Ci a ion: Machado, M.V. New
De elopmen s in Celiac Disease
T ea men . In . J. Mol. Sci. 2023,24,
945. h ps://doi.o g/10.3390/
ijms24020945
Academic Edi o : Dona ella Ba isani
Recei ed: 30 No embe 2022
Re ised: 18 Decembe 2022
Accep ed: 1 Janua y 2023
Published: 4 Janua y 2023
Copy igh : © 2023 by he au ho .
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
dis ibu ed unde he e ms and
condi ions o he C ea i e Commons
A ibu ion (CC BY) license (h ps://
c ea i ecommons.o g/licenses/by/
4.0/).
In e na ional Jou nal o
Molecula Sciences
Re iew
New De elopmen s in Celiac Disease T ea men
Ma iana Ve delho Machado 1,2
1Gas oen e ology Depa men , Hospi al de Vila F anca de Xi a, Es ada Ca los Lima Cos a, Nª 2,
2600-009 Vila F anca de Xi a, Po ugal; [email p o ec ed]; Tel.: +351-263-006-500
2Clínica Uni e si á ia de Gas en e ologia, Faculdade de Medicina, Uni e sidade de Lisboa,
A enida P o . Egas Moniz, 1649-028 Lisbon, Po ugal
Abs ac :
Celiac disease (CD) is a common au oimmune disease a ec ing a ound 1% o he popula ion.
I consis s o an immune-media ed en e opa hy, igge ed by glu en exposu e in suscep ible pa ien s.
All pa ien s wi h CD, i espec i e o he p esence o symp oms, mus endu e a li elong glu en- ee
die (GFD). This is no an easy ask due o a lack o awa eness o he glu en con en in oods and
he ex ensi e inco po a ion o glu en in p ocessed oods. Fu he mo e, a GFD imposes a sense o
limi a ion and migh be associa ed wi h dec eased quali y o li e in CD pa ien s. This esul s in glu en
con amina ion in he die o ou ou o i e celiac pa ien s adhe ing o a GFD. Fu he mo e, one in
h ee adul pa ien s will epo pe sis en symp oms and wo in h ee will no achie e ull his ological
eco e y when on a GFD. In ecen yea s, he e has been ex ensi e esea ch conduc ed in he ques o
ind he holy g ail o pha macological ea men o CD. This e iew will p esen a concise desc ip ion
o he cu en a ionale and main clinical ials ela ed o CD d ug he apy.
Keywo ds: celiac disease; glu en- ee die ; pha macological ea men s
1. In oduc ion
Celiac disease (CD) is an au oimmune disease in which, in suscep ible subjec s, he
inges ion o glu en igge s an immune a ack on he small bowel, as well as a se ological
esponse [
1
]. Unlike o he au oimmune diseases, he immunogenic an igens ha igge
he immune esponse in CD ha e al eady been iden i ied and highly cha ac e ized [
2
]. As
such, emo ing hose an igens by endu ing a glu en- ee die (GFD) is a known e ec i e
ea men o CD.
The p e alence o CD is es ima ed o be 1% o he popula ion [
3
]. Conside ing a
global popula ion o eigh billion people, he e a e oughly eigh y million pa ien s wi h
CD. The classical p esen a ion o CD is malabso p ion mani es a ions such as dia hea,
weigh loss, and nu i ion de ici s, al hough mos pa ien s will emain asymp oma ic o
wi h non-speci ic and ex ain es inal symp oms [
4
]. E en hough no consis en among
all coho s [
5
], pa ien s wi h CD seem o p esen inc eased mo ali y [
6
,
7
], which migh be
mi iga ed by achie ing mucosal healing h ough a GFD [8,9].
In he las decade, in ense e o s ha e been applied in he sea ch o pha macolog-
ical ea men s o CD. The ba is high as die a y ea men is al eady a ailable, which
is e ec i e and has no p edic able ad e se e ec s. Howe e , adhe ing o a s ic GFD
is challenging, esul ing in sel - epo ed adhe ence a es anging om 42% o 91% [
10
].
Fu he mo e, up o 80% o GFD-adhe en pa ien s migh ha e inad e en glu en con ami-
na ion in hei die [
11
]. Las ly, mucosal healing a e a GFD seems o occu in less han hal
o adul s wi h CD [
12
]. Up o 0.5% o pa ien s wi h CD will p og ess o e ac o y celiac
disease (RCD) [
13
], which when associa ed wi h abe an monoclonal T cell in il a ion
(RCD ype 2) p esen s a high isk o p og ession o en e opa hy-associa ed T cell lymphoma
(EATL) [14].
D ug disco e y o ea ing CD, as a complemen o a GFD, aims o in e ene in
di e en scena ios, including (a) main enance he apy, (b) escue he apy a e acu e glu en
exposu e, and (c) he mi iga ion o inad e en ch onic glu en exposu e [15].
