%PDF-1.6
%
1 0 obj
<>
endobj
2 0 obj
<>stream
Suneel Gupta, Jason T. Rodier, Ajay Sharma, Elizabeth A. Giuliano, Prashant R. Sinha, Nathan P. Hesemann, Arkasubhra Ghosh, Rajiv R. Mohan
Targeted AAV5-Smad7 gene therapy inhibits corneal scarring in vivo
www.plosone.org
www.plosone.org
endstream
endobj
3 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 13 0 R/Annots 14 0 R/Contents 15 0 R/TrimBox[0 0 612 792]>>
endobj
14 0 obj
[16 0 R 17 0 R 18 0 R 19 0 R 20 0 R 21 0 R 22 0 R 23 0 R 24 0 R 25 0 R 26 0 R 27 0 R 28 0 R 29 0 R 30 0 R 31 0 R 32 0 R 33 0 R 34 0 R 35 0 R 36 0 R 37 0 R 38 0 R 39 0 R 40 0 R 41 0 R 42 0 R 43 0 R]
endobj
16 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref002)>>
endobj
17 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref003)>>
endobj
18 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref004)>>
endobj
19 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref005)>>
endobj
20 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref006)>>
endobj
21 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref010)>>
endobj
22 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref011)>>
endobj
23 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref012)>>
endobj
24 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref006)>>
endobj
25 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref010)>>
endobj
26 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref013)>>
endobj
27 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref015)>>
endobj
28 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref016)>>
endobj
29 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref013)>>
endobj
30 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref017)>>
endobj
31 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref019)>>
endobj
32 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref009)>>
endobj
33 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref014)>>
endobj
34 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref020)>>
endobj
35 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref004)>>
endobj
36 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref014)>>
endobj
37 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref021)>>
endobj
38 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref022)>>
endobj
39 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref014)>>
endobj
40 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref023)>>
endobj
41 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref024)>>
endobj
42 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172928.ref027)>>
endobj
43 0 obj
<>/Border[0 0 0]/A 44 0 R>>
endobj
44 0 obj
<>
endobj
15 0 obj
[45 0 R 46 0 R 47 0 R 48 0 R 49 0 R 50 0 R 51 0 R 52 0 R 53 0 R 54 0 R 55 0 R 56 0 R 57 0 R 58 0 R 59 0 R 60 0 R 61 0 R 62 0 R 63 0 R 64 0 R 65 0 R 66 0 R 67 0 R 68 0 R]
