Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-05-30
2003-02-18
Fredman, Jeffrey (Department: 1655)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S024300, C536S022100, C435S006120, C435S091200
Reexamination Certificate
active
06521747
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to variation in genes that encode pharmaceutically-important proteins. In particular, this invention provides genetic variants of the human angiotensin receptor 1 (AGTR1) gene and methods for identifying which variant(s) of this gene is/are possessed by an individual.
BACKGROUND OF THE INVENTION
Current methods for identifying pharmaceuticals to treat disease often start by identifying, cloning, and expressing an important target protein related to the disease. A determination of whether an agonist or antagonist is needed to produce an effect that may benefit a patient with the disease is then made. Then, vast numbers of compounds are screened against the target protein to find new potential drugs. The desired outcome of this process is a lead compound that is specific for the target, thereby reducing the incidence of the undesired side effects usually caused by activity at non-intended targets. The lead compound identified in this screening process then undergoes further in vitro and in vivo testing to determine its absorption, disposition, metabolism and toxicological profiles. Typically, this testing involves use of cell lines and animal models with limited, if any, genetic diversity.
What this approach fails to consider, however, is that natural genetic variability exists between individuals in any and every population with respect to pharmaceutically-important proteins, including the protein targets of candidate drugs, the enzymes that metabolize these drugs and the proteins whose activity is modulated by such drug targets. Subtle alteration(s) in the primary nucleotide sequence of a gene encoding a pharmaceutically-important protein may be manifested as significant variation in expression, structure and/or function of the protein. Such alterations may explain the relatively high degree of uncertainty inherent in the treatment of individuals with a drug whose design is based upon a single representative example of the target or enzyme(s) involved in metabolizing the drug. For example, it is well-established that some drugs frequently have lower efficacy in some individuals than others, which means such individuals and their physicians must weigh the possible benefit of a larger dosage against a greater risk of side effects. Also, there is significant variation in how well people metabolize drugs and other exogenous chemicals, resulting in substantial interindividual variation in the toxicity and/or efficacy of such exogenous substances (Evans et al., 1999
, Science
286:487-491). This variability in efficacy or toxicity of a drug in genetically-diverse patients makes many drugs ineffective or even dangerous in certain groups of the population, leading to the failure of such drugs in clinical trials or their early withdrawal from the market even though they could be highly beneficial for other groups in the population. This problem significantly increases the time and cost of drug discovery and development, which is a matter of great public concern.
It is well-recognized by pharmaceutical scientists that considering the impact of the genetic variability of pharmaceutically-important proteins in the early phases of drug discovery and development is likely to reduce the failure rate of candidate and approved drugs (Marshall A 1997
Nature Biotech
15:1249-52; Kleyn P W et al. 1998
Science
281: 1820-21; Kola I 1999
Curr Opin Biotech
10:589-92; Hill A V S et al. 1999
in Evolution in Health and Disease
Stearns S S (Ed.) Oxford University Press, New York, pp 62-76; Meyer U. A. 1999
in Evolution in Health and Disease
Stearns S S (Ed.) Oxford University Press, New York, pp 41-49; Kalow W et al. 1999
Clin. Pharm. Therap
. 66:445-7; Marshall, E 1999
Science
284:406-7; Judson R et al. 2000
Pharmacogenomics
1:1-12; Roses AD 2000
Nature
405:857-65). However, in practice this has been difficult to do, in large part because of the time and cost required for discovering the amount of genetic variation that exists in the population (Chakravarti A 1998
Nature Genet
19:216-7; Wang D G et al 1998
Science
280:1077-82; Chakravarti A 1999
Nat Genet
21:56-60 (suppl); Stephens J C 1999
Mol. Diagnosis
4:309-317; Kwok P Y and Gu S 1999
Mol. Med. Today
5:538-43; Davidson S 2000
Nature Biotech
18:1134-5).
The standard for measuring genetic variation among individuals is the haplotype, which is the ordered combination of polymorphisms in the sequence of each form of a gene that exists in the population. Because haplotypes represent the variation across each form of a gene, they provide a more accurate and reliable measurement of genetic variation than individual polymorphisms. For example, while specific variations in gene sequences have been associated with a particular phenotype such as disease susceptibility (Roses A D supra; Ulbrecht M et al. 2000
Am J Respir Crit Care Med
161: 469-74) and drug response (Wolfe C R et al. 2000
BMJ
320:987-90; Dahl BS 1997
Acta Psychiatr Scand
96 (Suppl 391): 14-21), in many other cases an individual polymorphism may be found in a variety of genomic backgrounds, i.e., different haplotypes, and therefore shows no definitive coupling between the polymorphism and the causative site for the phenotype (Clark A G et al. 1998
Am J Hum Genet
63:595-612; Ulbrecht M et al. 2000 supra; Drysdale et al. 2000
PNAS
97:10483-10488). Thus, there is an unmet need in the pharmaceutical industry for information on what haplotypes exist in the population for pharmaceutically-important genes. Such haplotype information would be useful in improving the efficiency and output of several steps in the drug discovery and development process, including target validation, identifying lead compounds, and early phase clinical trials (Marshall et al., supra).
One pharmaceutically-important gene for the treatment of hypertension is the angiotensin receptor 1 (AGTR1) gene or its encoded product. AGTR1 is a G protein-coupled receptor that binds to the vasopressor angiotensin II, which is an important effector controlling blood pressure and volume in the cardiovascular system. AGTR1 appears to mediate the major cardiovascular effects of angiotensin II, and this is accomplished through activation of a phosphatidylinositol-calcium second messenger system (Murphy et al.,
Nature
1991; 351:233-236).
Pharmacologic agents that antagonize AGTR1 have been shown to be highly successful in the treatment of angiotensin II-dependent hypertension (Ramahi,
Postgrad. Med
2001; 109:115-122). This recently developed class of angiotensin II receptor blockers (ARBs) appear to be as effective as angiotensin-converting enzyme (ACE) inhibitors in delaying the progression of renal injury in animal models of diabetes (Barnett,
Blood Press
2001; 10 Suppl 1:21-26). They act by selectively blocking the binding of angiotensin II to AGTR1 and may therefore offer a more complete blockade of the renin-angiotensin system than ACE inhibitors, which inhibit the conversion of angiotensin I to angiotensin II.
Unlike the angiotensin converting enzyme (ACE) inhibitors, these new drugs block the effects of angiotensin II regardless of whether it is produced systemically in the circulation or locally via ACE- or non-ACE-dependent pathways in tissues.
With the AGTR1 receptor blocked, angiotensin II is available to activate AGTR2, which mediates several potentially beneficial effects in the cardiovascular system, including vasodilation, antiproliferation, and apoptosis (Siragy,
Am J Cardiol
. 1999; 84:3S-8S). ARBs control a number of angiotensin II effects that are relevant to the pathophysiology of cardiovascular disease, including vasoconstriction, renal sodium reabsorption, aldosterone and vasopressin secretion, sympathetic activation, and vascular and cardiac hyperplasia and hypertrophy. Thus, ARBs provide a highly selective approach for regulating the effects of angiotensin II (Siragy, supra).
Most notable among ARBs is losartan, which has been found to be an effective anti-hypertension drug as it has an active metabolite that prolongs its duration of
Anastasio Alison E.
Finkel Kevin
Koshy Beena
Lee Helen
Fredman Jeffrey
Genaissance Pharmaceuticals, Inc.
Henderson Melodie W.
Judisch Nathaniel D.
Shaner Sandra L.
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