In . J. Mol. Sci. 2023,24, 945. h ps://doi.o g/10.3390/ijms24020945 h ps://www.mdpi.com/jou nal/ijms
In . J. Mol. Sci. 2023,24, 945 2 o 17
This e iew will summa ize he a ionale ha has been applied o CD d ug de elop-
men , as well as he clinical ad ances in i s esea ch.
2. Glu en-F ee Die : The Cu en S anda d o Ca e
Sensum s ic um, glu en e e s o p o eins p esen in whea ha con ain wo majo
p o ein componen s: monome ic wa e -soluble gliadins and mul ime ic wa e -insoluble
glu enins. The p o eins secalin, in ye, and ho dein, in ba ley, sha e simila immunogenic
p ope ies and ha e also been called glu en in sensum la um [
16
]. Oa s a e phylogene ically
mo e dis an and a e usually ole a ed by CD pa ien s [17].
Pa ien s wi h CD independen o he p esence o symp oms, symp oma ic po en ial
CD ( ha is pa ien s wi h posi i e an i- ansglu aminase an ibody and no mal duodenal
his ology), de ma i is he pe i o mis, and glu en a axia should ollow a li elong GFD, since
a GFD is cu en ly he only p o en ea men o CD [
18
]. Rega ding pa ien s wi h asymp-
oma ic po en ial CD, only a mino i y will de elop illous a ophy and should be ollowed
a he han be ecommended a GFD [19].
CD is associa ed wi h a panoply o ex ain es inal mani es a ions and au oimmune
diseases, such as neu opsychia ic [
20
–
22
] and de ma ological mani es a ions [
23
], unex-
plained abno mal li e enzymes [
24
], ype 1 diabe es melli us, and au oimmune hy oid
diso de s [
25
]. Adhe ence o a GFD may imp o e mos o hose mani es a ions. Rega ding
neu opsychia ic mani es a ions, i is known o imp o e headache [
26
] and glu en a axia as
long as he e is no i e e sible loss o Pu kinje cells in he ce ebellum [
27
]. A GFD may also
imp o e esponse o d ug- esis an epilepsy [
28
], glu en-induced cogni i e impai men [
29
],
psychia ic diso de s (pa icula ly anxie y) [
26
], and a igue in up o 50% he pa ien s [
30
],
while esponse o pe iphe al neu opa hy is a iable wi h lowe esponse a es in pa ien s
p esen ing an i-neu onal an ibodies [
31
]. De ma i is he pe i o mis ypically esponds o
a GFD [
32
]. Pso iasis [
33
], ch onic u ica ia [
34
], and ecu en aph hous s oma i is may
also imp o e in pa ien s wi h CD, while den al enamel de ec s a e i e e sible [
35
]. Fu -
he mo e, a GFD may imp o e me abolic con ol in CD pa ien s wi h ype 1 diabe es
melli us [
33
], bone densi y [
36
], mens ual dis u bances and e ili y [
37
], and unexplained
ansamini is [38].
A GFD will only be e ec i e i he pa ien complies. In mos cases, less han 50% o CD
pa ien s achie e long- e m adhe ence o a GFD [
10
]. Indeed, die a y egimens a e he leas
appealing medical s a egies, being one o he ea men egimens wi h he lowes a e o
adhe ence (as opposed o medica ions ha ha e he highes adhe ence a e) [
39
]. A GFD is
pa icula ly di icul o ollow due o he omnip esence o glu en in p ocessed oods, e en
in unlikely oods (such as yogu and ozen ish) and p oduc s (such as oo hpas e and
lips ick). Glu en is he La in wo d o “glue”, and i s iscoelas ic p ope ies make i highly
appealing o he ood indus y. The emo al o glu en changes he physical p ope ies and
du abili y o oods. To compensa e o glu en emo al, he ood indus y ends o deli e
unheal hily high a and suga con en [
40
] and dec ease heal hy supplemen a ion, such as
he addi ion o ibe , i on, ola e, and zinc [
15
]. Glu en- ee p oduc s a e mo e expensi e
han hei glu en-con aining coun e pa s, e en hough he ecen popula i y, and hence
widesp ead a ailabili y, o glu en- ee p oduc s has ansla ed in o a dec ease in p ice [
41
].
Dining ou may be challenging as i is di icul o con ol o glu en con amina ion, which
may subsequen ly lead o social isola ion, anxie y, and impai ed quali y o li e [42].
Ano he ba ie o a GFD is inad e en glu en con amina ion. E en li elong GFD-
adhe en pa ien s s uggle o co ec ly asce ain glu en con en om comme cial p oduc
labels [
43
]. Indeed, 70–80% o pa ien s adhe en o a GFD p esen glu en con amina ion in
hei die [
11
,
12
,
44
], wi h an a e age glu en exposu e o a ound 150 mg/day [
45
], which is
much highe han he conside ed sa e amoun o up o 10 mg/day [
46
] and highe han
he 50 mg/day cu o (equi alen o 1% o a slice o b ead) ha is known o be able o
induce mucosal a ophy [
47
]. O no e, he glu en con en o a ypical Wes e n die is a ound
15–20 g/day [48].
