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  Methods and compositions for control of fetal growth via modulation of relaxinUSPTO Application #: 20080108572Title: Methods and compositions for control of fetal growth via modulation of relaxin Abstract: The invention relates to the method for treatment, diagnosis and prevention of diseases related to fetal growth and placental insufficiency and comprises methods including inhibiting or increasing relaxin synthesis, relaxin receptor synthesis, relaxin binding to the relaxin receptor, and relaxin receptor activity. The invention also relates to screening assays to identify compounds that modulate relaxin and/or relaxin receptor activity. The invention further relates to gene therapy methods utilizing relaxin and relaxin-related sequences for the treatment and prevention of diseases related to fetal growth and placental insufficiency. (end of abstract) Agent: Robins & Pasternak - Palo Alto, CA, US Inventor: Elaine Unemori USPTO Applicaton #: 20080108572 - Class: 514012000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 25 Or More Peptide Repeating Units In Known Peptide Chain Structure The Patent Description & Claims data below is from USPTO Patent Application 20080108572. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a divisional of U.S. patent application Ser. No. 11/478,267 filed Jun. 28, 2006, which is a divisional of U.S. patent application Ser. No. 11/120,582 filed May 2, 2005 which claims benefit of the U.S. provisional patent application No. 60/567,353, filed Apr. 30, 2004, the disclosure of which is incorporated herein by reference in its entirety for all purposes. BACKGROUND OF THE INVENTION [0002] Intrauterine growth retardation ("IUGR") is a syndrome whereby the size or growth rate of a fetus is unusually small for the gestational age of the fetus. Fetuses weighing below the 10.sup.th percentile for their gestational age, are by definition afflicted with IUGR. IUGR can result from a wide variety of causes, all of which result in the failure of a fetus to exhibit a normal rate of growth. Small gestational age (SGA) babies are defined as birth weight and/or length at least 2 standard deviations below the mean for gestational age (Lee et al., 2003, Pediatrics 111:1253-1261). Although some fetuses that are small for their gestational age can be simply constitutionally small and not otherwise unhealthy, other causes, such as placental insufficiency, infection, and genetic disorders, can result in significant perinatal morbidity and mortality. The individuals so affected are also more likely to duffer from abnormal structure, function, and disease in later life. Any method to reverse or ameliorate IUGR can thus provide significant benefit to these offspring. [0003] A number of conditions have been identified as increasing the risk that a fetus will display IUGR. Often the primary effect of these conditions is to cause placental insufficiency (Lepercq and Mahieu-Caputo, 1998, Horm. Res. 49(suppl 2):14-19). These conditions include maternal weight and height prior to pregnancy and low weight gin during the pregnancy; maternal history of stillbirth, neonatal death, and previous offspring with low birth weight; maternal activities during pregnancy, such as smoking, alcohol and drug use, and poor nutrition; early intrauterine infections; maternal medical diseases; multiparous pregnancies; and various complications arising during pregnancy. [0004] The maternal endocrine system likely has a role in controlling fetal growth rates, e.g. by regulating the placental nutrient supply. Insulin and insulin-like growth factor I have been shown to be involved in this process (Gluckman et al., 1990, Acta Paediatr. Scand. [Suppl] 367:105-110; U.S. Pat. No. 5,420,111). [0005] Recent studies have suggested that VEGF activity is critical to normal placental development (reviewed in Tsatsaris et al., 2003, J Clin Endocrinol Metab 88:5555-5563). The imbalance between expression of members of the VEGF family (including VEGF-A and placental growth factor (PlGF)) and their soluble and cell-associated receptors (s-flt and flt, respectively) may play a role in conditions associated with placental insufficiency. It is currently believed that upregulation of s-flt, which can antagonize VEGF and PlGF activity, shifts the balance of this family toward anti-angiogenic activity, thus interfering with normal vascular development of the placenta. It is also believed that inadequate placental perfusion may be upstream of maternal disorders, such as preeclampsia (Bdolah et al., 2004, Semin Nephrol 24:548-556), HELLP (Cho et al., 2003, J Korean Med Sci 18:402-428), as well as abnormal or inadequate fetal growth (Ahmed and Perkins, 2000, Baillieres Best Pract Res Clin Obstet Gynecol 14:981-998). Treatments that can prolong pregnancy are likely to be beneficial