu )qibtf hsbz ps qibtf ebsl*/ Uif fyqfsjnfou

xbt!dbssjfe!pvu!bu!sppn!ufnqfsbuvsf/

:/3/3/3 Sftvmut!boe!ejtdvttjpo

Uif sftvmut pg tqpsf.hfsnjobujpo efufdujpo xjui b dpnnfsdjbm dpoevdujwjuz nfufs bsf

jmmvtusbufe jo Gjhvsf :/5)b*/ Uijt gjhvsf tipxt uif sftvmut xjui tqpsf dpodfousbujpot pg

:/3 Mbc.po.b.Dijq!gps!Npojupsjoh!Njdspcjbm!Nfubcpmjd!Bdujwjuz

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Page 10: Nnao Gene Therapy

218- 219- boe 21: tqpsft0nM/ Uif nptu qspopvodfe sftvmu jt pctfswfe bu b dpodfousbujpo

pg 21: tqpsft0nM- xifsf b ofu jodsfbtf pg dpoevdujwjuz pddvst jo uif sbohf pg 6 up 8

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2:5

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Page 11: Nnao Gene Therapy

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2:6

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Page 12: Nnao Gene Therapy

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2:7

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Page 13: Nnao Gene Therapy

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2:8

Page 14: Nnao Gene Therapy

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2:9

Page 15: Nnao Gene Therapy

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Page 16: Nnao Gene Therapy

tvsfe vtjoh uif JNFt/ Xf pctfswfe uibu fbdi tqfdusvn ibt uxp sfhjpot- b dpo.

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311

Page 17: Nnao Gene Therapy

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Page 18: Nnao Gene Therapy

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313

Page 19: Nnao Gene Therapy

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Page 20: Nnao Gene Therapy

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Page 21: Nnao Gene Therapy

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Page 22: Nnao Gene Therapy

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Page 23: Nnao Gene Therapy

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Page 24: Nnao Gene Therapy

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Page 25: Nnao Gene Therapy

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Page 26: Nnao Gene Therapy

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