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T*
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T*
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T*
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T*
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T*
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T*
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T*
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T*
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T*
[(resulted)-305.4(in)-302.9(vefold)-301.3(increases)-300.5(in)-302.9(AAV)-306.5(production)-297.1(to)-302.9(date.)]TJ
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T*
[(tion)-367.4(can)-372.8(yield)-370.2(short,)-368.7(strong,)-367.2(and)-368.6(potentially)-372.7(cell-specic)]TJ
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[(medicine,)-363.7(but)-366.6(a)-365.9(crucial)-364(challenge)-366.4(is)-363.7(guring)-362.1(out)-366.6(how)-363.1(to)]TJ
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[(RNA)-326(\(siRNA\))-327.2(technology,)-323.3(which)-323.4(changes)-323.8(a)-328(sequence)-326.6(of)]TJ
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[(lem)-317.4(is)-314.9(delivering)-314.4(siRNA)-315.7(intracellularly)-316.1(as)-317(there)-317(are)-317.6(mul-)]TJ
T*
[(tifaceted)-497.7(barriers,)-501(such)-493(as)-501.2(nanocomplexation,)-494.4(transport)]TJ
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[(to)-438.4(the)-441.2(cells)-446.1(of)-440.6(interest,)-436.9(avoidance)-440.1(of)-440.6(nontargeted)-439.7(cells,)]TJ
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[(endocytosis,)-535.7(endosomal)-542(escape,)-540.1(release)-540.6(of)-538.2(RNA)-537.3(from)]TJ
T*
[(nanoparticle,)-286.8(and)-281.8(nuclear)-285.9(transport.)-281.8(In)-283.4(addition,)-286.2(it)-283.5(will)-287.1(be)]TJ
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[(DNA)-236(are)-236.3(highly)-229.1(charged)-234.9(large)-235.7(molecules)-234.1(that)-236.1(do)-235.7(not)-231.1(cross)]TJ
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[(cellular)-424.4(membranes,)-418.5(are)-420.6(prone)-424.4(to)-416.7(nuclease)-426.4(degradation,)]TJ
T*
[(and)-298.1(can)-296.9(induce)-300.3(immune)-297.7(responses.)-295.8(However,)-298(researchers)]TJ
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(e.g.,)Tj
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[(sequence)-407.9(selection)-403.5(to)-405.9(target)]TJ
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[(specicity)-751.2(and)-753.4(potency,)-748.1(chemical)-753.4(modication,)-744.5(and)]TJ
T*
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[(RNA,)-265.6(researchers)-270.6(are)-263.4(developing)-264.4(new)-264.4(ionizable)-266.9(lipids)-265(for)]TJ
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[(nanoparticle)-256.4(delivery)-252.2(\()]TJ
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(e.g.,)Tj
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(lipid-siRNA-nan)Tj
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[(oformul)-16.6(a)12.3(tio)-4.4(ns)-5.6(\).)]TJ
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T*
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T*
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[(or)-353.9(hepatocytes.)-353.3(Polymer)-350.9(nanoparticles)-352.4(have)-355.1(great)-354.9(poten-)]TJ
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T*
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[(potential)-259.4(for)-264.8(mRNA,)-259.6(with)-263.2(polymer)-256.6(nanoparticles)-265.7(yielding)]TJ
T*
[(better)-323.2(results)-325.4(than)-326(LNPs)-321.6(for)-324.4(delivery)-325.8(to)-324.6(the)-327.4(lungs.)-320.9(Chan-)]TJ
0 -1.1869 TD
[(ging)-419.3(the)-419.6(chemistry)-418.6(allows)-417.5(researchers)-422.4(to)-416.7(target)-420.8(specic)]TJ
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[(organs,)-222.9(which)-220.4(can)-226.5(further)-221.2(expand)-222.3(the)-219(therapeutic)-223.9(potential)]TJ
T*