endobj
45 0 obj
<>stream
q
0.83 0.64 0.02 0 k
288.2268 706.337 m
292.989 706.337 l
h
f*
295.2567 706.337 m
300.0189 706.337 l
h
f*
333.411 680.315 m
338.1732 680.315 l
h
f*
509.4992 641.3102 m
514.2614 641.3102 l
h
f*
351.8362 602.3055 m
356.5417 602.3055 l
h
f*
361.7575 602.3055 m
371.2252 602.3055 l
h
f*
429.8457 589.3228 m
439.3701 589.3228 l
h
f*
281.4803 550.3181 m
290.948 550.3181 l
h
f*
345.3165 537.3354 m
350.0787 537.3354 l
h
f*
355.2378 537.3354 m
364.7622 537.3354 l
h
f*
367.0299 537.3354 m
376.5543 537.3354 l
h
f*
381.7134 537.3354 m
391.2378 537.3354 l
h
f*
347.9244 511.3134 m
357.4488 511.3134 l
h
f*
263.452 485.348 m
272.9764 485.348 l
h
f*
275.2441 485.348 m
284.7118 485.348 l
h
f*
289.9276 485.348 m
299.3953 485.348 l
h
f*
334.4315 433.3039 m
339.1937 433.3039 l
h
f*
341.4614 433.3039 m
350.9291 433.3039 l
h
f*
355.4079 433.3039 m
364.9323 433.3039 l
h
f*
503.7732 407.3386 m
508.5354 407.3386 l
h
f*
513.0142 407.3386 m
522.5386 407.3386 l
h
f*
526.9606 407.3386 m
536.485 407.3386 l
h
f*
367.3701 381.3165 m
376.8945 381.3165 l
h
f*
430.6961 355.3512 m
440.1638 355.3512 l
h
f*
310.7906 329.3291 m
320.315 329.3291 l
h
f*
274.5638 303.3071 m
284.0315 303.3071 l
h
f*
289.2472 303.3071 m
298.715 303.3071 l
h
f*
0 g
1 j
1 J
0 w
10 0 0 10 200.0125 707.4141 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Americans)Tj
4.5524 0 Td
(each)Tj
2.0296 0 Td
(year)Tj
1.8992 0 Td
([)Tj
0.83 0.64 0.02 0 k
(2)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(3)Tj
0 g
(].)Tj
2.3073 0 Td
(Currently,)Tj
4.3484 0 Td
(no)Tj
1.2755 0 Td
(effective)Tj
3.5093 0 Td
(topical)Tj
2.914 0 Td
(treatments)Tj
4.4957 0 Td
(exist)Tj
2.0353 0 Td
(that)Tj
1.7801 0 Td
(cure)Tj
1.9673 0 Td
(corneal)Tj
-33.1141 -1.3039 Td
(scarring)Tj
3.4582 0 Td
(and)Tj
1.7348 0 Td
(the)Tj
1.4683 0 Td
(use)Tj
1.5307 0 Td
(of)Tj
1.0148 0 Td
(intra-operative)Tj
6.1852 0 Td
(drugs)Tj
2.4774 0 Td
(such)Tj
2.058 0 Td
(as)Tj
1.0148 0 Td
(MMC)Tj
2.6702 0 Td
(\(Mitomycin)Tj
5.0343 0 Td
(C\))Tj
1.2246 0 Td
(for)Tj
1.3889 0 Td
(prevention)Tj
4.5808 0 Td
(of)Tj
-35.841 -1.2982 Td
(corneal)Tj
3.1747 0 Td
(haze)Tj
2.0183 0 Td
(can)Tj
1.6214 0 Td
(be)Tj
1.1509 0 Td
(problematic)Tj
5.0343 0 Td
([)Tj
0.83 0.64 0.02 0 k
(4)Tj
0 g
(].)Tj
1.6044 0 Td
(Hence,)Tj
3.033 0 Td
(corneal)Tj
3.1748 0 Td
(transplantation)Tj
6.3325 0 Td
(remains)Tj
3.4413 0 Td
(the)Tj
1.4683 0 Td
(gold)Tj
1.9673 0 Td
(standard)Tj
-34.0212 -1.2983 Td
(for)Tj
1.3832 0 Td
(treatment)Tj
4.1386 0 Td
(of)Tj
1.0148 0 Td
(corneal)Tj
3.1748 0 Td
(blindness.)Tj
4.2349 0 Td
(However,)Tj
4.0762 0 Td
(limited)Tj
3.0671 0 Td
(availability)Tj
4.5354 0 Td
(of)Tj
1.0148 0 Td
(donor)Tj
2.6815 0 Td
(corneas)Tj
3.2882 0 Td
(and)Tj
1.7291 0 Td
(post-)Tj
-34.3386 -1.2983 Td
(transplantation)Tj
6.3325 0 Td
(complications)Tj
5.8393 0 Td
(including)Tj
