Beruflich Dokumente
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Review
Anatomy and physiology of the human eye:
effects of mucopolysaccharidoses disease on
structure and function a review
ceo_2363
2..11
Colin E Willoughby MD, PhD,1 Diego Ponzin MD,2 Stefano Ferrari PhD,2 Aires Lobo MD,3
Klara Landau MD, PhD4 and Yadollah Omidi PhD5
1
Centre for Vision Science and Royal Victoria Hospital, Belfast Queens University, Belfast, UK, 2The Veneto Eye Bank Foundation,
Venice, Italy; 3Moorelds at Bedford, Moorelds Eye Hospital NHS Foundation Trust, Bedford, UK; 4Department of Ophthalmology,
University Hospital Zurich, Zurich, Switzerland; and 5Research Centre for Pharmaceutical Nanotechnology, Tabriz University of Medical
Sciences, Tabriz, Iran
ABSTRACT
The current paper provides an overview of current
knowledge on the structure and function of the eye. It
describes in depth the different parts of the eye that are
involved in the ocular manifestations seen in the
mucopolysaccharidoses (MPS). The MPS are a group of
rare inheritable lysosomal storage disorders characterized by the accumulation of glycosaminoglycans
(GAGs) in cells and tissues all over the body, leading to
widespread tissue and organ dysfunction. GAGs also
tend to accumulate in several tissues of the eye,
leading to various ocular manifestations affecting both
the anterior (cornea, conjunctiva) and the posterior
parts (retina, sclera, optic nerve) of the eye.
Key words: anatomy, eye disease, mucopolysaccharidosis, physiology, review.
INTRODUCTION
The mucopolysaccharidoses (MPS) are a group of
inheritable lysosomal storage disorders, characterized by the progressive accumulation of incompletely degraded glycosaminoglycans (GAGs) in
tissues and organs due to a deficiency in one of
the enzymes involved in GAG catabolism (Table 1).
All MPS types have a progressive course and involve
multiple organs. They share several common clinical
features, but with variable degrees of severity.
Typical features of the MPS include coarse facial fea-
tures, affected hearing and vision, cardiorespiratory problems, reduced joint mobility, organomegaly
and skeletal deformities (dysostosis multiplex,
dwarfism) (Fig. 1).1 Patients with MPS IH (Hurler
syndrome), MPS III (Sanfilippo syndrome) and the
severe form of MPS II (Hunter syndrome) typically
show mental retardation. Patients with MPS IV
(Morquio syndrome) show bony lesions specific
for that disorder (dwarfism with short trunk and
neck). There is a wide spectrum of phenotypes and
progression rates within any one MPS type.
Characteristic ocular features in patients with
MPS include corneal clouding, glaucoma, retinopathy, optic disc swelling and optic atrophy.25 Ocular
problems in patients with MPS are among the
first symptoms to arise and can ultimately result in
visual impairment or blindness.4,5 This review of the
anatomy and physiology of the normal eye and overview of changes in structure and function seen in
MPS disease was presented at the International
Symposium MPS and the eye: What do we know
and how can we treat, which was held on 79
October 2009 in Venice, and provided the introduction necessary to focus on diagnosis and treatment of
eye disease in this patient group.
Correspondence: Dr. Diego Ponzin, The Veneto Eye Bank Foundation, c/o Padiglione G Rama, Via Paccagnella, 11, 30174 Zelarino, Venice, Italy. Email:
diego.ponzin@fbov.it
Received 10 May 2010; accepted 16 June 2010.
2010 The Authors
Journal compilation 2010 Royal Australian and New Zealand College of Ophthalmologists
MPS IV
MPS VI
MPS VII
MPS IX
Name
Enzyme deciency
a-L-iduronidase
Iduronate-2-sulfatase
Heparan N-sulfatase
N-acetylglucosaminidase
Acetyl CoA:a-glucosamine N-acetyltransferase
N-acetylglucosamine-6-sulfatase
N-acetylgalactosamine-6-sulfatase
b-galactosidase
N-acetylgalactosamine-4-sulfatase
b-D-glucuronidase
Hyaluronidase
(a)
(b)
(c)
THE
CORNEA
Willoughby et al.