In . J. Mol. Sci. 2023,24, 945 3 o 17
Finally, up o 30% o pa ien s epo pe sis en symp oms [
49
], and one o wo- hi ds
o adul s will no achie e his ological eco e y a e one yea on a s ic GFD [
50
]. O no e,
moni o ing o an i-ac in IgA an ibodies may help o p edic GFD-induced esolu ion o
in es inal mucosa damage [51].
3. Pa hophysiology-D i en S a egies o T ea Celiac Disease
3.1. Non-Immunogenic Glu en Deli e y
Glu en p o eins a e ich in p oline (15% o amino acid composi ion) and glu amine
(35% o amino acid composi ion), which con e s high esis ance o he ac ion o human
p o eases in he in es inal lumen [
16
] and esul s in he p oduc ion o pep ides up o
30–40 amino
acids in leng h ha a e highly immunogenic [
52
]. One s a egy o he ea -
men o CD, besides emo ing glu en om he die , would be o p esen non-immunogenic
a ian s o glu en. Di e en na u al whea a ian s p esen di e en T cell immunogenic-
i y [
53
]. Howe e , all a ian s, e en ancien ones, seem o p esen oxic po en ial [
54
,
55
].
Ano he s a egy would be o gene ically enginee non-immunogenic whea . This is no
an easy ask as a ound 100 genes encode glu en, and hence silencing one gene would no
be enough. Addi ionally, silencing genes esponsible o glu en immunogenici y migh
hampe i s iscoelas ic p ope ies [
56
]. One example is he E82 whea line p oduced by
RNAi echnology ha blocks ele an gliadin genes [
57
]. A pilo s udy wi h 21 CD pa ien s
ea ing E82 whea did show dec eased in e e on-
γ
(INF-
γ
) p oduc ion in pe iphe al blood
mononuclea cells and a e y low le el o glu en immunogenic pep ides (GIP) in s ool
samples om hose pa ien s, sugges ing low exposu e o immunogenic epi opes [58].
3.2. Blocking Immunogenic Glu en Exposu e
In o de o induce an immune esponse, glu en needs o o e come he in es inal ep-
i helial ba ie and each he lamina p op ia, whe e i will be p esen ed o he immune
sys em by an igen-p esen ing cells (APCs). Th ee s a egies ha e been p oposed o neu al-
ize glu en a e die a y exposu e: (a) diges ing glu en h ough he deli e y o exogenous
pep idases, (b) seques e ing glu en in he in es inal lumen, and (c) dec easing epi helial
pe meabili y. These s a egies in end o mi iga e immune esponses o ch onic inad e en
low le els o glu en exposu e as an adjunc i e o a GFD (Table 1).
Table 1. Rele an clinical ials on agen s ha block immunogenic glu en exposu e.
Agen S udy T ial Phase Popula ion T ea men Du a ion Main Resul s ( s. Placebo)
Endopep idases
La iglu enase
Tye-Din,
2010 [59]1
20 CD pa ien s
on a glu en
challenge
(16 g/day)
800 mg/day s.
placebo 3 days
• ↓ INF-γsec e ion by
glu en-speci ic T cells in
pe iphe al blood
Lahdeaho,
2014 [60]2a
41 CD pa ien s
on a glu en
challenge
(2 g/day)
900 mg/day s.
placebo 6 weeks
•P e en ed mucosal
de e io a ion (no ↓
Vh:Cd o ↑IEL)
•No imp o emen in
symp oms
Mu ay,
2017 [61];
Syage, 2017
[62]
2b
494 CD pa ien s
wi h mode a e
o se e e
symp oms on a
GFD ≥1 yea
100 mg, 300 mg,
450 mg, 600 mg,
o 900 mg/day
s. placebo
12 o 24
weeks
•No 6=in Vh:Cd o ↑IEL
•No 6=in se ology
•Imp o emen in he
symp oms o se oposi i e
pa ien s wi h ≥600
mg/day
In . J. Mol. Sci. 2023,24, 945 4 o 17
Table 1. Con .
Agen S udy T ial Phase Popula ion T ea men Du a ion Main Resul s ( s. Placebo)
Mu ay,
2022 [63]2b
43 CD pa ien s
on a glu en
challenge
(2 g/day)
1200 mg/day
s. placebo 6 weeks
•P e en ed mucosal
de e io a ion (lowe ↓
Vh:Cd)
•Tendency o dec ease
symp oms
NCT
04243551 2b
120
symp oma ic
CD pa ien s
unde going
pe iodic glu en
exposu e
s. placebo 6 weeks
Ongoing
Es ima ed comple ion May
2023
AN-PEP
Tack, 2013
[64]2
14 CD pa ien s
on a glu en
challenge
(7 g/day)
Topping wi h
ei he AN-PEP
o placebo
2 weeks
•No 6=in Vh:Cd o ↑IEL
•No 6=in e ms o quali y
o li e
NCT
04788797 4
14 CD pa ien s
on a daily
glu en
challenge
2 capsules/day
s. placebo 8 weeks Ongoing
Comple ion Decembe 2022
TAK-062 Pul z, 2021
[65]1
CD in GFD and
heal hy subjec s
a e a glu en
meal (3–9 g)
100–900 mg 6 weeks •Well ole a ed
Glu en seques a ion
AGY
Sample,
2017 [66]110 CD pa ien s
on a GFD 1000 mg bid 4 weeks • ↓ symp oms
• ↓ se ology
• ↓ LMER
NCT
03707730 2
Symp oma ic
CD pa ien s on
a GFD
Be o e meals s.