4.0422 0 Td
(drug-induced)Tj
5.709 0 Td
(toxicity,)Tj
3.4242 0 Td
(immunosuppression,)Tj
8.6966 0 Td
(and)Tj
-34.0438 -1.3039 Td
(graft)Tj
2.0749 0 Td
(failure)Tj
2.7779 0 Td
(and)Tj
1.7292 0 Td
(rejection)Tj
3.7417 0 Td
(limit)Tj
2.1203 0 Td
(the)Tj
1.4683 0 Td
(clinical)Tj
3.0727 0 Td
(success)Tj
3.1011 0 Td
(of)Tj
1.0148 0 Td
(corneal)Tj
3.1748 0 Td
(transplantation)Tj
6.3326 0 Td
([)Tj
0.83 0.64 0.02 0 k
(5)Tj
0 g
(].)Tj
1.6044 0 Td
(Therefore,)Tj
-32.2127 -1.2982 Td
(there)Tj
2.262 0 Td
(is)Tj
0.8504 0 Td
(an)Tj
1.2019 0 Td
(unmet)Tj
2.8346 0 Td
(clinical)Tj
3.0784 0 Td
(need)Tj
2.143 0 Td
(to)Tj
1.0261 0 Td
(develop)Tj
3.3222 0 Td
(novel)Tj
2.3981 0 Td
(therapies)Tj
3.8437 0 Td
(for)Tj
1.3833 0 Td
(treatment)Tj
4.1386 0 Td
(of)Tj
1.0148 0 Td
(corneal)Tj
3.1748 0 Td
(disorders.)Tj
-31.4757 -1.2983 Td
(Gene)Tj
2.3357 0 Td
(therapy)Tj
3.2428 0 Td
(is)Tj
0.8504 0 Td
(one)Tj
1.7008 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(most)Tj
2.2053 0 Td
(promising)Tj
4.3427 0 Td
(approaches)Tj
4.7395 0 Td
(for)Tj
1.3833 0 Td
(the)Tj
1.4683 0 Td
(treatment)Tj
4.1386 0 Td
(of)Tj
1.0148 0 Td
(ocular)Tj
2.7269 0 Td
(surface)Tj
-33.8284 -1.3039 Td
(disorders,)Tj
4.1612 0 Td
(including)Tj
4.0422 0 Td
(corneal)Tj
3.1747 0 Td
(scarring)Tj
3.464 0 Td
([)Tj
0.83 0.64 0.02 0 k
(6)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(10)Tj
0 g
(].)Tj
3.067 0 Td
(The)Tj
1.7802 0 Td
(cornea)Tj
2.931 0 Td
(is)Tj
0.8447 0 Td
(an)Tj
1.2076 0 Td
(ideal)Tj
2.1146 0 Td
(target)Tj
2.5115 0 Td
(tissue)Tj
2.4604 0 Td
(for)Tj
1.3833 0 Td
(gene)Tj
2.0806 0 Td
(trans-)Tj
-35.223 -1.2983 Td
(fer)Tj
1.3039 0 Td
(due)Tj
1.6951 0 Td
(to)Tj
1.0261 0 Td
(its)Tj
1.1452 0 Td
(well-defined)Tj
5.176 0 Td
(anatomy)Tj
3.7191 0 Td
(and)Tj
1.7291 0 Td
(easy)Tj
1.8935 0 Td
(accessibility)Tj
4.955 0 Td
([)Tj
0.83 0.64 0.02 0 k
(11)Tj
0 g
(])Tj
1.8481 0 Td
(that)Tj
1.7802 0 Td
(permits)Tj
3.2768 0 Td
(direct)Tj
2.5342 0 Td
(topical)Tj
2.914 0 Td
(instil-)Tj
-34.9963 -1.2983 Td
(lation)Tj
2.5171 0 Td
(of)Tj
1.0148 0 Td
(gene)Tj
2.0863 0 Td
(delivery)Tj
3.3845 0 Td
(vectors.)Tj
3.2882 0 Td
(Treatment)Tj
4.4447 0 Td
(follow-up)Tj
4.0932 0 Td
(could)Tj
2.4548 0 Td
(be)Tj
1.1508 0 Td
(performed)Tj
4.4674 0 Td
(non-invasively)Tj
6.0888 0 Td
(using)Tj
-34.9906 -1.3039 Td
(modalities)Tj
4.3709 0 Td
(such)Tj
2.058 0 Td
(as)Tj
1.0148 0 Td
(slit-lamp)Tj
3.7587 0 Td
(biomicroscopy)Tj
6.1568 0 Td
(and)Tj
1.7291 0 Td
(high-resolution)Tj
6.4176 0 Td
(imaging)Tj
3.4866 0 Td
(using)Tj
2.3868 0 Td
(slit-lamp)Tj
3.7587 0 Td
(and)Tj
-35.138 -1.2982 Td
(stereo)Tj
2.6021 0 Td
(microscopes)Tj
5.2044 0 Td
([)Tj
0.83 0.64 0.02 0 k
(12)Tj
0 g
(].)Tj
2.075 0 Td
(Different)Tj
3.8664 0 Td
(viral)Tj
1.9899 0 Td
(and)Tj
1.7348 0 Td
(non-viral)Tj
3.9458 0 Td
(vectors)Tj
3.0614 0 Td
(have)Tj
2.0579 0 Td
(been)Tj
2.1203 0 Td
(used)Tj
2.0636 0 Td
(to)Tj
