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Keywords:

  • anatomy;
  • eye disease;
  • mucopolysaccharidosis;
  • physiology;
  • review

Abstract

  1. Top of page
  2. A
  3. Introduction
  4. Introduction to the anatomy and physiology of the eye
  5. The cornea
  6. The retina
  7. Visual pathways
  8. Ocular barriers
  9. Ocular manifestations in the MPS
  10. Conclusion
  11. Acknowledgements
  12. References

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.


Introduction

  1. Top of page
  2. A
  3. Introduction
  4. Introduction to the anatomy and physiology of the eye
  5. The cornea
  6. The retina
  7. Visual pathways
  8. Ocular barriers
  9. Ocular manifestations in the MPS
  10. Conclusion
  11. Acknowledgements
  12. References

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 features, 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.

Table 1.  The mucopolysaccharidoses (MPS)
MPS typeNameEnzyme deficiency
MPS IH, IS, IH/SHurler, Scheie, Hurler/Scheieα-L-iduronidase
MPS IIHunterIduronate-2-sulfatase
MPS IIISanfilippo AHeparan N-sulfatase
Sanfilippo BN-acetylglucosaminidase
Sanfilippo CAcetyl CoA:α-glucosamine N-acetyltransferase
Sanfilippo DN-acetylglucosamine-6-sulfatase
MPS IVMorquio AN-acetylgalactosamine-6-sulfatase
Morquio Bβ-galactosidase
MPS VIMaroteaux-LamyN-acetylgalactosamine-4-sulfatase
MPS VIISlyβ-D-glucuronidase
MPS IXNatowiczHyaluronidase
image

Figure 1. Typical features of the mucopolysaccharidoses (MPS). (a) Claw hand of a patient with MPS IH/S (Hurler/Scheie). (b) Umbilical hernia in a child with MPS VI (Maroteaux-Lamy). (c) Coarse facial features in a child with MPS VI.

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Characteristic ocular features in patients with MPS include corneal clouding, glaucoma, retinopathy, optic disc swelling and optic atrophy.2–5 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 7–9 October 2009 in Venice, and provided the introduction necessary to focus on diagnosis and treatment of eye disease in this patient group.

Introduction to the anatomy and physiology of the eye

  1. Top of page
  2. A
  3. Introduction
  4. Introduction to the anatomy and physiology of the eye
  5. The cornea
  6. The retina
  7. Visual pathways
  8. Ocular barriers
  9. Ocular manifestations in the MPS
  10. Conclusion
  11. Acknowledgements
  12. References

The eye is one of the most complex organs of the human body. In the human eye, three layers can be distinguished (Fig. 2). The outer region consists of the cornea and the sclera. The cornea refracts and transmits the light to the lens and the retina and protects the eye against infection and structural damage to the deeper parts. The sclera forms a connective tissue coat that protects the eye from internal and external forces and maintains its shape. The cornea and the sclera are connected at the limbus. The visible part of the sclera is covered by a transparent mucous membrane, the conjunctiva. The middle layer of the eye is composed of the iris, the ciliary body and the choroid. The iris controls the size of the pupil, and thus the amount of light reaching the retina; the ciliary body controls the power and shape of the lens and is the site of aqueous production; and the choroid is a vascular layer that provides oxygen and nutrients to the outer retinal layers. The inner layer of the eye is the retina, a complex, layered structure of neurons that capture and process light. The three transparent structures surrounded by the ocular layers are called the aqueous, the vitreous and the lens.

image

Figure 2. Schematic illustration of the structure of the eye and the ocular barriers. The primary physiologic blockage against instilled drugs is the tear film. 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 flow after diffusing across the iris surface (1) or by the aqueous outflow (2). Drugs can be removed away from the vitreous through diffusion into the anterior chamber (3) or by the blood–retinal barrier (4). Adapted from Barar J et al.6

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The cornea

  1. Top of page
  2. A
  3. Introduction
  4. Introduction to the anatomy and physiology of the eye
  5. The cornea
  6. The retina
  7. Visual pathways
  8. Ocular barriers
  9. Ocular manifestations in the MPS
  10. Conclusion
  11. Acknowledgements
  12. References