placebo
14
weeks
Ongoing
Comple ion Decembe 2022
BL-7010 NCT
01990885 1
40
asymp oma ic
CD pa ien s
Dose- inding Single
dose
Comple ed in 2014
No da a published so a
Tigh junc ion modula ion
La azo ide
ace a e
Pa e son,
2007 [67]1
21 CD pa ien s
on a 1-day
glu en
challenge (2.5 g)
12 mg s.
placebo 3 days
• ↓ INF-γsec e ion
• ↓ symp oms
•No 6=in LMAR
Le le , 2012
[68]2a
86 CD pa ien s
±glu en
challenge
(2.4 g/day)
0.25 mg, 1 mg, 4
mg, o 8
mg/day s.
placebo
14 days • ↓ symp oms
•No 6=in LMAR
Kelly, 2013
[69]2b
177 CD pa ien s
on a glu en
challenge
(2.7 g/day)
1 mg, 4 mg, o 8
mg/day s.
placebo
6 weeks • ↓ symp oms
• ↓ se ology
•No 6=in LMER
Rega ding he i s s a egy, human p o eases a e ine ec i e a deg ading p oline-
and glu amine- ich glu en p o eins. As such, glu en deg ada ion could be achie ed by he
adminis a ion o exogenous endopep idases ha would diges , in he s omach, he glu en
p o eins in o small non-immunogenic pep ides be o e hey each he duodenum. Those
In . J. Mol. Sci. 2023,24, 945 5 o 17
endopep idases mus ul ill se e al equisi es: (a) be able o deg ade all di e en glu en
immunogenic sequences, (b) be s able and ac i e in he low pH gas ic en i onmen and
escape gas ic p o ease deg ada ion, and (c) no induce ad e se e ec s in he pa ien [
71
].
Se e al mic oo ganisms exp ess p olyl endopep idases ha ha e been shown
in i o
and
in i o
o be able o deg ade glu en p o eins [
72
], such as Aspe gillus nige ,Fla obac e ium
meningosep icum,Myxococcus xan hus, and Sphingomonas capsula e [
71
]. Simila ly, glu amine-
speci ic endop o eases can ha e a complemen a y ac ion on glu en deg ada ion. One
such example is EP-B2, a cys eine endop o ease exp essed in ge mina ing ba ley (Ho deum
ulga e) seeds [73].
The mos s udied endop o ease d ug o CD is la iglu enase, o mally dubbed ALV003.
La iglu enase is an o ally adminis e ed mix u e o wo glu en p o eases: ALV001 (a mod-
i ied ecombinan e sion o glu amine endopep idase EP-B2) and ALV002 (a modi ied
ecombinan e sion o p olyl endopep idase om S. capsula a). These pep idases ha e
complemen a y pep idase ac i i y in e ms o subs a e sequence and leng h [
72
]. In
2010, a placebo-con olled pilo s udy o o al la iglu enase adminis e ed wi h la ge glu en
meals (16 g/day) o e 3 days in 20 CD pa ien s ab oga ed glu en immune esponses, wi h
dec eased INF-
γ
sec e ion by glu en-speci ic T cells in pe iphe al blood om hose pa-
ien s [
59
]. A phase 2a dose- anging ial adminis e ed di e en doses o la iglu enase ( om
100mg o 900mg/day, o 12 o 24 weeks) o 494 CD pa ien s p esen ing pe sis en mode a e
o se e e symp oms despi e being on a s ic GFD o a leas one yea . Globally, la iglu e-
nase, compa ed o placebo, did no imp o e symp oms o his ology, i.e., in aepi helial
lymphocy osis (IEL) o illous heigh o c yp dep h a io (Vh:Cd) [
61
]. Howe e , in he
subg oup o se oposi i e pa ien s, he highes dose o la iglu enase (900 mg) was associa ed
wi h an imp o emen in abdominal pain and bloa ing when compa ed o placebo [
62
],
sugges ing a bene i o pa ien s wi h glu en con amina ion in hei die . Subsequen ly,
wo phase 2 andomized con olled ials (RCT) in 41 and 43 pa ien s wi h CD subjec ed
o a 2 g/day glu en challenge o 6 weeks showed ha he adminis a ion o high doses
o la iglu enase (a leas 900 mg) was able o p e en mucosal de e io a ion (ab oga ed
Vh:Cd dec ease and IEL in il a ion) and imp o e symp oms (a 1200 mg/day) [
60
,
63
]. An
ongoing phase 2 RCT (NCT 04243551) in pa ien s wi h CD subjec ed o pe iodic glu en
exposu e o 6 mon hs is es ima ed o be comple ed in May 2023.