1.0205 0 Td
(deliver)Tj
2.9367 0 Td
(thera-)Tj
-34.6788 -1.2983 Td
(peutic)Tj
2.6758 0 Td
(genes)Tj
2.4435 0 Td
(into)Tj
1.8368 0 Td
(the)Tj
1.474 0 Td
(cornea)Tj
/F12 1 Tf
2.9254 0 Td
[()12()]TJ
1.0148 0 Td
[()-13()15()3()]TJ
/F8 1 Tf
1.8198 0 Td
([)Tj
0.83 0.64 0.02 0 k
(6)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(10)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(13)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(15)Tj
0 g
(].)Tj
5.7146 0 Td
(Adeno-associated)Tj
7.302 0 Td
(virus)Tj
2.1997 0 Td
(\(AAV\))Tj
2.965 0 Td
(is)Tj
0.8447 0 Td
(a)Tj
0.6577 0 Td
(small,)Tj
-33.8738 -1.3039 Td
(nonpathogenic,)Tj
6.4629 0 Td
(single-stranded)Tj
6.3722 0 Td
(DNA)Tj
2.3755 0 Td
(virus)Tj
2.2053 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(parvovirus)Tj
4.4844 0 Td
(family)Tj
2.7326 0 Td
(that)Tj
1.7745 0 Td
(is)Tj
0.8504 0 Td
(a)Tj
0.6519 0 Td
(highly)Tj
2.7099 0 Td
(efficient)Tj
-33.1027 -1.2983 Td
(vector)Tj
2.6985 0 Td
(for)Tj
1.3833 0 Td
(gene)Tj
2.0806 0 Td
(therapy)Tj
3.2485 0 Td
(applications)Tj
5.04 0 Td
([)Tj
0.83 0.64 0.02 0 k
(16)Tj
0 g
(].)Tj
2.0806 0 Td
(We)Tj
1.6044 0 Td
(have)Tj
2.0636 0 Td
(successfully)Tj
4.8642 0 Td
(used)Tj
2.058 0 Td
(multiple)Tj
3.5659 0 Td
(AAV)Tj
2.2847 0 Td
(serotypes)Tj
-32.9723 -1.2982 Td
(for)Tj
1.3832 0 Td
(the)Tj
1.4741 0 Td
(efficient)Tj
3.4469 0 Td
(and)Tj
1.7291 0 Td
(safe)Tj
1.7234 0 Td
(delivery)Tj
3.3903 0 Td
(of)Tj
1.0148 0 Td
(therapeutic)Tj
4.7338 0 Td
(genes)Tj
2.4434 0 Td
(into)Tj
1.8369 0 Td
(rodent,)Tj
3.1237 0 Td
(rabbit,)Tj
2.829 0 Td
(canine,)Tj
3.0897 0 Td
(equine,)Tj
3.1465 0 Td
(and)Tj
-35.3648 -1.2983 Td
(human)Tj
3.0784 0 Td
(cornea)Tj
2.9253 0 Td
([)Tj
0.83 0.64 0.02 0 k
(13)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(17)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(19)Tj
0 g
(].)Tj
-4.8075 -1.3039 Td
(Multiple)Tj
3.6396 0 Td
(growth)Tj
3.0784 0 Td
(factors)Tj
2.9027 0 Td
(and)Tj
1.7291 0 Td
(cytokines,)Tj
4.2236 0 Td
(including)Tj
4.0422 0 Td
(transforming)Tj
5.4992 0 Td
(growth)Tj
3.0727 0 Td
(factor)Tj
/F13 1 Tf
2.5455 0 Td
()Tj
/F8 1 Tf
0.703 0 Td
(\(TGF)Tj
/F13 1 Tf
()Tj
/F8 1 Tf
(\),)Tj
-32.6322 -1.2983 Td
(released)Tj
3.4298 0 Td
(from)Tj
2.2054 0 Td
(corneal)Tj
3.1748 0 Td
(epithelium)Tj
4.5354 0 Td
(post)Tj
1.9048 0 Td
(injury)Tj
2.6476 0 Td
(play)Tj
1.8708 0 Td
(a)Tj
0.6577 0 Td
(critical)Tj
2.948 0 Td
(role)Tj
1.7688 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(induction)Tj
4.1329 0 Td
(of)Tj
1.0148 0 Td
(corneal)Tj
-32.7966 -1.2983 Td
(fibrosis)Tj
3.1464 0 Td
(by)Tj
1.1849 0 Td
(promoting)Tj
4.5184 0 Td
(myofibroblast)Tj
5.7883 0 Td
(formation)Tj
4.2632 0 Td
(as)Tj
1.0148 0 Td
(well)Tj
1.8199 0 Td
(as)Tj
1.0148 0 Td
(synthesis)Tj
3.8211 0 Td
(of)Tj
1.0147 0 Td
(extracellular)Tj
5.1307 0 Td
(matrix)Tj
-32.7172 -1.3039 Td
(\(ECM\))Tj
3.0217 0 Td
(and)Tj