[(for)-281(these)-281.3(molecules.)]TJ
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[(Sum)-9.4(mary)-335.3(of)-339.1(the)-338.3(past)-333.3(and)-342.6(the)-338.2(future)-337.8(of)-339.1(gene)]TJ
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[(therap)-10.7(ies)]TJ
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2.2437 0 TD
[(in)-292.1(vivo)]TJ
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3.0458 0 TD
[(gene)-295.5(therapy)-297.9(and)-292.7(gene)-295.5(editing)-299.2(have)-295.5(great)]TJ
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[(to)-297.5(review)-298.1(more)-296.5(recent)-298.1(research)-297.5(because)-300.9(clinical)-297.6(concerns)]TJ
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[(are)-463.9(generally)-464.2(related)-461.5(to)-460.1(legacy)-461.7(programs.)-463.8(As)-463.3(scientists)]TJ
T*
[(have)-468.9(gained)-473.8(a)-468.9(better)-475(understanding)-466.4(of)-473.1(human)-469.5(biology,)]TJ
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[(gene)-398.5(therapy)-400.9(technology)-399.9(has)-396.8(improved.)-395.4(Gene)-402.7(editing)-396.7(is)]TJ
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[(exciting,)-263.3(but)-269(as)]TJ
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6.3951 0 TD
[(in)-265(vivo)]TJ
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2.9916 0 TD
[(gene)-263(editing)-266.6(advances)-267(through)-262.4(the)]TJ
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[(research)-378.8(pipeline,)-382.6(researchers)-379(must)-378(pay)-379.4(particular)-382.7(atten-)]TJ
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[(tion)-497.4(to)-498(weighing)-494.8(the)-500.9(risks)-495.2(versus)-501.2(benets.)-496.7(Toxicity)-492.7(is)]TJ
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[(always)-636.3(a)-631.5(concern,)-635.3(and)-628.7(despite)-632.9(preclinical)-638(work,)-631(the)]TJ
T*
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1.1435 -1.1923 TD
[(Gene)-446(therapy)-444.3(platforms)-440.5(have)-447.3(the)-441.2(advantage)-445.5(that)-447.5(the)]TJ
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[(application)-694.4(to)-698.6(one)-699.2(clinical)-693.2(indication)-697(could)-698.6(provide)]TJ
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[(information)-482(about)-481.8(the)-484.6(use)-489(in)-481.8(other)-486.2(clinical)-481.8(conditions.)]TJ
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[(A)-235.9(disadvantage)-238.8(is)-239.1(that)-236.1(if)-236.9(the)-235.3(FDA)-239.5(issues)-234.7(a)-241.3(clinical)-238(hold)-235.1(on)]TJ
T*
[(a)-295.5(trial)-290.1(using)-294.5(a)-295.5(platform,)-288.2(it)-294.3(will)-292.5(affect)-297.1(other)-291.1(research)-297.5(trials)]TJ
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[(using)-451.7(that)-458.3(foundation,)-453.6(and)-449.9(this)-455.3(loss)-454.2(of)-456.9(momentum)-452.9(can)]TJ
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[(generate)-191.2(panic)-187.9(in)-194.5(rare)-190.5(disease)-191.7(genetic)-186.1(correction)-190.8(programs.)]TJ
T*
[(Therefore,)-240(as)-246.5(technologies)-236.7(emerge)-242.5(and)-243.9(progress,)-242(it)-240.1(will)-243.7(be)]TJ
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[(important)-344.9(to)-340.9(focus)-344.3(on)-344.1(programs)-345.3(that)-344.5(have)-344.3(a)-344.3(high)-343.5(chance)]TJ
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[(of)-402.7(succeeding)-401.9(and)-406.5(on)-398.3(diseases)-402.9(with)-404.1(a)-403.9(signicant)-405.5(unmet)]TJ
T*
[(treatment)-282.9(need)-279.2(with)-279.4(a)-279.2(robust)-275.8(benet-to-risk)-277.7(ratio.)]TJ
1.1435 -1.1869 TD
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[(a)-338.8(clinical)-340.9(trial,)-338.2(biomarkers)-332.7(are)-339.3(critical)-339.9(and)-341.5(provide)-331.6(some)]TJ
T*
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[(to)-292.1(consider)-286.9(the)-289.5(path)-288.1(to)-292.1(registrationpartic)5.1(ularly)-291.9(the)-289.5(end-)]TJ