Figure 2. Schematic illustration
of the structure of the eye and the
ocular barriers. The primary physiologic blockage against instilled
drugs is the tear lm. Cornea is
the main route for drug transport
to the anterior chamber (I). The
retinal pigment epithelium and the
retinal capillary endothelium are
the main barriers for systemically
administered drugs (II). Intravitreal
injection is an invasive strategy
to reach the vitreous (III). The
administered drugs can be carried
away from the anterior chamber
either by venous blood ow after
diffusing across the iris surface
(1) or by the aqueous outow
(2). Drugs can be removed away
from the vitreous through diffusion into the anterior chamber
(3) or by the bloodretinal barrier
(4). Adapted from Barar J et al.6
Epithelium
Basement membrane
Bowmans layer
Stroma
Descemets membrane
Endothelium
the peripheral cornea.9 Therefore, the peripheral and central cornea are very distinct in terms of
physiology and pathology.
Five layers can be distinguished in the human
cornea: the epithelium, Bowmans membrane, the
lamellar stroma, Desemets membrane and the
endothelium (Fig. 3).10 The surface of the corneal
epithelium is covered by the tear film, which protects
the corneal surface from chemical, toxic or foreign
body damage and from microbial invasion and
smoothes out micro-irregularities of the surface of the
epithelium.10 It consists of an outer lipid layer and an
inner water-mucous layer. The mucous layer interacts
with the epithelial cells, allowing the tear film to
spread with each eyelid blink.
The corneal epithelium is composed of two to
three layers of superficial cells, two to three layers of
wing cells and one layer of basal cells.10 The surface
THE
RETINA
Willoughby et al.
Vitreous chamber
Internal limiting
membrane
ILM
Ganglion cell
NFL
GCL
IPL
Amacrine cell
Horizontal cell
Bipolar
cell
Inner nuclear
layer
INL
Middle limiting
membrane
ONL
OPL
External limiting
membrane
R&CL
Mllers
fiber (glia)
OLM
PE
Cone
Choroid
Rod
Light
Figure 4. The cells and layers of the retina. GCL, ganglion cell layer; ILM, inner limiting membrane; INL, inner nuclear layer; IPL, inner
plexiform layer; NFL, nerve bre layer; OLM, outer limiting membrane; ONL, outer nuclear layer; OPL, outer plexiform layer; (R)PE, (retinal)
pigment epithelium; R&CL, rods and cones layer. Reproduced from Yanoff & Duker Ophthalmology,19 with permission from Elsevier.
Macula
Optic disc
NASAL
Fovea
Temporal
Venule
Arteriole
Figure 5. The fundus of the eye showing the macula, the fovea
and the optic disc.
VISUAL
PATHWAYS
7
be apparent in the optic disc, which may become
swollen or develop pallor (optic atrophy). Increased
intracranial pressure results in the swelling of
both optic discs (papilloedema) that may cause optic
atrophy when untreated. The hallmarks of chiasmal
lesions are defects that affect the temporal visual field
in each eye. A lesion behind the optic chiasm is
characterized by homonymous visual field defects
occurring in both eyes (e.g. the temporal field in one
eye and the nasal field in the other eye).
OCULAR
BARRIERS
The transport of fluids and solutes in the eye is controlled by several membranes and barriers. These
barriers can hamper the delivery of topical ocular
drugs (i.e. eye drops) and systemically (i.e. orally or
intravenously) administered drugs.
Topical ocular drugs, mostly given as eyedrops, are
the most frequently used dosage forms for treating
ocular diseases. The first barrier to cross for these
drugs is the tear film, which rapidly removes instilled
compounds from the eye, resulting in low bioavailability. Other membranous barriers are located in the
cornea, the conjunctiva, the irisciliary body and the
retina.25,26 Depending on the physiochemical characteristics of the compounds, delivery of drugs can occur
through the corneal route and/or the conjunctival/
scleral route (Fig. 2). The corneal route is the main route
for delivery of drugs to the anterior chamber. Permeation of hydrophilic drugs and macromolecules
through the corneal epithelium is limited by the presence of tight junctions between adjacent outer superficial epithelial cells.10 The abundant presence of
hydrated collagen in the stroma may hamper the
diffusion of highly lipophilic agents. The endothelium is more permeable and allows the passage of
hydrophilic drugs and macromolecules between the
aqueous and the stroma due to the presence of leaky
tight junctions called desmosomes or macula adherens. The passage of topical ocular drugs through the
corneal route depends on their lipophylicity, molecular weight, charge and degree of ionization. Particularly small lypophilic drugs can easily permeate
through the cornea. After crossing the cornea, the
drug diffuses into the aqueous and to the anterior
uvea.