1.7348 0 Td
(cytoskeletal)Tj
4.8302 0 Td
(proteins)Tj
3.5149 0 Td
([)Tj
0.83 0.64 0.02 0 k
(9)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(14)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
2.4378 0 Td
(20)Tj
0 g
(].)Tj
1.7348 0 Td
(TGF)Tj
/F13 1 Tf
()Tj
/F8 1 Tf
2.5625 0 Td
(signaling)Tj
3.8211 0 Td
(plays)Tj
2.2336 0 Td
(a)Tj
0.652 0 Td
(crucial)Tj
2.914 0 Td
(role)Tj
1.7688 0 Td
(in)Tj
1.0375 0 Td
(transdiffer-)Tj
-32.2637 -1.2982 Td
(entiation)Tj
3.8097 0 Td
(of)Tj
1.0148 0 Td
(keratocytes)Tj
4.7111 0 Td
(into)Tj
1.8425 0 Td
(myofibroblasts,)Tj
6.3723 0 Td
(the)Tj
1.474 0 Td
(abnormal)Tj
4.0875 0 Td
(proliferation)Tj
5.2668 0 Td
(of)Tj
1.0148 0 Td
(which)Tj
2.6475 0 Td
(leads)Tj
2.211 0 Td
(to)Tj
1.0262 0 Td
(aber-)Tj
-35.4782 -1.2983 Td
(rant)Tj
1.8708 0 Td
(collagen)Tj
3.5149 0 Td
(deposition)Tj
4.4447 0 Td
(causing)Tj
3.2485 0 Td
(fibrosis)Tj
3.1465 0 Td
(and)Tj
1.7291 0 Td
(ultimately)Tj
4.2349 0 Td
(loss)Tj
1.6951 0 Td
(of)Tj
1.0148 0 Td
(visual)Tj
2.5115 0 Td
(acuity)Tj
2.6249 0 Td
([)Tj
0.83 0.64 0.02 0 k
(4)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.2642 0 Td
(14)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.3946 0 Td
(21)Tj
0 g
(].)Tj
1.7348 0 Td
(Smad)Tj
-34.4293 -1.3039 Td
(\(Suppressor)Tj
4.9946 0 Td
(of)Tj
1.0148 0 Td
(mothers)Tj
3.5262 0 Td
(against)Tj
3.0274 0 Td
(decapentaplegic\))Tj
6.9335 0 Td
(proteins)Tj
3.515 0 Td
(have)Tj
2.0579 0 Td
(been)Tj
2.126 0 Td
(shown)Tj
2.8459 0 Td
(to)Tj
1.0262 0 Td
(be)Tj
1.1508 0 Td
(specifically)Tj
-32.2183 -1.2983 Td
(activated)Tj
3.7813 0 Td
(by)Tj
1.1792 0 Td
(TGF)Tj
/F13 1 Tf
()Tj
/F8 1 Tf
2.5626 0 Td
(superfamily)Tj
4.9265 0 Td
(members)Tj
3.9458 0 Td
([)Tj
0.83 0.64 0.02 0 k
(22)Tj
0 g
(])Tj
1.8539 0 Td
(and)Tj
1.7291 0 Td
(they)Tj
1.9276 0 Td
(regulate)Tj
3.4072 0 Td
(cell)Tj
1.559 0 Td
(growth,)Tj
3.2995 0 Td
(proliferation,)Tj
-30.1717 -1.2983 Td
(migration,)Tj
4.422 0 Td
(and)Tj
1.7291 0 Td
(differentiation.)Tj
6.2022 0 Td
(Therefore,)Tj
4.3936 0 Td
(Smad)Tj
2.4775 0 Td
(proteins)Tj
3.5149 0 Td
(provide)Tj
3.2882 0 Td
(an)Tj
1.2019 0 Td
(attractive)Tj
3.9231 0 Td
(target)Tj
2.5115 0 Td
(for)Tj
1.389 0 Td
(devel-)Tj
-35.053 -1.2982 Td
(oping)Tj
2.5228 0 Td
(novel)Tj
2.4037 0 Td
(interventional)Tj
5.8564 0 Td
(strategies)Tj
3.9231 0 Td
(for)Tj
1.3833 0 Td
(corneal)Tj
3.1748 0 Td
(scarring)Tj
3.4639 0 Td
([)Tj
0.83 0.64 0.02 0 k
(14)Tj
0 g
(].)Tj
2.0749 0 Td
(Various)Tj
3.3846 0 Td
(Smad)Tj
2.4775 0 Td
(proteins)Tj
3.5092 0 Td
(mediate)Tj
-34.1742 -1.3039 Td
(downstream)Tj
5.193 0 Td
(signaling)Tj
3.8211 0 Td
(cascades)Tj
3.6113 0 Td
(during)Tj
2.9253 0 Td
(corneal)Tj
3.1748 0 Td
(wound)Tj
3.016 0 Td
(repair)Tj
2.6022 0 Td
(processes,)Tj
4.1953 0 Td
(especially)Tj
4.0195 0 Td
(during)Tj
2.9253 0 Td
(the)Tj
-35.4838 -1.2983 Td
(regenerative)Tj
5.125 0 Td
(healing)Tj
3.1294 0 Td
(phase)Tj
