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‘Pivotal’ anti-TGF antibody therapy
reduces filtering bleb wound formation, says report
Stefanie
Petrou-Binder MD
in Berlin
HUMAN mononuclear anti-TGF-beta 2 antibody therapy reduces filtering
bleb wound formation and is well tolerated by glaucoma patients,
according to a preliminary report at the annual meeting of the German
Society of Ophthalmology.
“Transforming growth factor-beta (TGF-beta) stimulates wound
healing in many different organs and is pivotal to the ophthalmic
research now underway,” reported German specialist Iris Wimmer
MD.
She reported preliminary 12-month data from a trial in which investigators
injected four doses of 100 microlitres anti-TGF-beta-2 antibodies
subconjunctivally, immediately before and after the trabeculectomy
operation, and on postoperative days one and seven. They applied
5-FU in cases with an increased tendency to form scar tissue.
That showed that the anti-TGF patients required less repeat surgery
and anti-glaucoma drop therapy than patients who did not receive
the antibody.
Even cases of combined phaco-trabeculectomies which received anti-TGF
antibodies had reduced intraocular pressure (IOP) when compared
to controls. This confirmed the results of an earlier pilot study,
which is now two years out and has shown no long-term side-effects.
Dr Wimmer said that it was interesting to note that in addition
to inhibiting scar tissue formation, the anti-TGF-beta-2 antibodies
reduced the extent of cell differentiation and capsular contraction
responsible for posterior capsular fibrosis.
She believes this effect may recommend anti-TGF antibody therapy
for post-cataract patients as well. Adverse side-effects are an
important issue in therapeutic modalities which implement scar-formation
inhibition. Studies investigating the effects on wound healing of
such anti-metabolites as 5-fluorouracil and mitomycin-C found that
although scar tissue formation of the trabeculectomy was reduced,
the agents were poorly tolerated by patients because of their toxic
side-effects.
Current research has therefore focused on the inhibition of growth
factors in the induction of wound healing as a therapeutic alternative.
A large, international, multicentre, prospective, randomised, placebo-controlled
study is now underway which will investigate the long-term effects
of anti-TGF-beta-2 monoclonal antibodies on wound healing following
primary trabeculectomy.
There are five known mammalian TGF-beta subgroups, of which TGF-beta-1
and 2 are in highest concentration in the eye. The highest level
of TGF-beta-2 is in the aqueous humour. It has also been reported
that levels of TGF-beta-2 are higher in the aqueous humour of patients
with primary open-angle glaucoma compared to controls (cataract
patients).
These studies also verified an increased tendency to form scar tissue
of the filtering bleb of open-angle glaucoma patients with elevated
TGF-beta-2 concentrations.
Conversely, they reported less scar tissue of the filtering bleb
in cases with lower levels of TGF-beta-2.
Dr Wimmer said this could indicate that active TGF-beta-2 may be
used as an early marker for elevated scarring activity of the bleb
after trabeculectomy in open-angle glaucoma patients.
Pseudoexfoliation glaucoma cases reveal higher levels of TGF-beta-1
and lower levels of TGF-beta-2 compared to the levels measured in
control groups.
Contributing role
TGF-beta-1 seems to play a contributing role in the initiation of
cell contractions of the vitreous in cases of proliferative vitreoretinopathy,
which would suggest an almost antagonistic function of the TGF-beta-1
and 2 groups.
The TGF-beta cytokines regulate a wide spectrum of cellular functions,
such as cell differentiation, proliferation, adhesion and migration.
They induce aspects of various inflammatory, proliferative and remodelling
phases of the wound healing process.
TGF-beta is produced locally in the trabecular meshwork, ciliary
body, cornea and pigment epithelium of the eye.
Past research has shown that TGF-beta-2 stimulates fibroblasts and
macrophage migration, fibroblast proliferation, angiogenesis and
collagen synthesis.
It modulates the synthesis of proteolytic enzymes, the secretion
of elastin, fibronectin and proteoglycans, as well as the formation
of the extracellular protein matrix.
The side-effects associated with the long-term use of anti-TGF-beta-2
antibodies has yet to be evaluated, although the results described
in animal models and the human trials carried out so far reveal
none of the lasting, more detrimental side-effects of antimetabolites
or gene therapies.
Researchers have reported blepharitis, conjunctivitis, hyposphagma
and hyphaema. The more serious hypotonia, hypersensitivity reactions,
or serious intraocular inflammations seen in alternative therapeutic
modalities have not been noted.
A new multicentre trial is being planned which will compare anti-TGF-beta-2
and antimetabolites in monotherapy so that a clear comparison between
the two can be drawn.
Iris
Wimmer MD
Julius-Maximillian University Eye Clinic, Würzburg, Germany
Email: wimmer_i@klinik.uni-wuerzburg.de
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