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Robert E MacLaren

Publications and source records attributed to Robert E MacLaren.

8 recordsLinked to original sources
PubMed2006

In contrast to AAV-mediated Cntf expression, AAV-mediated Gdnf expression enhances gene replacement therapy in rodent models of retinal degeneration.

While AAV- and lentivirus-mediated gene replacement therapy can produce structural and functional improvements in various animal models of inherited retinal degeneration, this approach often has very limited effects on the rate of photoreceptor cell loss. Neurotrophic factors such as ciliary neurotrophic factor (CNTF) and glial cell line-derived neurotrophic factor (GDNF) have been shown to prolong photoreceptor survival in rodent models of retinal degeneration, but AAV-mediated Cntf expression also results in suppression of electrophysiological responses from the retina. In this study using mice, we show that while the deleterious effects mediated by CNTF are dose-dependent, administering a dose of CNTF that does not adversely affect retinal function precludes its ability to delay photoreceptor cell death. In evaluating GDNF as a neuroprotective agent, we show that AAV-mediated Gdnf expression does not produce adverse effects similar to those of CNTF. In addition, we demonstrate the ability of AAV-mediated delivery of Gdnf to slow cell death in two rodent models of retinitis pigmentosa and to enhance retinal function in combination with the relevant gene replacement therapy. These data show for the first time that a combination of these approaches can provide enhanced rescue over gene replacement or growth factor therapy alone.

Animals↗
PubMed2006

CNTF gene transfer protects ganglion cells in rat retinae undergoing focal injury and branch vessel occlusion.

Ciliary neurotrophic factor (CNTF) has been shown to protect ganglion cells in a variety of acute ischaemia models. Here we assess the efficacy of local CNTF gene transfer in protecting retinal ganglion cells when there is focal ischaemia combined with interruption of axoplasmic flow. This dual injury may be more representative of the pathological mechanisms operating in acute retinal diseases, such as vascular events acting at the optic nerve head. Fourteen rats received an intravitreal injection of an adeno-associated viral (AAV) vector expressing a secretable form of CNTF into the right eye and a control vector into the left eye. Three weeks later, each rat underwent a symmetrical small vertical 2mm standardised retinal crush injury approximately 2mm temporal to the optic disc. The injury also occluded the temporal retinal arteriole so that the axon crush was combined with an acute retinal infarction visible on fundoscopy. Changes in the damaged sector were compared histologically four weeks after injury and ganglion cell survival was estimated by comparing cell counts on retinal flat-mounts immunostained with RT-97 antibody. This mode of injury led to a profound loss of both the inner nuclear and ganglion cell layers, but was limited to the lesioned sector. In AAV.CNTF-treated eyes approximately 12% of ganglion cells survived compared with approximately 2% in control eyes (p=0.01). The scotopic electroretinogram (ERG), however, was reduced to about 50% in AAV.CNTF-treated eyes, both before and after injury. We therefore show that CNTF gene transfer confers neuroprotection to ganglion cells undergoing an acute ischaemic injury combined with interruption of axoplasmic flow. This approach may be relevant to optic nerve trauma and a variety of retinal vascular diseases that lead to swelling of the optic nerve head, provided CNTF can be delivered in a way that does not significantly suppress retinal function.

Animals↗
PubMed2006

Effective gene therapy with nonintegrating lentiviral vectors.

Retroviral and lentiviral vector integration into host-cell chromosomes carries with it a finite chance of causing insertional mutagenesis. This risk has been highlighted by the induction of malignancy in mouse models, and development of lymphoproliferative disease in three individuals with severe combined immunodeficiency-X1 (refs. 2,3). Therefore, a key challenge for clinical therapies based on retroviral vectors is to achieve stable transgene expression while minimizing insertional mutagenesis. Recent in vitro studies have shown that integration-deficient lentiviral vectors can mediate stable transduction. With similar vectors, we now show efficient and sustained transgene expression in vivo in rodent ocular and brain tissues. We also show substantial rescue of clinically relevant rodent models of retinal degeneration. Therefore, the high efficiency of gene transfer and expression mediated by lentiviruses can be harnessed in vivo without a requirement for vector integration. For therapeutic application to postmitotic tissues, this system substantially reduces the risk of insertional mutagenesis.

Animals↗
PubMed2006

Uveitic glaucoma and Rosai-Dorfman disease (sinus histiocytosis).

PURPOSE: To report a novel association of uveitic glaucoma with Rosai-Dorfman disease. METHODS: Case report. RESULTS: A 67-year-old Caucasian woman presented with a chronic bilateral granulomatous uveitis which did not respond to conventional topical steroid therapy. She also had raised intraocular pressures, glaucomatous optic disc changes and diffuse nodular fibrous skin lesions. Subsequent skin biopsy immuno-cytochemistry showed S-100 staining, consistent with Rosai-Dorfman disease. The uveitis and glaucoma were highly resistant to standard medical treatments, but completely resolved together with the systemic features of the disease after six months. CONCLUSIONS: Rosai-Dorfman disease has not previously been reported to cause uveitic glaucoma and should be considered in non-responsive cases presenting with a rash. The disease is entirely self-limiting and early diagnosis may therefore avoid unnecessary trabeculectomy and/or systemic immune suppression.