T*
[(points)-300.7(that)-301.1(would)-297.5(convince)-301.8(others)-296.3(that)-301.1(the)-300.3(agent)-301.7(is)-298.7(effec-)]TJ
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T*
[(of)-288.9(a)-290.1(successful)-285.3(commercial)-289.8(product,)-287.6(as)-289.9(researchers)-286.9(might)]TJ
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[(learn)-208.6(additional)-203.8(important)-204(information)-205.6(about)-205.4(the)-202.8(condition)]TJ
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[(under)-278(study.)]TJ
1.1435 -1.1923 TD
[(The)-297.9(utility)-293.9(of)-294.3(animal)-298(models)-298.1(is)-293.3(never)-298.5(completely)-293.4(vali-)]TJ
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[(dated)-361.4(until)-357.3(results)-357.9(of)-359.3(human)-361.2(the)-354.5(clinical)-362.6(trials)-360.4(are)-360.9(avail-)]TJ
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T*
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[(cases)-392.8(to)-395.1(reduce)-393.5(the)-392.5(risk)-392.4(from)-394.3(an)-391.6(approach.)-390(An)-391.6(ongoing)]TJ
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[(DIRE)-8.6(CTIONS)-342.9(AND)-339.2(RESOU)-9.9(RCE)-335.9(NEED)-10.5(S)-330.6(I)0(N)-338.3(NHLB)-9.2(I)-333.6(GENE)-340.6(THERA)-10.5(PY)-336.9(RESEARC)-12.2(H)]TJ
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(87)Tj
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[(limitation)-204.9(in)-205.4(rare)-212.2(diseases)-207.8(is)-206.6(the)-208.2(lack)-205.6(of)-207.6(animal)-205.8(models)-206(that)]TJ
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[(phenocopy)-348.1(human)-350.3(disease)-354.3(and)-346.9(very)-355.3(often)-350.7(the)-349.1(lack)-351.9(of)-353.9(an)]TJ
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[(studies.)-423.3(CRISPR)-423.7(technology)-427(can)-421.6(be)-424.2(used)-428(to)-422.2(selectively)]TJ
T*
[(develop)-277.3(these)-281.3(animal)-281.7(models.)]TJ
1.1435 -1.1869 TD
[(Although)-414.7(the)-425(manufacturing)-415(of)-418.9(gene)-420.2(therapy)-422.6(vectors)]TJ
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[(has)-304.7(greatly)-300.2(improved,)-303.3(current)-302.3(vector)-304.8(technology)-297(may)-304.3(not)]TJ
T*
[(serve)-624.9(future)-624.7(needs.)-625.2(However,)-623.2(researchers)-622.9(should)-623.7(not)]TJ
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[(abandon)-199.2(AAV)-203.5(vectors)-207(because)-203.4(\(1\))-199.7(researchers)-205.6(have)-203.4(a)-203.4(deep)]TJ
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[(knowledge)-273.2(of)-278(what)-276(they)-277.2(can)-275.2(and)-276.4(cannot)-278.7(do,)-272.9(\(2\))-281(AAV)-274(can)]TJ
T*
[(be)-207.4(modied)-205.6(to)-205.4(have)-208.8(properties)-204(that)-209(natural)-202.6(variant)-208(may)-206.8(not)]TJ
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[(scope)-468.7(of)-462.3(innovation)-468.4(should)-461.1(go)-468.7(beyond)-461.9(capsid)-469.5(biology,)]TJ
T*
[(including)-599.8(addressing)-599.6(the)-603.8(need)-604.4(to)-601(perfect)-599.2(devices)-602.4(for)]TJ
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[(injection,)-269.6(garnering)-272.4(a)-273.8(better)-269(understanding)-271.3(of)-272.6(the)-267.8(route)-274.8(of)]TJ
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T*
[(trans-gene)-184.3(that)-181.9(can)-183.1(be)-180.3(specically)-179.5(regulated)-182.3(in)-183.7(certain)-179.7(cells)]TJ
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[(Rapid)-635.5(heme)-632.3(panels)-637.5(using)-630.5(targeted)-639(next-generation)]TJ
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[(sequencing)-403.1(\(NGS\))-408.1(panels)-404.5(to)-405.9(identify)-405.1(genetic)-402.9(alterations)]TJ
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[(ar)10.4(e)-490.6(i)0(n)11.4(c)0(r)10.4(e)0(a)10.6(s)0(i)10.2(ngl)12.8(y)-486.4(bei)14(ng)-479.5(exp)16.2(lor)13.8(ed)-483.8(as)-485(di)11.4(agn)16.2(os)12.4(tic)-481.4(to)11.4(ol)11.4(s)-487.6(for)]TJ