The cornea is the most anterior part of the eye, in front of the iris and pupil. It is the most densely innervated tissue of the body, and most corneal nerves are sensory nerves, derived from the ophthalmic branch of the trigeminal nerve.7 The cornea of an adult human eye has an average horizontal diameter of about 11.5 mm and a vertical diameter of 10.5 mm, and a curvature that remains rather constant throughout life.8 The optic zone (pre-pupillary cornea), which provides most of the cornea's refractive function, has a diameter of 4 mm and is located in the centre of the cornea, anterior to the pupil, in photopic conditions. The cornea is avascular and the branches of the anterior ciliary arteries stop at the limbus where they form arcades that supply 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, Bowman's membrane, the lamellar stroma, Desçemet's 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.

image

Figure 3. Schematic presentation of the different layers of the cornea. Reproduced from Daniels JT et al.,11 with permission of John Wiley and Sons.

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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 of the superficial epithelial cells is irregular due to the presence of microplicae (ridge-like folds of the plasmalemma) that interact with the overlying tear film. The cells of the corneal epithelium are renewed every 7–10 days from a pluripotent stem cell population, which resides in the palisades of Vogt at the corneoscleral limbus. The stem cells differentiate into transient amplifying cells when they migrate to the central cornea.11,12 Recent research has also identified oligopotent stem cells in the corneal epithelium of mice and pigs, suggesting that the limbus is not the only niche for corneal stem cells.13 The corneal epithelium is extremely impermeable and stable due to the presence of cell junctions.10 It is also anchored very strongly to the basal lamina. The latter is secreted by the basal cells and mainly consists of type IV collagen and laminin. Because innervations are essential for the physiology of the epithelium, practically all epithelial cells are in contact with nerve cells.

The corneal lamellar stroma (500-µm-thick) provides structural integrity to the cornea. Stromal keratocytes secrete collagen and proteoglycans, which are ultimately fundamental for the transparency of the cornea and hydration. The stroma is separated from the epithelium by the Bowman's layer, an acellular zone of 10–15 µm beneath the basal lamina. The bulk of the stromal extracellular matrix consists of collagen fibrils arranged in 200–250 parallel lamellae that run from limbus to limbus.14 The network of collagen fibrils is responsible for the mechanical strength of the cornea and its regular organization is essential for corneal transparency. In the pre-pupillar cornea, the fibrils are packed more compact than in the peripheral cornea, probably contributing to the mechanical strength and dioptric stability in the cornea.15 The stromal collagen fibrils are surrounded by proteoglycans consisting of keratan sufate or chondroitin sulfate/dermatan sulfate side chains. These proteoglycans have an important structural function and help regulate hydration. Keratocytes are the predominant cell type in the stroma and play a role in maintaining its organization. These stellar-shaped cells contact to each other by long cytoplasmatic extensions (morphologic and functional syncytium) and also interact with the corneal epithelium.

The corneal endothelium consists of a single layer of five- to seven-sided cuboidal cells with little or no self-renewing potential. The endothelial cell density at birth in a normal cornea is 3500–7000 cells/mm2. They secrete the Descemet's membrane that separates the endothelium from the stroma. This elastic membrane thickens with age and is composed of an anterior layer with a banded appearance and a posterior layer with an amorphous texture.16 The endothelium possesses intracellular and membrane-bound ion transport systems that establish an osmotic gradient from a relatively hypo-osmotic stroma to a hypertonic aqueous. The osmotic gradient produces a net fluid flux from the stroma to the aqueous that produces a constant percentage of water in the stroma (78% H2O), which is essential for the clarity and transparency of the cornea.10 This process is called deturgescence. Corneal oedema may develop if deturgescence is disturbed for some reason.

Incident light on the cornea can be transmitted, absorbed or scattered. In a normal transparent cornea, visible light is not absorbed and scattering is negligible. Only irregularities with dimensions similar to the wavelength of visible light (400–700 nm) will affect the retinal image. An increase of corneal scattering can arise in case of corneal oedema, the relaxation of collagen fibrils, haze (extracellular matrix production by keratocytes) or irregularities due to surgery.17

The retina

  1. Top of page
  2. A
  3. Introduction
  4. Introduction to the anatomy and physiology of the eye
  5. The cornea
  6. The retina
  7. Visual pathways
  8. Ocular barriers
  9. Ocular manifestations in the MPS
  10. Conclusion
  11. Acknowledgements
  12. References

The retina is the tissue that lines the inner surface of the eye, surrounding the vitreous cavity. During embryogenesis, the vertebral retina develops from the optic cup. The latter is formed by invagination of the optic vesicle, which is an outgrowth of the embryonic forebrain. The inner wall of the optic cup (surrounding the vitreous cavity) ultimately becomes the neural retina; the outer wall (surrounded by the choroid and sclera) becomes the retinal pigment epithelium (RPE).18,19 The retina is protected and held in the appropriate position by the surrounding sclera and cornea.