Ano he p olyl endopep idase ha is de i ed om Aspe gillus nige , AN-PEP, also
showed
in i o
glu en-deg ading ac i i y [
74
,
75
]. Two pilo s udies in ol ing 12 heal hy
subjec s and 19 glu en-sensi i e pa ien s showed AN-PEP o be capable o achie ing signi -
ican gas ic deg ada ion o glu en [
76
,
77
]. A sho phase 2 RCT in ol ing 12 CD pa ien s
subjec ed o a 7 g/day glu en challenge ailed o demons a e symp oma ic ad an ages o e
placebo. Howe e , i should be no ed ha e en he g oup on placebo did no ha e wo s-
ened symp oms due he glu en challenge [
64
]. An ongoing phase 4 RCT (NCT 04788797) in
pa ien s wi h CD on a s ic GFD was es ima ed o be comple ed in Decembe 2022.
Mo e ecen ly, TAK-62, a glu enase e ec i e
in i o
[
78
], was shown o be well ole -
a ed and capable o deg ading 97% o glu en in gas ic aspi a es om CD pa ien s a e a
glu en challenge [65].
The second s a egy is o seques e and neu alize glu en p o eins in he in es inal
lumen, p e en ing i s diges ion in immunogenic glu en pep ides. Two main he apies ha e
been s udied: AGY, an o al egg yolk an i-gliadin polyclonal an ibody [
66
], and BL-7010,
a non-abso bable high molecula weigh copolyme o hyd oxye hyl me hac yla e and
s y ene sul ona e—P(HEMA-co-SS) [79].
AGY was shown o neu alize glu en p o eins in mouse models [
80
] and dec ease
symp oms, se ology, and in es inal pe meabili y (assessed wi h lac ulose:manni ol exc e ion
a io, LMER) in a phase 1 open-label single-a m ial in ol ing 10 CD pa ien s on a GFD [
66
].
An ongoing phase 2 RCT on AGY in symp oma ic CD pa ien s on a GFD (NCT 03707730)
was es ima ed o be comple ed in Decembe 2022.
BL-7010 was shown o bind wi h high a ini y o gliadin
in i o
[
79
], o ab oga e
glu en-induced in es inal inju y
in i o
in oden models [
79
,
81
], and o dec ease umo

In . J. Mol. Sci. 2023,24, 945 6 o 17
nec osis ac o -
α
(TNF-
α
) sec e ion ex i o in mucosal biopsies om CD pa ien s in he
p esence o pa ially diges ed gliadin [
81
]. A phase 1 RCT in CD pa ien s was comple ed in
2014, howe e no da a ha e been published so a (NCT 01990885).
Las ly, in es inal pe meabili y o glu en has been add essed h ough modula ion o
igh junc ions. La azo ide ace a e, o me ly dubbed AT1001, is a syn he ic oc apep ide
s uc u ally ela ed o he zonula occludens oxin (ZOT) p oduced by he bac e ium Vib-
io chole a [
82
]. La azo ide imp o es in es inal ba ie unc ion by ac ing as an inhibi o
o zonulin by blocking i s ecep o [
83
,
84
]. Glu en induces zonulin sec e ion a e bind-
ing o ecep o CXCR3 in en e ocy es. Zonulin will hen bind o he ecep o complex
epide mal g ow h ac o ecep o (EGFR) and p o ease-ac i a ed ecep o -2 (PAR2) in en e-
ocy es, ini ia ing a signaling pa hway ha is Myd88-dependen and which leads o he
polyme iza ion o ac in mic o ilamen s and subsequen igh junc ion disassembly, hence
inc easing in es inal pe meabili y [
85
]. A phase 1 double-blind RCT compa ed la azo ide
a a dosage o 12mg o placebo adminis e ed o e 3 days in 21 pa ien s wi h CD who we e
subjec ed o one day o a 2.5 g glu en challenge. La azo ide was associa ed wi h ewe
symp oms and INF-
γ
immune esponse, e en hough i ailed o demons a e imp o e-
men s in in es inal pe meabili y (assessed by LMER) [
67
]. Subsequen ly, h ee sho - e m
(14 days [
84
], 6 weeks [
69
], and 12 weeks [
70
]) phase 2 RCTs and one me a-analysis [
82
]
en olling
626 CD pa ien s
, ea ed wi h la azo ide doses ha anged om 1mg o 8mg h ee
imes pe day, showed imp o emen s in symp oms a e a glu en challenge, bu no in
pa ien s on a s ic GFD. While no da a on his ology we e desc ibed, hose ials did no
demons a e an imp o emen in e ms o LMER, which migh be explained by LMER
baseline a iabili y [
68
]. In e es ingly, he au ho s ound an in e se dose– esponse ela ion-
ship (lowe doses p esen ing be e esul s), which migh be explained by an inc ease in
la azo ide agmen a ion a highe doses (wi h la azo ide agmen s being compe i i ely
less e ec i e) o by pep ide agg ega ion comp omising i s unc ion a highe doses [
70
]. A
phase 3 RCT among symp oma ic CD pa ien s on a GFD (NCT 03569007) named CeDLa a
(
Ce
liac
D
isease
La a
zo ide) planned o en oll 525 pa ien s. Howe e , an in e im analysis o
hal o he ini ial a ge en ollmen showed disappoin ing esul s, leading o discon inua ion
o he s udy in June 2022. S a egies aiming o dec ease in es inal pe meabili y a e hinde ed
by anscellula ou es o glu en which allow i o espass om he lumen in o he lamina
p op ia [1].
