The Ocular Anomalies in a Cystinosis Animal Model Mimic Disease Pathogenesis

Abstract

Cystinosis is a lysosomal storage disorder characterized by abnormal accumulation of cystine, which forms crystals at high concentrations. The causative gene CTNS encodes cystinosin, the lysosomal cystine transporter. The eye is one of the first organs affected (corneal lesions and photophobia in the first and visual impairment in the second decade of life). We characterized the ocular anomalies of Ctns Ϫ/Ϫ mice to determine whether they mimic those of patients. The most dramatic cystine accumulation was seen in the iris, ciliary body, and cornea of Ctns Ϫ/Ϫ mice. Consistently, Ctns Ϫ/Ϫ mice had a low intraocular pressure (IOP) and seemed mildly photophobic. Retinal cystine levels were elevated but increased less dramatically with age. Consistently, the retina was intact and electroretinogram (ERG) profiles were normal in mice younger than 19 mo; beyond this age, retinal crystals and lesions appeared. Finally, the lens contained the lowest cystine levels and crystals were not seen. The temporospatial pattern of cystine accumulation in Ctns

Successful treatment of the murine model of cystinosis using bone marrow cell transplantation

“…4 Cystine crystals are found first in the periphery of the cornea and then in the center. 33 Ctns Ϫ/Ϫ mice demonstrate similar ocular anomalies to patients, 14,34 and cystine crystals are also first found at the periphery of the cornea. In addition to the decreased cystine content, BMC transplantation led to a significant decrease in the number of mice with corneal cystine crystals (43% WT BMCs vs 86% of Ctns Ϫ/Ϫ BMCs; P Ͻ .05).…”

Treatment of Inherited Eye Defects by Systemic Hematopoietic Stem Cell Transplantation

“…13,24 IOP measures in Ctns À/À mice were significantly higher compared to wild-type mice (see Table), reaching greater than 20 mm Hg in 5 of 54 eyes. In contrast, high-and low-HSPC engraftment in HPSC-treated Ctns À/À mice demonstrated decreased IOP compared to Ctns À/À mice, with no observed measures above 20 mm Hg (P ¼ 0.006, v 2 test).…”

“…11,13,14,18 To evaluate whether HSPCs prevent corneal atrophy in Ctns À/À mice, we measured the CCT in hematoxylin-stained eye sections, as described previously. 31 We found that the cornea of old Ctns À/À mice (approximately 13 months of age; n ¼ 4) was significantly thinner than in wild-type animals (n ¼ 4), an effect most apparent in the epithelial layer (Fig.…”

“…[7][8][9][10] Kidneys and eyes are the primary tissues impacted by the disease in mice and humans 11,12 ; Ctns À/À mice develop ocular pathology similar to humans. 11,13,14 The main ocular manifestation is crystal deposition in the cornea, which begins in infancy, increases with age, and gradually leads to photophobia, blepharospasm, keratopathy, and recurrent corneal erosions. 15 In older patients, filamentous keratopathy, band keratopathy, and peripheral corneal neovascularization also are observed.…”

“…[15][16][17] A similar spectrum is seen in the mouse model, with central corneal opacification and loss of the corneal cellular architecture, and eventually phthisis bulbi. 11,13,14,18 Crystals also accumulate in conjunctiva, lens, sclera, ciliary body, iris, trabecular meshwork, choroid, retinal pigment epithelium, and retina, and can cause retinopathy. 19,20 The current treatment for cystinosis is the drug cysteamine, but taken orally it does not improve ocular manifestations of the disease, presumably due to the lack of bioavailability in the cornea.…”