Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-03-10
2004-03-30
Myers, Carla J. (Department: 1634)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C536S023500, C536S024310, C536S024330
Reexamination Certificate
active
06713253
ABSTRACT:
This application is the national phase of PCT Patent Application GB97/02790 filed on Oct. 9, 1997; which claims priority to UK Provisional Application No. GB 9621129.7, filed on Oct. 10, 1996.
BACKGROUND OF THE INVENTION
1. Technical Field of the Invention
This invention relates to a method of detecting a predisposition to, and determining risk of, sight-threatening diabetic retinopathy. The invention also provides diagnostic kits for the assessment of risk of developing sight-threatening diabetic retinopathy.
2. Description of the Prior Art
Insulin dependent (Type I) and non-insulin dependent (Type II) diabetes mellitus are distinct diseases and patients with either form of the disease are at risk of developing microvascular and macrovascular complications such as neuropathy, nephropathy, retinopathy, atherosclerosis and cardiovascular disease. These complications are a major clinical burden in diabetes, but their pathogenesis is not well understood. Susceptibility to diabetic complications has been reported to be inherited independently of diabetes itself. [Seaquist et al., 1989; Ko et al., 1995].
In the United States there are approximately 16 million diabetics, of which it is estimated that only half are diagnosed [CDC, 1995]. Retinal disease (retinopathy) is one of several complications of diabetes and is primarily the result of disruption of small blood vessels, such as capillary leakage, destruction or occlusion of capillaries leading to ischemia, and the uncontrolled growth of new vessels. In many situations, these changes affect the macula, which is the area of the retina that is specialized to color and visual acuity. All of these are consequences of retinal capillary closure or leakage and are not thought of as retinal inflammation.
Characteristic anatomical and physiological changes occur in the retinal circulation. Clinically, they may be classified as background changes, maculopathy and proliferative disease. Any may be present at any level of retinopathy in the same patient, but not all cause visual loss.
Sight-threatening diabetic retinopathy is one of the most common complications of diabetes and is the most common cause of vision loss in the under 65 years age group in developed countries, as a result of non-resolving vitreous hemorrhage, traction retinal detachment or diabetic maculopathy. Sight-threatening diabetic retinopathy refers to diabetic complications affecting the retina that predictably lead to severe loss of vision. These changes include non-resolving vitreous hemorrhage, tractional retinal detachment, or retinal edema.
The following is a description of characteristic anatomical and physiological changes which occur in the retinal circulation in diabetes.
Background Diabetic Retinopathy (BDR)
Microaneurysms and intra-retinal microvascular abnormalities (IRMA) are found adjacent to areas of retinal capillary non-perfusion. Infarcts of the nerve fiber layer (sometimes called cotton-wool spots) and intra-retinal hemorrhages are also included in BDR, as are any areas where fluid swells the retina (retinal edema) which does NOT threaten the central vision. Background retinopathy is not associated with visual loss and does not therefore require treatment.
Maculopathy, Including Clinically-significant Macular Edema (CSME)
The macula lies at the posterior pole of the retina and is specialized for color and accurate vision (high visual acuity) at the fovea which lies centrally in the macula. It may be altered structurally by fluid or lipids collecting in the retina from localized for widespread leaking retinal capillaries (focal or diffuse maculopathy respectively) or by non-perfusion of para-foveal capillaries (ischemic maculopathy). Additionally, retinal traction, macular hemorrhage or macular hole formation will reduce visual acuity.
Proliferation Diabetic Retinopathy (PDR)
As areas of capillary non-perfusion enlarge new vessels arise from the venous circulation at the optic disc (NVD: new vessels at the disc) or from branch retinal veins (NVE: new vessels elsewhere).
Prior to the formation of frank new vessels, there is a pre-proliferative stage which is recognized clinically, as indicated by dilated, beaded retinal veins and signs of widespread retinal non-perfusion. Once the pre-proliferative stage has been identified, the risk of developing PDR in one year is 52% and of developing ‘high-risk, PDR in five years is 60% (ETDRS12, 1991).
High-risk proliferative diabetic retinopathy is a characteristic appearance of the retina in which 50% of the patients will develop severe visual loss within 5 years. Severe visual loss is a fall of 3 or more lines of visual acuity on the eye chart on two separate occasions 3 months apart. The characteristic retinal findings that would qualify for the diagnosis of high-risk PDR include one or more of the following:
1. New vessels at the disc (NVD) that involve at least ¼ to ⅓ of the disc area. This is diagnosed by comparison to Standard Photograph 10A of the Modified Airlee House Classification of Diabetic Retinopathy [DRS Report No. 7, 1981];
2. NVD less than ¼ of the disc area if fresh vitreous hemorrhage is present; and
3. New vessels elsewhere (NVE) greater than or equal to ½ the disc area in size if fresh vitreous hemorrhage is present.
Appropriately timed laser treatment can reduce the two year incidence of severe visual loss (SVL) in ‘high-risk, proliferative disease by 50% and the incidence of moderate visual loss (MVL) over two years in those with macular edema by 50%. [DRS8, 1981; ETDRS1, 1985; ETDRS9, 1991].
Advanced Diabetic Retinopathy
Initially, these new vessels leak and are fragile, with the resulting vitreous hemorrhage causing a sudden, often profound, loss of vision. The blood may resolve over the following weeks, but it may become organized into a dense opaque mass in the vitreous which does not resolve.
Fibrous tissue appears adjacent to these new vessels, which subsequently contracts, leading to tractional retinal detachments. New vessels may also grow across the iris and prevent fluid draining from the eye, causing rubeotic glaucoma.
Epidemiology
Approximately 16 million people in the United States have diabetes mellitus, of which 50% are diagnosed. Of these, 10-15% have insulin-dependent diabetes mellitus (Type I; IDDM) which is usually diagnosed before the age of 40 years of age. The majority have non-insulin dependent diabetes (Type II DM; NIDDM), some of which may be treated with insulin. From the Wisconsin epidemiological study of diabetic retinopathy, duration of diabetes is associated with increasing incidence of diabetic retinopathy [Klein et al, 1994]. Other risk factors include age less than 30 at diagnosis, being male, raised glycosylated hemoglobin (HbA
1c
), hypertension, hyperlipidemia, pregnancy and diabetic nephropathy.
Genetic testing is now possible (see U.S. Pat. Nos. 4,582,788 and 5,110,920) for diseases associated with, or caused by, one to two genes, once the genes are identified, to determine the risk of a person carrying a given gene for the disease (see for example U.S. Pat. Nos. 4,623,619, 4,801,531, 4,666,828 and 5,268,267).
U.S. Pat. Nos. 5,039,606 and 5,196,308, as well as Pociot et al. (1992) disclose methods of identifying people who are at risk for developing diabetes. However, these references do not provide methods of determining among diabetics those who are at risk for developing sight-threatening retinopathy. Ko et at. (1995) do provide a single factor, a polymorphic marker at the 5′ end of the aldose reductase gene, that is associated with early onset of diabetic retinopathy in Chinese patients with NIDDM. However, this provides only one marker, which as shown in the Ko et al. reference does not identify all persons at risk. Additionally, the population studied is not the same ethnic population as found in the United States and much of Europe, therefore the data may not be completely applicable to US and European populations.
The pathogenesis of retinal complications from dia
Duff Gordon W.
Rennie Ian G.
Richardson Patrick R. S.
Elrifi Ivor E.
Interleukin Genetics Inc.
Mintz Levin Cohn Ferris Glovsky and Popeo P.C.
Myers Carla J.
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