2.4831 0 Td
([)Tj
0.83 0.64 0.02 0 k
(23)Tj
0 g
(].)Tj
2.0806 0 Td
(Smad7)Tj
2.948 0 Td
(negatively)Tj
4.2407 0 Td
(regulates)Tj
3.77 0 Td
(TGF)Tj
/F13 1 Tf
()Tj
/F8 1 Tf
2.5568 0 Td
(signaling)Tj
3.8268 0 Td
(by)Tj
1.1792 0 Td
(binding)Tj
3.3505 0 Td
(to)Tj
1.0262 0 Td
(the)Tj
-35.7163 -1.2983 Td
(TGF)Tj
/F13 1 Tf
()Tj
/F8 1 Tf
2.5568 0 Td
(type)Tj
1.9162 0 Td
(1)Tj
0.6973 0 Td
(receptor)Tj
3.5546 0 Td
(through)Tj
3.4469 0 Td
(its)Tj
1.1452 0 Td
(MH2)Tj
2.3528 0 Td
(domain)Tj
3.3278 0 Td
(and)Tj
1.7291 0 Td
(competing)Tj
4.4901 0 Td
(with)Tj
1.9956 0 Td
(R-Smad-Smad4)Tj
6.531 0 Td
(complex)Tj
-33.7434 -1.3039 Td
(for)Tj
1.3832 0 Td
(DNA)Tj
2.3811 0 Td
(binding)Tj
3.3506 0 Td
([)Tj
0.83 0.64 0.02 0 k
(24)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(27)Tj
0 g
(].)Tj
3.5433 0 Td
(Since)Tj
2.3584 0 Td
(Smad7)Tj
2.9536 0 Td
(blocks)Tj
2.761 0 Td
(epithelial)Tj
3.8721 0 Td
(to)Tj
1.0204 0 Td
(mesenchymal)Tj
5.7033 0 Td
(transition)Tj
4.1216 0 Td
(as)Tj
1.0148 0 Td
(well)Tj
1.8198 0 Td
(as)Tj
-36.2832 -1.2982 Td
(transdifferentiation)Tj
7.9879 0 Td
(of)Tj
1.0148 0 Td
(fibroblasts)Tj
4.371 0 Td
(into)Tj
1.8369 0 Td
(myofibroblasts,)Tj
6.3779 0 Td
(we)Tj
1.3266 0 Td
(hypothesized)Tj
5.4708 0 Td
(that)Tj
1.7745 0 Td
(AAV-mediated)Tj
-30.1604 -1.2983 Td
(targeted)Tj
3.4582 0 Td
(delivery)Tj
3.3902 0 Td
(of)Tj
1.0148 0 Td
(Smad7)Tj
2.9537 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(corneal)Tj
3.1748 0 Td
(stroma)Tj
3.0104 0 Td
(could)Tj
2.4491 0 Td
(effectively)Tj
4.2122 0 Td
(treat)Tj
2.0466 0 Td
(corneal)Tj
3.1748 0 Td
(fibrosis.)Tj
3.3732 0 Td
(Here,)Tj
-34.7638 -1.3039 Td
(we)Tj
1.3266 0 Td
(investigated)Tj
4.9889 0 Td
(the)Tj
1.4683 0 Td
(potential)Tj
3.7588 0 Td
(therapeutic)Tj
4.7338 0 Td
(efficacy)Tj
3.2258 0 Td
(and)Tj
1.7291 0 Td
(safety)Tj
2.4775 0 Td
(of)Tj
1.0148 0 Td
(AAV5-Smad7)Tj
5.845 0 Td
(targeted)Tj
3.4582 0 Td
(gene)Tj
-34.0268 -1.2983 Td
(therapy)Tj
3.2484 0 Td
(in)Tj
1.0318 0 Td
(an)Tj
1.2019 0 Td
(established)Tj
4.5978 0 Td
(high)Tj
2.0069 0 Td
(diopter)Tj
3.1351 0 Td
(photorefractive)Tj
6.3326 0 Td
(keratectomy)Tj
5.1703 0 Td
(\(PRK\))Tj
2.7553 0 Td
(induced)Tj
3.4639 0 Td
(corneal)Tj
-32.944 -1.2983 Td
(fibrosis)Tj
3.1464 0 Td
(model)Tj
2.7439 0 Td
(in)Tj
1.0375 0 Td
(rabbits)Tj
/F12 1 Tf
2.965 0 Td
[()12()]TJ
1.0148 0 Td
[()-13()15()3()]TJ
/F8 1 Tf
(.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 209.0267 cm
BT
/F3 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Materials)Tj
4.5071 0 Td
(and)Tj
1.989 0 Td
(methods)Tj
/F0 1 Tf
-6.4961 -1.5023 Td
(Primary)Tj
3.6283 0 Td
(human)Tj
3.2457 0 Td
(corneal)Tj
3.4536 0 Td
(fibroblast)Tj
4.2236 0 Td
(culture)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 173.9905 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Primary)Tj
3.4979 0 Td
(human)Tj
3.0784 0 Td
(corneal)Tj
3.1691 0 Td