The neural retina consists of six major classes of neurons: photoreceptors, bipolar cells, horizontal cells, amacrine cells and ganglion cells, which capture and process light signals, and the Müllerian glia, which act as the organizational backbone of the neural retina. The cells of the neural retina are arranged in several parallel layers (Fig. 4).18–20 The nuclei of the photoreceptor cells lie in the outer nuclear layer, their outer segments lie proximal from the nuclei, close to the RPE. The nuclei of the Müllerian glia, the bipolar cells, the amacrine and the horizontal cells are located in the inner nuclear layer of the retina. The inner nuclear layer has plexiform layers at both sides. In the outer plexiform layer, the photoreceptors connect with bipolar and horizontal cells, whereas in the inner plexiform layer, bipolar and amacrine cells synapse with ganglion cells. The nuclei of the ganglion cells lie in the ganglion layer, their axons in the nerve fibre layer. Processes of the Müllerian glia extend throughout the retina. The apical processes form the outer limiting membrane by making junctional complexes with one another and with photoreceptors. The apposed end-feet of the vitreal processes form the inner limiting membrane. Lateral processes of the Müllerian glia contact with blood vessels and neurons and form synapses with dendrites within the plexiform layers and axons in the nerve fiber layer.18

image

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 fibre 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.

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The eyes of most vertebrates contain two types of photoreceptors: rods and cones. In humans, rods are approximately 20 times more abundant than cones.18 The photoreceptors are responsible for phototransduction, the conversion of light into an electrical signal. For this purpose, the membranes of the outer segment discs of the photoreceptors contain pigments. Cones, which are responsible for colour vision, have pigments with absorption peaks in the blue, green or yellow parts of the spectrum. Pigments of the rods have an absorption peak in the blue-green part of the spectrum. Rods are active with low light levels, and are not involved in colour vision.

The density of rods and cones varies between different regions of the retina. In humans, about 50% of the cones are located in the central 30% of the visual field, roughly corresponding with the macula. The macula lutea refers to an area in the retina between the temporal vascular arcades containing xanthophylls pigment (Figs 2,5).19 Histologically, the macula has several layers of ganglion cells, whereas in the surrounding peripheral retina the ganglion cell layer is only one-cell thick. The excavation near the centre of the macula is called the fovea (Fig. 5). This area of the retina is responsible for sharp central vision and contains the largest concentration of cones in the eye.19 Visual acuity is highest in the foveola, the thin, avascular bottom of the fovea, which contains only densely packed cone cells. Due to the high density of cone cells in the foveola, the cone synaptic terminals and the ganglion cells to which they connect are pushed away from its centre, resulting in elongations between the nuclei and synaptic terminals of the cone cells, called Henle's fibres.18 At the level of the internal nuclear layer, the foveola is surrounded by a circular system of capillaries, the vascular arcades. No photoreceptor cells are present at the optic disc or optic nerve head where the axons from the ganglion cells exit the eye to form the optic nerve (Fig. 5).

image

Figure 5. The fundus of the eye showing the macula, the fovea and the optic disc.

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The RPE is a monolayer of cuboidal epithelial cells intercalated between the photoreceptors and the choriocapillaris, a layer of capillaries adjacent to the innermost layer of the choroid. The RPE incorporates about 3.5 million epithelial cells arranged in a hexagonal pattern, with a density that is relatively uniform throughout the retina. At the apical side, the cells of the RPE form long microvilli that reach up between the outer segments of rod photoreceptors.19 Numerous pigment (melanin and lipofuscin) granules are present in the apical cytoplasm of RPE cells. Important functions of the RPE include the maintenance of photoreceptor function (phagocytosis of photoreceptor wastes, regeneration and synthesis of pigments), retinal adhesion, storage and metabolism of vitamin A, the production of growth factors necessary for nearby tissues and wound healing after injury or surgery.19,21–24 In addition, the RPE plays an important role in the blood–retinal barrier (BRB) function, which will be discussed later.

