X-linked retinoschisis maculopathy treated with topical dorzolamide, and relationship to genotype

Khandhadia, Samir; Trump, Dorothy; Menon, Geeta; Lotery, Andrew

doi:10.1038/eye.2011.91

Cited by 33 publications

(35 citation statements)

References 27 publications

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“…Anecdotal reports suggest that topical carbonic anhydrase inhibitors may provide some reduction in the degree of schisis detected by OCT and improvement in visual acuity in some but not all patients, [4][5][6][7][8] but the absence of controlled clinical trials makes interpretation of these reports difficult.…”

Section: X-linked Retinoschisis (Xlrs)mentioning

confidence: 96%

Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-CB-hRS1, a Recombinant Adeno-Associated Virus Vector Expressing Retinoschisin

Budzynski

Sonnentag

et al. 2015

Human Gene Therapy Clinical Development

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Applied Genetic Technologies Corporation is developing rAAV2tYF-CB-hRS1, a recombinant adenoassociated virus (rAAV) vector for treatment of X-linked retinoschisis (XLRS), an inherited retinal disease characterized by splitting (schisis) of retinal layers causing poor vision. We report here results of a study evaluating the safety and biodistribution of rAAV2tYF-CB-hRS1 in normal cynomolgus macaques. Three groups of male animals (n = 6 per group) received an intravitreal injection in one eye of either vehicle, or rAAV2tYF-CB-hRS1 at one of two dose levels (4 · 10 10 or 4 · 10 11 vg/eye). Half the animals were sacrificed after 14 days and the others after 91 or 115 days. The intravitreal injection procedure was well tolerated in all groups. Serial ophthalmic examinations demonstrated a dose-related anterior and posterior segment inflammatory response that improved over time. There were no test article-related effects on intraocular pressure, electroretinography, visual evoked potential, hematology, coagulation, clinical chemistry, or gross necropsy observations. Histopathological examination demonstrated minimal or moderate mononuclear infiltrates in 6 of 12 vector-injected eyes. Immunohistochemical staining showed RS1 labeling of the ganglion cell layer at the foveal slope in vector-injected eyes at both dose levels. Serum anti-AAV antibodies were detected in 4 of 6 vector-injected animals at the day 15 sacrifice and all vector-injected animals at later time points. No animals developed antibodies to RS1. Biodistribution studies demonstrated high levels of vector DNA in the injected eye but minimal or no vector DNA in any other tissue. These results support the use of rAAV2tYF-CB-hRS1 in clinical studies in patients with XLRS.

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Section: X-linked Retinoschisis (Xlrs)mentioning

confidence: 96%

Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-CB-hRS1, a Recombinant Adeno-Associated Virus Vector Expressing Retinoschisin

Budzynski

Sonnentag

et al. 2015

Human Gene Therapy Clinical Development

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“…Treatment has been attempted using carbonic anhydrase inhibitors (2% topical dorzolamide), which are effective in several conditions involving cystoid macular edema (14). While this treatment reduced the schisis cavities, it did not necessarily correlate with improvement in visual acuity (15,16). Rs1-KO mouse models reproduce the human XLRS disease phenotype and have been used to understand the cellular and molecular mechanisms of disease (11,17,18).…”

Section: Introductionmentioning

confidence: 99%

Synaptic pathology and therapeutic repair in adult retinoschisis mouse by AAV-RS1 transfer

Ou¹,

Vijayasarathy²,

Ziccardi³

et al. 2015

J. Clin. Invest.

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“…The patients’ mother and the unaffected sister were heterozygous for the mutation c.589C>T. The nucleotide change in the patients predicted an amino acid change from arginine (CGC) to cysteine (TGC). This mutation was previously reported in a British patient but not in patients with Italian ethnicity 13,20…”

Section: Resultsmentioning

confidence: 59%

“…A beneficial effect from the use of a topical or, alternatively, systemic carbonic anhydrase inhibitor (CAI) has been reported in patients with cystoid macular edema in retinal dystrophies including RS1. One study described the successful treatment of a patient with a p.Arg197Cys, and other mutations, in RS1 13. No follow-up was reported in this study after the discontinuation of the therapy with acetazolamide.…”

Section: Introductionmentioning

confidence: 79%

Rebound macular edema following oral acetazolamide therapy for juvenile X-linked retinoschisis in an Italian family

Galantuomo¹,

Fossarello²,

Cuccu³

et al. 2016

OPTH

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BackgroundJuvenile X-linked retinoschisis (RS1, OMIM: 312700) is a hereditary vitreoretinal dystrophy characterized by bilateral foveal schisis and, in half of the patients, splitting through the nerve fiber layer in the peripheral retina. In the first decade of life, patients usually develop a decrease in visual acuity. Long-term visual outcomes can be poor due to the limited number of known successful treatments.PurposeThe purposes of this study were to present, for the first time, a p.Arg197Cys missense mutation in the RS1 gene (OMIM: 300839) in a four-generation Italian family with RS1 and to examine the clinical response to the treatment with acetazolamide tablets alone or in combination with dorzolamide eye drops as assessed by spectral-domain optical coherence tomography (SD-OCT).MethodsEleven individuals, including two brothers with RS1 (patients 1 and 2), underwent a full medical history examination and a comprehensive ocular assessment that involved SD-OCT, fluorescein angiography, electroretinography and DNA analysis. Each RS1 patient received oral acetazolamide (375 mg daily) during the first three months. Thereafter, patient 1 continued only with dorzolamide eyedrops three times a day for a period of three months, while patient 2 spontaneously stopped both medications.ResultsSequence analysis of the RS1 gene identified a hemizygous c.589C>T (p.Arg197Cys) missense mutation in exon 6, which has not been previously reported in an Italian family. A different response to the medical therapy was observed in the four eyes of the two affected brothers hemizygous for this abnormality. Of note, after acetazolamide interruption, a rebound effect on cystoid macular edema reduced the beneficial effects of the initial therapy for RS1 from p.Arg197Cys mutation. Indeed, a minimal rebound effect on cystoid macular edema, and an improvement in visual acuity, was observed in patient 1 during the six months of treatment. Conversely, in patient 2, an initial improvement in cystoid macular edema was not associated with visual acuity changes, followed by a marked rebound effect.ConclusionThis study showed that the sequential use of acetazolamide tablets and dorzolamide eye drops should be considered and studied further as a possible treatment for macular edema and visual impairment in patients with RS1 from a hemizygous p.Arg197Cys mutation.

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X-linked retinoschisis maculopathy treated with topical dorzolamide, and relationship to genotype

Cited by 33 publications

References 27 publications

Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-CB-hRS1, a Recombinant Adeno-Associated Virus Vector Expressing Retinoschisin

Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-CB-hRS1, a Recombinant Adeno-Associated Virus Vector Expressing Retinoschisin

Synaptic pathology and therapeutic repair in adult retinoschisis mouse by AAV-RS1 transfer

Rebound macular edema following oral acetazolamide therapy for juvenile X-linked retinoschisis in an Italian family

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