(fibroblast)Tj
4.0082 0 Td
(\(HCF\))Tj
2.8573 0 Td
(cultures)Tj
3.4015 0 Td
(were)Tj
2.1203 0 Td
(established)Tj
4.5978 0 Td
(from)Tj
2.2053 0 Td
(donated)Tj
3.4866 0 Td
(human)Tj
3.0784 0 Td
(cor-)Tj
-35.5008 -1.2982 Td
(neas)Tj
1.9785 0 Td
(procured)Tj
3.8778 0 Td
(from)Tj
2.194 0 Td
(an)Tj
1.1962 0 Td
(eye)Tj
1.508 0 Td
(bank)Tj
2.1997 0 Td
(\(Saving)Tj
3.1918 0 Td
(Sight,)Tj
2.4718 0 Td
(Kansas)Tj
3.0217 0 Td
(City,)Tj
2.1203 0 Td
(MO,)Tj
2.0749 0 Td
(USA\).)Tj
2.6703 0 Td
(Briefly,)Tj
3.067 0 Td
(human)Tj
3.0671 0 Td
(corneal)Tj
-34.6391 -1.2983 Td
(tissues)Tj
2.8176 0 Td
(were)Tj
2.1203 0 Td
(washed)Tj
3.1804 0 Td
(twice)Tj
2.3187 0 Td
(with)Tj
1.9956 0 Td
(serum)Tj
2.7213 0 Td
(free)Tj
1.7291 0 Td
(sterile)Tj
2.6079 0 Td
(minimum)Tj
4.2916 0 Td
(essential)Tj
3.5829 0 Td
(medium)Tj
3.6057 0 Td
(\(MEM\))Tj
3.2541 0 Td
(culture)Tj
-34.2252 -1.3039 Td
(medium)Tj
3.6056 0 Td
(\(Thermo)Tj
3.8211 0 Td
(Fischer)Tj
3.1181 0 Td
(Scientific,)Tj
4.1272 0 Td
(Grand)Tj
2.8176 0 Td
(Island,)Tj
2.9027 0 Td
(NY,)Tj
1.8141 0 Td
(USA\),)Tj
2.6816 0 Td
(epithelial)Tj
3.8721 0 Td
(and)Tj
1.7291 0 Td
(endothelial)Tj
4.6715 0 Td
(layers)Tj
-35.1607 -1.2983 Td
(were)Tj
2.1203 0 Td
(gently)Tj
2.6588 0 Td
(removed)Tj
3.7474 0 Td
(with)Tj
1.9956 0 Td
(surgical)Tj
3.3165 0 Td
(blade)Tj
2.3584 0 Td
(and)Tj
1.7291 0 Td
(remaining)Tj
4.3654 0 Td
(tissue)Tj
2.4604 0 Td
(was)Tj
1.6951 0 Td
(sub-sectioned)Tj
5.7487 0 Td
(for)Tj
1.3889 0 Td
(explant)Tj
-33.5846 -1.2982 Td
(culture.)Tj
3.2598 0 Td
(The)Tj
1.7858 0 Td
(convex)Tj
3.0444 0 Td
(surface)Tj
3.0444 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.474 0 Td
(stromal)Tj
3.2541 0 Td
(sections)Tj
3.4129 0 Td
(was)Tj
1.6951 0 Td
(placed)Tj
2.795 0 Td
(face)Tj
1.7858 0 Td
(down)Tj
2.4888 0 Td
(onto)Tj
2.0806 0 Td
(a)Tj
0.652 0 Td
(10)Tj
1.1735 0 Td
(cm)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 542.0409 113.4425 cm
BT
/F8 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(2)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 547.8236 109.0204 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(tissue)Tj
-34.7808 -1.3039 Td
(culture)Tj
3.0387 0 Td
(dish)Tj
1.8992 0 Td
(and)Tj
1.7348 0 Td
(incubated)Tj
4.1782 0 Td
(in)Tj
1.0318 0 Td
(a)Tj
0.6577 0 Td
(humidified)Tj
4.6601 0 Td
(5%)Tj
1.4513 0 Td
(CO)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 400.6488 94.337 cm
BT
/F8 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(2)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 406.4314 95.9811 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(incubator)Tj
4.1045 0 Td
(at)Tj
0.9524 0 Td
(37C.)Tj
2.4491 0 Td
(The)Tj
1.7859 0 Td
(explants)Tj
3.5092 0 Td
(were)Tj
2.126 0 Td
(cul-)Tj
-35.5688 -1.2982 Td
(tured)Tj
2.3697 0 Td
(in)Tj
1.0318 0 Td
(MEM)Tj
2.5739 0 Td
(supplemented)Tj
5.8563 0 Td
(with)Tj
1.9956 0 Td
(10%)Tj
1.9332 0 Td
