Volume 5, Number 4
Monday, January 31, 2005



In this issue: (click heading to view article)
Micropulse Laser Treatment of Retinal-choroidal Anastomoses in ARMD
Identifying Genes Responsible for Cone Dystrophies
Trace Microalbuminuria in Inflammatory Cystoid Macular Edema
Relationship of Diabetic Retinopathy to Preclinical Diabetic Glomerulopathy Lesions in Type I Patients
Briefly











Micropulse Laser Treatment of Retinal-choroidal Anastomoses in ARMD

High-energy, short-duration laser appears to be a reproducible technique to obtain closure of retinal-choroidal anastomoses (RCAs) associated with advanced macular degeneration, according to a study by the National Retina Institute (Chevy Chase, MD).

RCAs are a common finding in advanced cases of age-related macular degeneration (ARMD). These high-flow lesions are associated with extensive subretinal exudation. Investigators in this study examined the role of high-energy, short-duration (micropulse) laser pulses in effectively closing these shunts and reducing subretinal fluid.

Nineteen consecutive eyes with advanced ARMD undergoing treatment of RCAs to reduce subretinal exudation in a referral-only retina practice were reviewed retrospectively. RCAs were identified using high-speed indocyanine green angiography, and they were closed using a high-energy, short-duration laser pulse technique. Outcome measures included visual acuity, resolution of subretinal fluid and persistence of RCAs.

All 19 eyes with RCA associated with macular degeneration were successfully treated. Mean baseline visual acuity was 20/140 (HM to 20/50). All eyes (100 percent) had subretinal exudation and 73 percent had subretinal fibrosis at the time initial treatment. At mean follow-up of 11.7 (two to 23) months, patients had undergone an average of 3.52 (one to 12) sessions of laser treatment. Average final visual acuity was 20/146 (CF to 20/40). Fifty-three percent of eyes had complete resolution of subretinal fluid; 100 percent had subretinal fibrosis; 43 percent had complete closure of RCA. No significant complications were encountered. The authors of the study believe that the technique is associated with stabilization of visual acuity without significant risk of complication.

SOURCE: Johnson TM, Glaser BM. Micropulse laser treatment of retinal-choroidal anastomoses in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2005 Jan 14 [epub ahead of print]. 		Table of Contents











Identifying Genes Responsible for Cone Dystrophies

In this case-control study by the Jules Stein Eye Institute’s department of ophthalmology, investigators studied 240 unrelated patients diagnosed with cone dystrophy, cone-rod dystrophy, macular dystrophy, macular degeneration or Stargardt disease; 95 control individuals; and two unrelated families with a distinctive type of cone dystrophy. Their aim was to identify genes responsible for cone dystrophies and determine the functional consequences of their underlying mutations.

The DNA of the 240 patients was screened for sequence variants in the PDE6H gene, which encodes the inhibitory gamma-subunit of cone cyclic guanosine monophosphate (cGMP)-phosphodiesterase (PDE), using single-strand conformation polymorphism electrophoresis. They analyzed the effect of a nucleotide substitution in the DNA of a patient on gene expression efficiency by in vitro transcription/translation.

Results showed a heterozygous G to C substitution in the 5" untranslated region (UTR) of the PDE6H gene in the DNA of a patient with a distinctive form of cone dystrophy, her sibling and their father. This rare form of disease is very different in manifestation from other cone dystrophies and has been described as "cone dystrophy with nyctalopia and supernormal rod responses," "cone dystrophy with supernormal scotopic ERGs" and "supernormal and delayed rod ERG syndrome." Among the 240 patients in the study, only one had the G to C variant. None of the 95 controls had this nucleotide change. Investigators also determined that the PDE6H variant was not present in another family affected with this particular type of cone dystrophy. Because the 5" UTR of mRNAs plays a critical role in the regulation of protein synthesis, they determined the effect of the G to C change in this process. By use of in vitro transcription/translation experiments, they demonstrated that this substitution could lead to an increase in PDE6H gene expression.

Investigators believe that if the effect of the G to C substitution they observed in vitro also occurs in vivo, it will lead to PDE6H overexpression in the photoreceptors. Excess of PDEgamma may affect normal cone cGMP-PDE function by inhibiting the catalytic PDEalpha-beta activity and lead to pathogenic elevation of cGMP and eventual degeneration of cone photoreceptors.

SOURCE: Piri N, Gao YQ, Danciger M, et al. A substitution of G to C in the cone cGMP-phosphodiesterase gamma subunit gene found in a distinctive form of cone dystrophy. Ophthalmol 2005;112(1):159-66.		 Table of Contents






Trace Microalbuminuria in Inflammatory Cystoid Macular Edema

Researchers in the Netherlands recently conducted a matched case-control study to assess the role of cardiovascular morbidity, its risk factors and microalbuminuria in the development of inflammatory cystoid macular edema (CME).

Twenty-four consecutive patients with uveitis and CME, and 24 uveitis patients without CME, matched for age and duration of uveitis, were included in the study. Patients and controls were interviewed for the presence of cardiovascular risk factors and cardiovascular morbidity. All medications were registered. Researchers measured morning urinary albumin concentration, blood pressure, C-reactive protein and creatinine in blood. Patients suffering from diabetes mellitus were excluded from the study.