Aged↗
PubMed2006

Variable phenotypes in patients diagnosed with idiopathic multifocal choroiditis.

PURPOSE: To report investigations in a case series of patients diagnosed with idiopathic multifocal choroiditis (MFC) in order to determine whether or not a new clinical phenotype could be identified and to determine the long-term visual prognosis. METHODS: Twenty-eight patients were identified from the clinic database of approximately 1200 and subsequently reviewed. After ocular examination, which included fluorescein angiography, 20 of these patients were determined to have idiopathic MFC. Visual outcome, patient demographics, presenting symptoms, the distribution of inflammatory cells, the pattern of chorioretinal lesions and the development of peripapillary atrophy, choroidal new vessels or cystoid macular oedema were compared. RESULTS: The range of follow up was 1-27 years (mean 10 years). A Kaplan-Meier plot showed that approximately 60% of patients maintained their best-corrected visual acuity for 10 years after diagnosis. Poor vision at final review was associated with eyes having choroidal new vessels or cystoid macular oedema. Oral steroids were used to treat 11 patients, of which 10 responded with a visual improvement. The one non-responsive patient had foveal ischaemia angiographically. Generally the idiopathic phenotype was variable and only four patients showed some overlap with known subgroups of MFC. Unusual vascular features were observed in two patients. CONCLUSIONS: No specific phenotype was seen to emerge from this cohort of patients diagnosed with idiopathic MFC, although most were significantly different from the retinal white dot syndromes currently described. The visual prognosis was relatively good and most cases responded to oral steroids.

Adolescent↗
PubMed2005

Biometry accuracy using zero- and negative-powered intraocular lenses.

PURPOSE: To audit the accuracy of biometry using the SRK/T formula when negative- or zero-powered intraocular lenses (IOLs) are predicted and to compare the results between A-scan, B-scan, and optical methods of biometry. SETTING: Moorfields Eye Hospital, London, United Kingdom. METHODS: This retrospective analysis comprised 78 eyes of 54 patients having cataract surgery with zero- or negative-powered IOLs. Axial lengths were measured with A-scan, B-scan, applanation, or optical methods. Differences between SRK/T-predicted and actual postoperative refraction were analyzed for 75 eyes having cataract surgery. Ocular comorbidity, visual acuity, and biometry readings were also compared. RESULTS: Forty-one percent of 75 patients analyzed were within +/-1.00 diopter (D) of the predicted refraction, although there was a significant tendency toward a hyperopic overcorrection by 1.14 D (95% confidence interval, 0.89-1.39 D). This overcorrection error was consistent across all 3 biometry methods used to estimate axial length and increased with the use of stronger (more negative) IOLs. CONCLUSION: Surgeons should be aware of the tendency for negative-powered lenses to overcorrect and lead to a hyperopic outcome when using the SRK/T biometry formula in highly myopic eyes. A weaker-powered negative IOL is recommended to aim for a more myopic postoperative outcome by about 1.00 to 2.00 D.

Accommodation, Ocular↗
PubMed2005

Long-term results of submacular surgery combined with macular translocation of the retinal pigment epithelium in neovascular age-related macular degeneration.

PURPOSE: To provide long-term (> or =5 years) follow-up data on patients who had previously undergone macular retinal pigment epithelium (RPE) translocation surgery for choroidal new vessels (CNVs) associated with age-related macular degeneration. DESIGN: Retrospective interventional case series. PARTICIPANTS: Four of 9 patients who originally underwent surgery and whose results were reported after 2 years of follow-up were reviewed again 5 to 6 years after surgery. METHODS: All surviving patients from the original trial were contacted, and those who consented to full ocular examination were called in for review. Examination included best-corrected visual acuity (VA), optical coherence tomography (OCT), fundus autofluorescence, fluorescein angiography (FA), and indocyanine green angiography. MAIN OUTCOME MEASURES: Long-term success of RPE translocation was assessed by VA, imaging, angiography, and maintenance of overlying foveal fixation. Comparisons were made to the original 2-year follow-up data previously published. RESULTS: Over the long term, VA had declined further in 3 patients and improved slightly in 1 patient. Significantly, all 4 patients had lost foveal fixation and autofluorescence of translocated RPE, which had been present at the original 2-year follow-up assessment. The RPE graft, however, seemed viable when assessed by OCT, FA, and indocyanine green angiography, and no patient had suffered a recurrence of CNVs. CONCLUSIONS: In these 4 patients, RPE choroidal grafts had survived in the subfoveal space for at least 5 to 6 years, but rescue of visual function had been transient. The long-term loss of foveal fixation and graft autofluorescence might be explained by chronic photoreceptor apoptosis, initiated by either surgery or the disease process itself. Caution should be applied when drawing firm conclusions from similar studies that provide data after only 2 years' follow-up.

Aged↗