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[(tat)11.8(io)11.4(n)-242.5(o)0(f)-234.7(a)-241.3(rec)13(ent)14(ly)-237.9(des)15(ig)11.4(ned)-233.1(com)15.4(pre)17.2(hen)16.2(si)10.2(ve)-239.9(95)13.6(-ge)11.8(ne)-234.5(NGS)]TJ
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[(pan)16.2(el)-366.8(tar)15(get)14(ed)-364.5(for)-362.3(hem)15.4(ato)14(lo)11.4(gi)11.4(cal)-364.2(mal)13.2(ig)11.4(nan)16.2(ci)12.6(es)-371.1(ar)10.4(e)-371.4(o)0(n)13.6(go-)]TJ
T*
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T*
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T*
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T*
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[(cell)-332.5(collection,)-329.3(conditioning,)]TJ
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16.4811 15.0016 TD
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T*
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6.5441 -1.2519 TD
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[(Pharm-Tox)-327.4(studies)]TJ
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[(Regulatory)-332.3(assistance)]TJ
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T*
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[(CAR-T)-330.5(cell)-332.5(and)]TJ
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12.4764 3.7486 TD
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T*
[(Manufacturing)-327.4(of)-331.9(vectors)-333.9(for)]TJ
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[(GLP)-330.3(Pharm-Tox)-327.4(studies)]TJ
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[(cGMP)-331.7(vector)-327.6(manufacturing)-328.6(and)]TJ
/F8 1 Tf
12.2915 0 TD
[(ex)-334.6(vivo)]TJ
/F7 1 Tf
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T*
[(Study)-330(monitoring,)-335.8(including)-325.3(CRA)-333(and)]TJ
1.003 -1.2519 TD
[(medical)-330.2(monitor)]TJ
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[(Long-term)-329.8(follow-up)]TJ
16.4811 8.7492 TD
[(Titering)-336.7(assessme)11.8(nts)]TJ
0 -1.2519 TD
[(Reference)-329.8(standards)]TJ
-51.7481 -8.7492 TD
[(Gene)-333.4(editing)-3576.7(Bioinformat)7.8(ics)-335(consultation)-330(for)]TJ
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[(design)-326.2(of)-339(sgRNA)]TJ
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/F7 1 Tf
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/F8 1 Tf
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(a)Tj
/F7 1 Tf
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[(Cas-9)-330(plasmids,)]TJ
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[(mRNA,)-323.7(and)-337.7(puried)-324.7(proteins)]TJ
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1.003 -1.2519 TD
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12.4764 8.7492 TD
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T*
[(Manufacturing)-327.4(of)-331.9(vectors)-333.9(for)]TJ
1.003 -1.2448 TD
[(Pharm-Tox)-327.4(studies)]TJ
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[(GLP)-330.3(Pharm-Tox)-327.4(studies)]TJ
13.4794 5.0005 TD
[(cGMP)-331.7(vector)-327.6(manufacturing)-328.6(and)]TJ
/F8 1 Tf
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[(ex)-334.6(vivo)]TJ
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0 -1.2519 TD
[(Electronic)-334.9(data)-327(capture)]TJ
T*
[(Study)-330(monitoring,)-335.8(including)-325.3(CRA)-333(and)]TJ
1.003 -1.2448 TD
[(medical)-330.2(monitor)]TJ
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[(Long-term)-329.8(follow-up)]TJ
16.4811 8.7492 TD
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0 -1.2519 TD
[(Reference)-329.8(standards)]TJ
T*
[(Off-target)-326.1(editing)-333.2(assessment)]TJ
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1.0029 -1.2519 TD
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61.9193 0 TD
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7.9702 0 0 7.9702 540.1629 49.1527 Tm
(oparticle;)Tj
-59.9913 -1.131 TD
[(POC,)-333.1(proof)-325.8(of)-328.7(concept.)]TJ
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