The retina receives its blood supply from two circulatory systems: the retinal and the choroidal blood vessels.18,19 The retinal circulation supplies the inner retina, except for the avascular foveal zone. The outer avascular retinal layers receive their nutrients by diffusion from the choroid vessels. The choriocapillaris is fenestrated, which allows leakage of molecules to the RPE. Specialized transport systems in the RPE control the transportation of fluid and nutrients to the photoreceptors.

Retinal function depends on several factors, including the region of the retina being illuminated, the wavelength and intensity of the light stimulus and the state of light adaptation.

Visual pathways

  1. Top of page
  2. A
  3. Introduction
  4. Introduction to the anatomy and physiology of the eye
  5. The cornea
  6. The retina
  7. Visual pathways
  8. Ocular barriers
  9. Ocular manifestations in the MPS
  10. Conclusion
  11. Acknowledgements
  12. References

Light that enters the eye via its anterior components travels through the different layers of transparent neurons of the retina where it is captured by the photoreceptors at the back of the retina. As visual images are inverted as they pass through the lens, the right half of the image is projected on the nasal retina of the right eye (and the temporal retina of the left eye), whereas the left half of the image is projected on the temporal retina of the right eye (and the nasal retina of the left eye).

The neurons of the neural retina translate the visual information into nerve impulses, which travel through the optic nerve to the brain. The photoreceptors, the bipolar cells and the ganglion cells form a direct pathway to the brain (Fig. 4). The horizontal and amacrine cells form lateral pathways that modify and control the signal that passes through the direct pathway.19 The axons of the ganglion cells first travel towards the nerve fibre layer at the vitreal surface and then towards the optic disc, where they make a sharp turn to the optic nerve. The optic nerve extends from the eye to the optic chiasm. The next synapses lie deep in the brain, in the lateral geniculate nuclei (LGN).18 Both LGN receive information from both eyes, but only from one half of the visual field. This is due to a hemidecussation of both optic nerves in the optic chiasm, before they reach the LGN. Neurons from the LGN send their axons to the ipsilateral primary visual cortex. The left primary visual cortex receives information from the right visual field, and vice versa.

A lesion in one or both optic nerves will result in visual loss in one or both eyes, respectively. This will 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

  1. Top of page
  2. A
  3. Introduction
  4. Introduction to the anatomy and physiology of the eye
  5. The cornea
  6. The retina
  7. Visual pathways
  8. Ocular barriers
  9. Ocular manifestations in the MPS
  10. Conclusion
  11. Acknowledgements
  12. References

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 iris–ciliary 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 passage of drugs from the anterior to the posterior segments of the eye is not very efficient due to the aqueous turnover. Therefore, ocular surface administered drugs usually do not reach the posterior segments of the eye (retina, vitreous, choroid) in sufficient therapeutic concentrations.

Intravenous and intravitreal administrations appear to be the main strategies for treating posterior segment infections/diseases. However, intravenous administration has limited success primarily due to the exclusion of the eye from the systemic circulation. Of the ocular barriers, the BRB selectively controls traverse of substances and pharmaceuticals after systemic and periocular administration to the retina (Fig. 2). Despite some similarity, the BRB differs from the blood–brain barrier (BBB) by the functional presence of its outer barrier that is formed by the RPE. The inner barrier is formed by the endothelial cells of retinal vessels (Fig. 6).18,25,26 Both barriers display restricted tight junctions, by which the permeation/transfer of hydrophilic substances and macromolecules can selectively be regulated in inward and outward directions, that is, blood to vitreous and vice versa.26 Transcellular passive permeation is the main route for the inward/outward traverse of small molecules across the BRB, whereas the paracellular permeability of RPE is quite low. Besides, there exists an inverse correlation between the molecular weight and permeability. For example, in isolated bovine RPE choroids, the inward permeability differs between dextrans with various molecular weights (i.e. 2.36, 0.46 and 0.27 × 10−7 cm/s for 4, 40 and 80 kDa macromolecules).27 The following equation represents overall flux of drug across the BRB: J = C × P × S = C × CL, with J (µg/min), C (µg), P (cm/s) and S (cm2) representing the overall flux of the drug, the concentration gradient of the drug, the permeability in the barrier and the surface area of the barrier. CL represents the drug clearance into the tissue.27

image

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

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Various pharmaceuticals appear to be substrates/inhibitors of carrier- or receptor-mediated transporters, which might open the door to a more advanced intraocular delivery and targeting. Although the current knowledge on ocular drug transporters within the BRB is far from complete, the functional expressions of many transporters have been reported, including efflux and influx transport machineries such as organic anion transporter, organic cation transporter and organic anion-transporting polypeptide. The expression of clathrin and caveolin-1 in retinal vascular endothelial cells highlights the importance of the endocytic pathway for circulation of hormones, peptides and proteins.28,29