3.3. T ansglu aminase Inhibi ion
Once glu en eaches he lamina p op ia, i unde goes deamida ion by he enzyme
issue ansglu aminase-2 (TG-2), which con e s glu amine esidues in glu amic acid [
16
].
This is a c i ical s ep o inc easing glu en immunogenici y by inc easing he s abili y o
glu en-HLA DQ2/8 complex [
86
]. TG-2 also induces deg ada ion o he an i-in lamma o y
PPAR-
γ
and p omo es anscellula in es inal pe meabili y o glu en [
87
]. This enzyme is
also he au oan igen o classical se ology in CD diagnosis [
1
]. One s a egy ha aims o
dec ease glu en immunogenici y is he inhibi ion o TG-2 ac i i y.
Inhibi ion o TG-2 has been shown o ab oga e glu en-induced immune ac i a ion
in i o
[
88
,
89
] and ex i o in in es inal biopsies om CD pa ien s [
89
], and has also
been shown o dec ease en e opa hy in animal models [
90
]. O no e, mice de icien in
TG-2 de elop sys emic au oimmuni y wi h splenomegaly and glome uloneph i is due o
impai ed clea ance o apop o ic cells du ing hymus in olu ion, which should p omp
u he in es iga ion o he possible side e ec s o TG-2 inhibi ion [
91
]. Fu he mo e, TG
has a ole in ex acellula ma ix emodeling and he epai o mucosal damage, which
mus be aken in o accoun in he apeu ic s a egies based on TG inhibi ion [92].
ZED1227 is an o al i s -in-class selec i e inhibi o o TG-2. Phase 1 clinical ials
among 100 heal hy emale and male olun ee s (Eud aCT 2014-003044-13 and 2015-005283-
42), ea ed wi h up o 500 mg o ZED1227, p o ed i o be sa e and well ole a ed [
93
].
Recen ly, a phase 2 p oo -o -concep ial es ed inc easing doses o ZED1227 (10 mg, 50 mg,
o 100 mg) o 6 weeks and compa ed hem o placebo in 160 CD pa ien s unde going a
In . J. Mol. Sci. 2023,24, 945 7 o 17
glu en challenge (3 g/day) [
94
]. ZED1227 ab oga ed in es inal mucosa inju y (blun ing
he glu en-induced dec ease in Vh:Cd and inc ease in IEL) and imp o ed symp oms and
quali y o li e. I was well ole a ed, wi h he de elopmen o a cu aneous ash in only 8%
o pa ien s on 100 mg o ZED1227.
3.4. Immune Modula ion
A he lamina p op ia, immunogenic deamida ed glu en pep ides will be exhibi ed a
he su ace o APCs, bound o majo his ocompa ibili y complex (MHC) class II p o eins in
a lock–key ashion. The sub ype o human leukocy e an igen (HLA)-DQ2/DQ8 is he lock
o ha key, and ca ying hose haplo ypes is a necessa y albei no su icien condi ion
o he de elopmen o CD [
95
]. Those APCs will p esen glu en epi opes o CD4
+
T cells,
igge ing a Th1/Th17 pheno ype wi h he p oduc ion o p oin lamma o y cy okines such
as TNF-α, INF-γ, in e leukin (IL)-18, and IL-21, as well as a B cell esponse [96].
S a egies o block HLA-DQ2/DQ8 a e being s udied bu emain in he p eclinical
phase. One such s a egy is o deli e compe i i e inhibi o s wi h glu en pep ide analogues
ha p esen highe binding a ini y han glu en while also no being ecognized by T cells.
Those inhibi o s showed mild blun ing o T cell ac i a ion in silico [
97
] and
in i o
[
98
,
99
].
The ques o such he apy has been challenging, wi h issues ega ding apid deg ada ion
o he pep ide ligand and possible in e e ence wi h o he i al MHC immune su eillance
unc ions [100,101].
Ano he echnique o immune modula ion is he inhibi ion o lymphocy e a icking
and homing o he small bowel. This can be achie ed by a ge ing he adhesion molecules
on gu endo helial cells (mucosal add essin cellula adhesion molecule-1, MadCAM-1) o
hei coun e pa in eg in ecep o s in lymphocy es (in eg in ecep o
α
4
β
7), as well as
by a ge ing issue-speci ic chemokine ecep o s on lymphocy es (chemokine ecep o -9,
CCR9) (Table 2).
