Brian Leonard

XIAP Protection of Photoreceptors in Animal Models of Retinitis Pigmentosa

Background Retinitis pigmentosa (RP) is a blinding genetic disorder that is caused by the death of photoreceptors in the outer nuclear layer of the retina. To date, 39 different genetic loci have been associated with the disease, and 28 mutated genes have been identified. Despite the complexity of the underlying genetic basis for RP, the final common pathway is photoreceptor cell death via apoptosis. Methodology/Principal Findings In this study, P23H and S334ter rhodopsin transgenic rat models of RP were used to test the neuroprotective effects of anti-apoptotic gene therapy. Adeno-associated viruses (AAV) carrying the X-linked inhibitor of apoptosis (XIAP) or green fluorescent protein (GFP) were delivered subretinally into the eye of transgenic rat pups. Histological and functional measures were used to assess neuroprotection. XIAP is known to block apoptosis by inhibiting the action of caspases-3, -7 and -9. The results show that XIAP gene therapy provides long-term neuroprotection of photoreceptors at both structural and functional levels. Conclusions/Significance Our gene therapy strategy targets the apoptotic cascade, which is the final common pathway in all forms of retinitis pigmentosa. This strategy holds great promise for the treatment of RP, as it allows for the broad protection of photoreceptors, regardless of the initial disease causing mutation.

Vigabatrin effect on inner retinal function

OBJECTIVE To determine the degree of electroretinal dysfunction in a group of patients taking Vigabatrin (VGB). Additionally, to investigate the role of cumulative dosage, the role of VGB alone or in combination with other anticonvulsants, and whether recent discontinuance of VGB affects electroretinal function as measured by the electroretinogram (ERG). DESIGN Retrospective, comparative case series. PARTICIPANTS Forty patients (18 male, 22 female) with a mean age of 35 years were studied as three groups: the VGB multitherapy group (n = 24) included those taking VGB with other anticonvulsants, the VGB monotherapy group (n = 9) included those taking VGB alone, and the off-VGB group (n = 7) included those who had discontinued VGB in the last 6 months. METHODS Scotopic flash, photopic flash, and 30-Hz flicker ERG results were recorded according to the International Society for Clinical Electrophysiology of Vision (ISCEV) standard. The clinical electro-oculogram (EOG) results were recorded according to the ISCEV standard. MAIN OUTCOME MEASURES Implicit time and amplitudes of the A- and B-waves of the flash and 30-Hz flicker ERGs were recorded. Summed amplitude of the first three oscillatory potential wavelets were recorded. The light-peak to-dark-trough Arden ratio of the EOG was evaluated. RESULTS Although photopic ERG B-wave reduction was most frequent in patients in the VGB multitherapy group (48% of eyes), a significant number of eyes in all three groups had scotopic ERG B-wave reduction. The 30-Hz flicker ERG result was abnormally reduced in all three groups. There was no significant difference in the frequency of occurrence in ERG result abnormalities between the VGB monotherapy and VGB multitherapy groups. The EOG results revealed reduced Arden ratios in all three groups; however, there was a significantly lower frequency of EOG abnormalities noted in the off-VGB group (P = 0. 0373). There was no statistically significant relationship between the frequency of electrodiagnostic abnormalities and the duration of use or the total cumulative dosage of Vigabatrin in any of the three groups. CONCLUSIONS These findings of scotopic ERG result abnormalities suggest that VGB alone has an effect on inner electroretinal function at the level of the Müller cell. Concomitant EOG abnormalities suggest a substantial effect of VGB on outer retinal function that may be reversible after cessation of VGB treatment.

Controlled Release of Bevacizumab Through Nanospheres for Extended Treatment of Age-Related Macular Degeneration

Bevacizumab (Avastin®) has been used by ophthalmologists in many countries as an off-label drug for the treatment of wet age-related macular degeneration (AMD). Due to its short half-life necessitating frequent intravitreal injection, a method for sustained delivery is in need. We demonstrated that bevacizumab could be released in a sustained fashion over 90 days from nano- and microspheres fabricated from poly(DL-lactide-co-glycolide) and poly(ethylene glycol)-b-poly(D,L-lactic acid), respectively. The drug release rate could be adjusted by alteration of the drug/polymer ratio. The use of such nano- and microspheres as bevacizumab delivery vehicles may improve the treatment of wet AMD.

Treatment of Susac syndrome with gamma globulin and corticosteroids

Susac syndrome is a rare vasculopathy characterized by visual, hearing, and cognitive dysfunction. Optimal treatment is unknown, but many patients require chemotherapy to control disease activity. We describe two patients with Susac syndrome and their response to intravenous immune globulin (IVIg) and corticosteroids. Both patients improved following acute treatment with IVIg and intravenous methylprednisolone (IVMP), and no further relapses were observed. One patient showed significant improvement in hearing and MRI lesions shortly following acute treatment. Treatment with IVIg and corticosteroids provides a therapeutic option that avoids the toxicities of chemotherapy and suggests the possible importance of pathologic antibodies in the pathogenesis of Susac syndrome.

Bilateral simultaneous central retinal artery occlusions in wegener granulomatosis.

A 46-year old woman developed simultaneous central retinal artery occlusions (CRAOs) in Wegener granulomatosis (WG). She had presented six years earlier with xerostomia, skin rash, and arthralgias and received a diagnosis of Sjogren syndrome. Anti-neutrophilic cytoplasmic antibody (ANCA) was negative. Months prior to the CRAOs, she had developed hearing loss, proptosis, and scleritis that were not responsive to prednisone 50 mg/d. The CRAOs occurred while she was being treated at this dose level. ANCA was now positive. This is the 12th case of CRAO in WG and the 6th case of bilateral CRAOs reported in the English literature. It emphasizes that serious irreversible visual complications may occur even when the patient is being treated with substantial corticosteroid doses.

Long-term follow-up of a modified technique for laser-induced chorioretinal venous anastomosis in nonischemic central retinal vein occlusion

PURPOSE To evaluate the long-term outcomes of a modified technique for laser chorioretinal venous anastomosis in nonischemic central vein occlusion (CVO). DESIGN Prospective, noncomparative, consecutive case series. PARTICIPANTS Nineteen eyes of 19 patients. METHODS Nineteen consecutive eyes with nonischemic CVO were observed for a mean period of 48 months after attempted laser-induced chorioretinal venous anastomosis therapy using a technique modified intentionally to avoid vein wall rupture. MAIN OUTCOME MEASURES Anastomosis patency, visual acuity, maintenance of nonischemic status, and complications were measured. RESULTS At least one patent anastomosis developed eventually in 19 of 19 eyes (100%). Two anastomoses developed in 5 of 19 eyes (26%). There were one or two nonfunctioning sites in 8 of 19 eyes (42%). The maximum number of treatment attempts in a single eye was four. Snellen visual acuity was unchanged in 3 of 19 eyes (16%) and improved from 1 to 11 lines (mean improvement, 5 lines) in 16 of 19 eyes (84%) during the mean follow-up period of 48 months. Nineteen of 19 eyes (100%) maintained nonischemic status. Treatment complications were limited to localized preretinal fibrosis. CONCLUSIONS Rupture of the vein wall is not required to form a functioning laser-induced chorioretinal venous anastomosis in eyes with nonischemic CVO. A technique modified intentionally to avoid vein wall rupture seems to be safer and more predicable.