Intravitreal injection may be associated with patient non-compliance and endophthalmitis, cataract, astigmatism and retinal detachment. To avoid such complications, a variety of innovative drug delivery systems [e.g. Vitrasert® (Bausch & Lomb Inc., Rochester, NY, USA) for 6 months constant release of ganciclovir from the pars plana area of the vitreous; Retisert®(Bausch & Lomb Inc., Rochester, NY, USA) for 2.5 years constant release of fluocinolone acetonide] have been exploited. More recently, a branched PEGylated anti-vascular endothelial growth factor (VEGF) aptamer [pegaptanib sodium marketed as Macugen® (OSI pharmaceuticals Inc., Long Island, NY, USA] was approved by the Food and Drug Administration for the treatment of neovascular age-related macular degeneration (AMD). Ranibizumab Lucentis® (developed and marketed by Genentech Inc., South San Francisco, CA, USA and Novartis International AG, Basel, Switzerland) is a recombinant humanized monoclonal antibody fragment that targets VEGF-A and reduces neovascularization and leakage in wet AMD. Unlike RhuMAb VEGF [bevacizumab, Avastin® (developed and marketed by Genentech Inc., South San Francisco, CA, USA and Roche Applied Science, Basel, Switzerland) 148 kDa], ranibizumab (48 kDa) is able to penetrate 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-phosphate-terminated 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 Leber's 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

  1. Top of page
  2. A
  3. Introduction
  4. Introduction to the anatomy and physiology of the eye
  5. The cornea
  6. The retina
  7. Visual pathways
  8. Ocular barriers
  9. Ocular manifestations in the MPS
  10. Conclusion
  11. Acknowledgements
  12. References

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.2–5 Corneal clouding develops as a result of the intracellular and extracellular deposition of GAG in the cornea, which can affect keratocyte size and disrupt the regular network of collagen fibrils in the stroma.5,37,38 Narrowing of the angle secondary to GAG accumulation within the cornea can result in raised intraocular pressure and subsequent chronic or acute angle closure glaucoma.39 GAG deposition in the trabeculocytes and subsequent outflow obstruction can lead to open-angle glaucoma.5 Retinopathy results from GAG deposition in the RPE and the inter-photoreceptor matrix, leading to retinal degeneration and photoreceptor loss.4 Optic disc swelling and secondary optic atrophy can have several causes. Optic disc swelling can arise due to chronic elevation of intracranial pressure (papilloedema), impingement of the optic nerve due to thickening of the sclera or as a result of GAG deposition within ganglion cells.3,4,40

Ocular problems in patients with MPS can ultimately result in visual impairment or blindness.4,5 As many patients with MPS first present with ocular features, it is important that ophthalmologists are aware of the typical clinical features of MPS and can recognize them as being of metabolic origin, so that they can refer the patients to paediatricians for further diagnosis. The severity of the ocular findings differs between MPS types.41

Conclusion

  1. Top of page
  2. A
  3. Introduction
  4. Introduction to the anatomy and physiology of the eye
  5. The cornea
  6. The retina
  7. Visual pathways
  8. Ocular barriers
  9. Ocular manifestations in the MPS
  10. Conclusion
  11. Acknowledgements
  12. References

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

  1. Top of page
  2. A
  3. Introduction
  4. Introduction to the anatomy and physiology of the eye
  5. The cornea
  6. The retina
  7. Visual pathways
  8. Ocular barriers
  9. Ocular manifestations in the MPS
  10. Conclusion
  11. Acknowledgements
  12. References

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.

References

  1. Top of page
  2. A
  3. Introduction
  4. Introduction to the anatomy and physiology of the eye
  5. The cornea
  6. The retina
  7. Visual pathways
  8. Ocular barriers
  9. Ocular manifestations in the MPS
  10. Conclusion
  11. Acknowledgements
  12. References