Table 2. Rele an clinical ials on agen s ha induce immune modula ion.
Agen S udy T ial Phase Popula ion T ea men Du a ion Main Resul s ( s. Placebo)
Lymphocy e a icking
PTG-100
(an i-α4β7)
NCT
04524221 1b
30 CD pa ien s on a
glu en challenge
600 mg bid
s. placebo 42 days Comple ed in Ap il 2022
No da a published so a
Vedolizumab
(an i-α4β7)
NCT
02929316 2CD pa ien s on a
glu en challenge
300 mg s.
placebo 6 weeks Te mina ed in 2018 due o
lack o en ollmen
Ve cinon
(an i-CCR9)
NCT
00540657 2
30 CD pa ien s on a
glu en challenge
250 mg bid
s. placebo
13
weeks
Comple ed in 2008
No da a published so a
IL-15 a ge ing
PRN-015 o
AMG714
(an i-IL-15)
Lähdeaho,
2019 [102]2a
64 CD pa ien s on a
glu en challenge
(2–4 g/day)
150 mg, 300
mg/day s.
placebo
12
weeks
• ↓ symp oms (dia hea)
• ↓ IEL a 300 mg
•No 6=in se ology o
Vh:Cd
Cellie , 2019
[103]2a Type II RCD
8 mg/kg
2×/week
s. placebo
12
weeks
• ↓ symp oms (dia hea)
•No 6=in IEL, abe an
IEL, o Vh:Cd
•
Ad e se e en s: 26% s.
11%
In . J. Mol. Sci. 2023,24, 945 8 o 17
Table 2. Con .
Agen S udy T ial Phase Popula ion T ea men Du a ion Main Resul s ( s. Placebo)
NCT
04424927 2b
220 CD pa ien s
non- esponsi e o a
GFD
36=a ms s.
placebo
28
weeks
Ongoing
Comple ion Decembe 2023
Hu-Mik-β1
(an i-IL15Rβ1)
NCT
01893775 1 5 RCD pa ien s E e y 3
weeks 9 weeks
Comple ed in Decembe
2019
No da a published so a
To eci inib
(pan-JAK
inhibi o )
Eud a CT:
2018-001678-
10
2
Type II RCD
(open-label)
pa ien s
10 mg bid 12
weeks Ongoing
PTG-100 is an o ally adminis e ed, po en , and selec i e
α
4
β
7 pep ide an agonis . I
was al eady es ed in a phase 2a RCT in pa ien s wi h ulce a i e coli is and showed high
gas oin es inal exposu e, limi ed sys emic exposu e, and a dose– esponse imp o emen
in endoscopy and his ology [
104
]. A phase 1b s udy (NCT 04524221) e alua ing PTG-100
a a dose o 600 mg wice a day e sus placebo in 30 CD pa ien s on a glu en challenge
was comple ed in Ap il 2022. Vedolizumab is an an i-
α
4
β
7 an ibody ha is widely used
in in lamma o y bowel disease. A la ge epidemiological s udy ound ha pa ien s wi h
in lamma o y bowel disease ea ed wi h s e oids, 5-aminosalicyla es, and immunomodu-
la o s (bu no edolizumab) had a lowe isk o de eloping CD compa ed o un ea ed
pa ien s, which may sugges a lack o e icacy when using edolizumab in he ea men o
CD. A phase 2 RCT e alua ing edolizumab in CD s a ed in 2016 bu was e mina ed in
2018 due o lack o en ollmen (NCT02929316).
Ve ci non is an o al selec i e an agonis o CCR9 ha has shown p omising esul s in
ea ly s udies o i s use in he ea men o C ohn’s disease [
105
], e en hough subsequen ly
a phase 3 RCT ailed o show e icacy when used o induc ion he apy [
106
]. A phase 2
s udy o e ci non in CD was comple ed in 2008 (NCT00540657), bu i s esul s we e no
published.
IL-15 seems o be a pi o al cy okine in he pa hogenesis o CD [
90
]. IL-15 is p oduced
by APCs and epi helial cells and induces ac i a ion and p oli e a ion o IEL, hus p omo ing
illous a ophy [
102
]. The IL-15 ecep o consis s o h ee chains: (a) a common cy okine
ecep o
γ
-chain ha is sha ed wi h he ecep o s o IL-2, IL-4, IL-7, IL-9, and IL-21; a
β
-chain (IL-15R
β
) ha is sha ed wi h he IL-2 ecep o ; and an IL-15 speci ic
α
-chain (IL-
15R
α
) [
71
]. The IL-15 ecep o signals h ough he Janus kinase–signal ansduce and
ac i a o o ansc ip ion (JAK/STAT) [107].