Investigators found a positive association between trace- and/or microalbuminuria and inflammatory CME (odds ratio 13.0, 95 percent CI 2.5 to 68.1 and; odds ratio 5.9, 95 percent CI 1.6 to 22.6), but no relation between CME and cardiovascular morbidity or its risk factors. No additional association between trace- and/or any microalbuminuria and general characteristics of patients, specific factors related to general disease as a cause of ocular inflammation, location of uveitis, duration of uveitis and medication were found. The authors believe that their finding brings new insight into the pathogenesis of CME and could open up new avenues for treating it.

SOURCE: van Kooij B, Fijnheer R, Roest M, Rothova A. Trace microalbuminuria in inflammatory cystoid macular edema. Am J Ophthalmol 2004;138(6):1010-5. 		Table of Contents






Relationship of Diabetic Retinopathy to Preclinical Diabetic Glomerulopathy Lesions in Type I Patients

Few epidemiological data exist regarding the correlation of anatomic measures of diabetic retinopathy and nephropathy, especially early in the disease processes. The aim of the Renin-Angiotensin System Study (RASS), conducted by researchers at the University of Wisconsin Medical School, the University of Toronto, McGill University (Montreal) and the University of Minnesota, was to examine the association of severity of diabetic retinopathy with histological measures of diabetic nephropathy in normoalbuminuric patients with Type I diabetes.

The study included 285 participants in RASS, a multicenter diabetic nephropathy primary prevention trial, who were aged 16 and older and had two to 20 years of Type I diabetes with normal baseline renal function measures. Researchers measured albumin excretion rate (AER), blood pressure, serum creatinine and glomerular filtration rate (GFR) using standardized protocols. Diabetic retinopathy was determined by masked grading of 30-degree color stereoscopic fundus photographs of seven standard fields using the ETDRS severity scale. Baseline renal structural parameters, including fraction of the glomerulus occupied by the mesangium or mesangial fractional volume [Vv(Mes/glom)] and glomerular basement membrane width, were assessed by masked electron microscopic morphometric analyses of research percutaneous renal biopsies.

No retinopathy was present in 36 percent, mild nonproliferative diabetic retinopathy in 53 percent, moderate to severe nonproliferative diabetic retinopathy in nine percent, and proliferative diabetic retinopathy in two percent of the cohort. Retinopathy was not related to AER, blood pressure, serum creatinine or GFR. All renal anatomical endpoints were associated with increasing severity of diabetic retinopathy, while controlling for other risk factors. Investigators believe that their data show a significant association between diabetic retinopathy and preclinical morphologic changes of diabetic nephropathy in Type I diabetic patients.

SOURCE: Klein R, Zinman B, Gardiner R, et al. The relationship of diabetic retinopathy to preclinical diabetic glomerulopathy lesions in Type I diabetic patients: the Renin-Angiotensin System Study. Diabetes 2005;54(2):527-33. 		Table of Contents





BRIEFLY
  • ANGIOSYN ACQUIRED BY PFIZER IN $527 MILLION DEAL. Angiosyn, Inc., a privately held biopharmaceutical company, has agreed to be acquired by Pfizer, Inc., in a $527 million deal. The acquisition will extend Pfizer"s research commitment in ophthalmology and allows the company to further develop Angiosyn"s novel angiostatic agent. The agent"s primary therapeutic indication is for ophthalmic diseases, such as macular degeneration, in which uncontrolled blood vessel growth can lead to decreased vision and blindness. Under the terms of the agreement, Angiosyn would be merged into a wholly owned subsidiary of Pfizer and its stockholders would receive an up-front payment and other compensation, which together total about $527 million, plus royalties on future sales. Full payment is contingent on successful completion of commercial development for an ophthalmic indication and a second therapeutic area. The merger is subject to customary closing conditions (including approval under the Hart-Scott-Rodino Antitrust Improvements Act of 1976), and is expected to close in the first quarter of 2005.
  • GENERIC CIPROFLOXACIN OPHTHALMIC SOLUTION APPROVED. Hi-Tech Pharmacal Co., Inc., has received FDA approval for its Abbreviated New Drug Application (ANDA) for ciprofloxacin ophthalmic solution USP, 0.3%, the generic equivalent of Alcon Laboratories" Ciloxan Ophthalmic Solution, 0.3% indicated for the treatment of bacterial infections. Hi-Tech expects to start marketing its solution in February 2005.
  • MACUGEN NOW AVAILABLE. Macugen (pegaptanib sodium injection), manufactured by Eyetech Pharmaceuticals, Inc., is now available through three distributors in the United States: McKesson Specialty, Priority Healthcare and Besse Medical. The distributors have begun providing the drug to retinal specialists, who will make the product available to patients suffering from "wet" age-related macular degeneration. Macugen was approved by the FDA on December 17, 2004, for use in treating the wet form of the disease.
  • GERMAN BIOTECH FIRM SIGNS DEVELOPMENT DEAL WITH ALCON. Jerini, a Germany-based biotech firm, has entered into a discovery and development collaboration with Alcon, Inc., to use Jerini’s Peptides-to-Drugs technology to make eye disease treatments. Jerini will get upfront and license fees, personnel funding and milestone payments when certain targets are met; it will also receive royalties on sales from Alcon. No additional details were released.

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