The non-corneal or conjunctival/scleral route is
usually less efficient for drug delivery, but may be
used for the delivery of hydrophilic and larger molecules, which cannot easily diffuse through the
corneal epithelium.25 Unlike the cornea, the conjunctiva has a rich vasculature and a large amount of the
administered drug crossing it is removed by the systemic circulation. The remaining drug penetrates
through the sclera, which is more permeable than the
cornea, but less permeable than the conjunctiva. The
Willoughby et al.
Figure 6. The retinal cellular architecture. The schematic structure of the retinal pigmented epithelial (RPE) cells and the retinal capillary
endothelial (RCE) cells represent the outer and inner retinal barriers, respectively. RPE and RCE are the main organization of the transport
limiting layers. The outer layer of the RPE displays tight barriers due to the presence of tight junctions (zona occludens). The inner RCE
cells possessing tight junctions are non-fenestrated compared with choroidal capillary endothelial cells that are fenestrated. Adapted
from Barar J et al.6
9
the retina and enter the subretinal space after
intravitreal injection because of the notable size
difference.26
Enzyme replacement therapy (ERT), that is,
replacement of a defective or absent enzyme by a
recombinant variant, has raised high expectations for
the treatment of some devastating ocular diseases
such as ocular manifestations of MPS I and VI.
For example, Naglazyme (BioMarin Pharmaceutical
Inc., Novato, CA, USA) (galsulfase marketed by
BioMarin) is a variant form of the polymorphic
human enzyme, N-acetylgalactosamine-4-sulfatase.
The intravenously administered galsulfase can be
taken up into lysosomes and increase the catabolism
of GAGs.30,31 Such lysosomal uptake is most likely
mediated by the binding of mannose-6-phosphateterminated oligosaccharide chains of galsulfase to
specific mannose-6-phosphate receptors.30 The effectiveness of ERT on the central nervous system and
ocular manifestations of MPS needs further investigations, as its traverse through the BBB and BRB is
not fully understood.
There is growing interest in ocular gene therapy
for treating inherited retinal degenerations, such
as Lebers congenital amaurosis due to defects in
the gene encoding the enzyme RPE65.32,33 Futuristic
genomedicines for ocular diseases are deemed to
become more effective therapeutics by exploiting
molecular Trojan delivery systems for safe shuttling
(e.g. antisense, ribozyme and short-interfering RNA
[siRNA]) and targeting the desired biomarkers.34,35
There is particularly much excitement about the
potential of the siRNA.
Encapsulated cell technology (ECT) and cell
therapy also appear to have treatment potentials
for ocular diseases. ECT implants consist of
living cells encapsulated within a semipermeable
polymer membrane and supportive matrices, which
are genetically engineered to produce a specific
therapeutic substance to target a specific disease or
condition. Once implanted, it allows the outward
passage of the therapeutic product.36 This may be a
novel treatment strategy for some life-threatening
diseases (e.g. MPS), for which an in situ source for
ERT could be developed.
OCULAR
MANIFESTATIONS IN THE
MPS
Membrane-bound vacuoles containing GAG deposits have been found in almost all ocular tissues in
MPS patients, where they can alter the cellular shape
and tissue ultrastructure.5,37 Therefore, both the
anterior and posterior segments of the eye can be
affected. Characteristic ocular features in patients
with MPS include corneal clouding, glaucoma, retinopathy, optic disc swelling and optic atrophy.25
Corneal clouding develops as a result of the
10
Willoughby et al.
CONCLUSION
The anatomy and function of the eye is extremely
complex and pathological events can lead to a wide
range of ocular disease manifestations that may
occur. MPS patients may present with a variety of
ocular diseases in both the anterior and posterior
components of the eye, resulting from GAG accumulation in various tissues. The treatment of these
ocular features warrants the investigation of methods
to circumvent various ocular barriers that hamper
drug delivery.
ACKNOWLEDGEMENTS
The authors are grateful to Ismar Healthcare NV for
their writing assistance, which was funded by BioMarin Europe Ltd. The content of the manuscript is
based on presentations and discussions during a scientific meeting entitled MPS and The Eye, which
took place from 7 to 9 October 2009 in Venice, Italy.
This meeting was supported by an educational grant
from BioMarin Europe Ltd, London, UK. BioMarin
had no role in the content presented and discussed at
the meeting. All authors participated in the development and writing of the manuscript and are fully
responsible for its content.
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