PRN-015, p e iously dubbed AMG714, was he i s an i-IL-15 e alua ed in CD in
a p oo -o -concep phase 2a RCT [
102
]. PRN-015 is a ully human IgG1k monoclonal
an ibody ha binds o IL-15. This s udy e alua ed 64 CD pa ien s on a 2–4 g daily glu en
challenge who we e subcu aneously adminis e ed he an ibody e e y o he week o
10 weeks. Acco ding o he s udy, he an ibody was well ole a ed. Compa ed o placebo,
PRN-015 ea men was associa ed wi h a dec ease in IEL and a symp oma ic bene i (less
dia hea de elopmen ), bu ailed o show a bene i in e ms o se ology o Vh:Cd [
102
].
PRN-015 was also e alua ed in 28 pa ien s wi h ype II RCD in a phase 2a RCT, and while
i was associa ed wi h imp o emen in dia hea, i showed no his ological bene i o e
placebo [
103
]. Impo an ly, in hose pa ien s, PRN-015 was associa ed wi h signi ican
ad e se e en s, such as ube culosis and ce ebella synd ome. An ongoing phase 2b RCT
(NCT 04424927) in pa ien s wi h CD who a e non- esponsi e o a GFD is es ima ed o be
comple ed in Decembe 2023.
Rega ding a ge ing he IL-15 ecep o , a phase 1 RCT o a humanized monoclonal
an ibody agains IL-15R
β
(Hu-Myk-
β
1) was comple ed among i e pa ien s wi h RCD in
Decembe 2019, bu i s esul s ha e no been published (NCT 01893775).
In . J. Mol. Sci. 2023,24, 945 9 o 17
To aci inib is an o al small molecule pan-JAK inhibi o . In p eclinical s udies wi h
ansgenic mice ha o e exp essed IL-15 and hus de eloped he pa hologic ea u es o
CD, o aci inib was able o e e en e opa hy [
108
]. Case epo s also showed his ological
imp o emen in a CD pa ien on a glu en-con aining die [
109
], as well as in a pa ien wi h
ype II RCD [
110
]. A phase 2 open-label ial o o aci inib in ype II RCD is ongoing (Eud a
CT: 2018-001678-10). (Table 2).
In liximab, an an i-TNF-
α
an ibody and a co ne s one in he ea men o in lamma o y
bowel disease, showed encou aging esul s in case epo s o s e oid-un esponsi e RCD
pa ien s [111–114].
S e oids, pa icula ly budesonide, may ha e a ole in he ea men o non- esponsi e
pa ien s o hose wi h RCD despi e he equen elapse a e ape ing sugges ed by case
epo s and case se ies [
115
–
117
]. In newly diagnosed CD howe e , a pilo s udy among
27 pa ien s ailed o show any bene i om budesonide as an adjunc i e ea men o a GFD
when a emp ing o accele a e in es inal mucosal eco e y [118].
3.5. Inducing Immune Tole ance
CD is cha ac e ized by a loss o immune ole ance, wi h T egula o y cells (T eg)
unable o supp ess e ec o T cells [
119
–
121
]. Fou s a egies ha e been s udied o e-
es ablish immune glu en ole ance in pa ien s wi h CD: (a) desensi iza ion h ough he
p esen a ion o gliadin p o eins in nanopa icles [
122
] o (b) ed-blood cell moie ies [
123
],
(c) he apeu ic accina ion [
124
], o (d) in es a ion wi h helmin hs [
125
]. These app oaches
ha e he ad an age o a oiding impai men s o sys emic immune unc ion [15] (Table 3).
Table 3. Rele an clinical ials on agen s ha induce immune ole ance.
Agen S udy T ial Phase Popula ion T ea men Du a ion Main Resul s ( s. Placebo)
Nanopa icles o gliadin p esen a ion
TAK-101
(TIMP-GLIA)
Kelly, 2021
[126]2
33 CD pa ien s
on a glu en
challenge
8 mg day 1 and
8 s. placebo 5 weeks
• ↓ g ow h o
glu en-speci ic INF-γ
p oducing cells
• ↓ Vh:Cd la ening
NCT
04530123 2
168 CD pa ien s
on a glu en
challenge
1–4 mg day 1
and 8 s.
placebo
20 weeks Ongoing
Comple ion Janua y 2024
Glu en e y h ocy e moie y on ed blood cells
KAN-101 NCT
04248855 2b 41 CD pa ien s Dose- anging
s. placebo 4 weeks
Comple ed in Decembe
2021
No da a published so a
The apeu ic accine
Nex ax-2
Da eson,
2017 [127]1
36 HLA-DQ2.5
CD pa ien s on
a GFD
3–900 µg
2×/week ID s.
placebo
6 weeks
•T ansien symp oms
esembling a glu en
challenge
•Sa e and well ole a ed
Goel, 2017
[124]2
108 HLA-DQ2.5
CD pa ien s on
a glu en
challenge
60–150 µg
2×/week ID s.
placebo
8 weeks
•T ansien symp oms
esembling a glu en
challenge
•No 6=↓Vh:Cd
T ui , 2019
[128]2
146 HLA-DQ2.5
CD pa ien s on
a glu en
challenge
32 doses SC s.
placebo 26 weeks Te mina ed 2019 o u ili y
In . J. Mol. Sci. 2023,24, 945 16 o 17
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