(fetal)Tj
1.9049 0 Td
(bovine)Tj
2.931 0 Td
(serum)Tj
2.7211 0 Td
(for)Tj
1.389 0 Td
(approximately)Tj
5.9754 0 Td
(20+)Tj
1.7518 0 Td
(days)Tj
1.9956 0 Td
(by)Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 107.1496 23.6976 re
W* n
q
107.0929 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 420.548 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Smad7)Tj
3.3378 0 Td
(gene)Tj
2.4024 0 Td
(therapy)Tj
3.4937 0 Td
(inhibits)Tj
3.2669 0 Td
(corneal)Tj
3.4371 0 Td
(scarring)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
0.83 0.64 0.02 0 k
81.5811 34.9228 m
237.8835 34.9228 l
h
f*
0 g
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(ONE)Tj
2.3669 0 Td
(|)Tj
0.83 0.64 0.02 0 k
0.4748 0 Td
(https://doi.or)Tj
5.4142 0 Td
(g/10.137)Tj
3.8198 0 Td
(1/journal.po)Tj
5.1236 0 Td
(ne.01729)Tj
4.089 0 Td
(28)Tj
0 g
2.0906 0 Td
(March)Tj
2.9622 0 Td
(24,)Tj
1.5874 0 Td
(2017)Tj
34.3562 0 Td
(2)Tj
0.7654 0 Td
(/)Tj
0.496 0 Td
(18)Tj
/F9 1 Tf
-0.025 Tc
-66.402 84.0904 Td
(Competing)Tj
4.3795 0 Td
(interests)Tj
3.3307 0 Td
(:)Tj
/F10 1 Tf
0.4819 0 Td
(Author)Tj
2.5016 0 Td
(s)Tj
0.6449 0 Td
(have)Tj
1.9559 0 Td
(no)Tj
1.1693 0 Td
(financial)Tj
3.267 0 Td
(or)Tj
-17.7308 -1.3748 Td
(proprietary)Tj
4.2732 0 Td
(interest)Tj
2.9693 0 Td
(in)Tj
0.8859 0 Td
(the)Tj
1.3748 0 Td
(material)Tj
2.9622 0 Td
(s)Tj
0.6449 0 Td
(presented)Tj
ET
endstream
endobj
46 0 obj
<>stream
endstream
endobj
47 0 obj
<>stream
endstream
endobj
48 0 obj
<>stream
endstream
endobj
49 0 obj
<>stream
endstream
endobj
50 0 obj
<>stream
endstream
endobj
51 0 obj
<>stream
endstream
endobj
52 0 obj
<>stream
endstream
endobj
53 0 obj
<>stream
endstream
endobj
54 0 obj
<>stream
endstream
endobj
55 0 obj
<>stream
endstream
endobj
56 0 obj
<>stream
endstream
endobj
57 0 obj
<>stream
endstream
endobj
58 0 obj
<>stream
endstream
endobj
59 0 obj
<>stream
endstream
endobj
60 0 obj
<>stream
endstream
endobj
61 0 obj
<>stream
endstream
endobj
62 0 obj
<>stream
endstream
endobj
63 0 obj
<>stream
endstream
endobj
64 0 obj
<>stream
endstream
endobj
65 0 obj
<>stream
endstream
endobj
66 0 obj
<>stream
endstream
endobj
67 0 obj
<>stream
endstream
endobj
68 0 obj
<>stream
BT
0 81.3407 Td
(herein.)Tj
ET
Q
endstream
endobj
69 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 13 0 R/Annots 72 0 R/Contents 73 0 R/TrimBox[0 0 612 792]>>
endobj
71 0 obj
<>
endobj
74 0 obj
<>stream
/CIDInit/ProcSet findresource begin
12 dict begin begincmap
/CMapName/Adobe-Identity-UCS def
/CIDSystemInfo<>def
/CMapType 2 def
1 begincodespacerange
<0000>
endcodespacerange
1 beginbfchar
<010C><03B2>
endbfchar
endcmap
CMapName currentdict /CMap defineresource pop end end
endstream
endobj
75 0 obj
<>/FontDescriptor 76 0 R/DW 250/W[268[495]]>>
endobj
76 0 obj
<>
endobj
77 0 obj
<>stream
cvt 0Y "fpgm2Msf bglyfX headZ8U 6hhea $hmtx
loca e
maxpx prep
y_<