in allowing both short-term fetal growth and obviation of long term developmental impairment. [0006] Because of the current lack of effective treatments for IUGR or placental insufficiency, there is a strong need to develop new therapeutic approaches for this condition. BRIEF SUMMARY OF THE INVENTION [0007] The present invention provides compositions and methods for the treatment, diagnosis and prevention of conditions, disorders or diseases involving fetal growth, including, but not limited to, intrauterine growth retardation ("IUGR") and placental insufficiency. The invention provides methods for modulating signaling pathways related to the polypeptide hormone, relaxin. More particularly, the present invention provides methods relating to the modulation of relaxin synthesis, relaxin receptor synthesis, relaxin binding to its receptor, and relaxin signaling. [0008] The present invention also provides methods for the identification and prophylactic or therapeutic use of compounds in the treatment and diagnosis of conditions, disorders, or diseases involving fetal growth, including, but not limited to, intrauterine growth retardation ("IUGR") and placental insufficiency. Additionally, methods are provided for the diagnostic monitoring of patients undergoing clinical evaluation for the treatment of conditions or disorders involving fetal growth, for monitoring the efficacy of compounds in clinical trials and for identifying subjects who may be predisposed to such conditions, disorders, or diseases involving fetal growth. [0009] Specifically, in one embodiment the invention provides a method of increasing intrauterine fetal growth rate, comprising the step of administering to a pregnant mammal a therapeutically effective amount of relaxin for a time sufficient to increase fetal growth rate. In related embodiments, the relaxin is administered during the first, second, and/or third trimester of pregnancy. In another related embodiment, the relaxin is administered for at least 2 weeks starting at ovulation. In yet another embodiment, the relaxin is administered before and after ovulation. In yet another embodiment, the relaxin is administered for about a week before ovulation and about four weeks after ovulation. [0010] In another embodiment, the invention provides a method of increasing intrauterine fetal growth rate wherein the relaxin is administered in an amount sufficient to result in the birth of a baby of at least around normal birth weight. In a related embodiment, the relaxin is administered in an amount sufficient to maintain a serum concentration in the pregnant mammal of at least around 1 ng/mL. In yet another related embodiment, the relaxin may be administered parenterally or by continuous subcutaneous infusion or intravaginally. In yet another embodiment, the relaxin is administered at a dose between 10 .mu.g/kg/day and 200 .mu.g/kg/day. [0011] In another embodiment, the invention provides a method of increasing intrauterine fetal growth rate comprising the step of administering to a pregnant mammal a therapeutically effective amount of relaxin for a time sufficient to increase fetal growth rate, wherein the increase in fetal growth rate is assessed by an imaging technique. In a related embodiment, the imaging technique is selected from the group consisting of ultrasonic imaging and magnetic resonance imaging. In yet another embodiment, the pregnant mammal is diagnosed as hosting a fetus with intrauterine growth retardation. In one embodiment, the diagnosis of intrauterine growth retardation is obtained through the use of an imaging technique, e.g., ultrasonic imaging or magnetic resonance imaging. [0012] In another embodiment, the invention provides a method of increasing intrauterine fetal growth rate comprising the step of administering to a pregnant mammal a therapeutically effective amount of relaxin wherein the mammal has a condition that increases the risk of fetal intrauterine growth retardation or low birth weight. In a related embodiment, the condition that increases the risk of fetal intrauterine growth retardation is selected from the group consisting of lupus, hyperthyroidism, hypertension, preeclampsia, malarial infection, serum antiphospholipid antibodies, a history of recurrent spontaneous abortion, a history of intrauterine growth retardation, a history of having children with low birth weight, a multiple-gestation pregnancy, and a pregnancy resulting from in vitro fertilization and embryo transfer. [0013] In some embodiments, the methods of the invention may be use to treat pregnant humans. In other embodiments, the methods may be used to treat other pregnant mammals, e.g., a horse, cow, sheep, pig, deer, dog, cat, rat, or a mouse. [0014] The invention also provides, in one embodiment, a method of reducing the risk or incidence of spontaneous abortion in a pregnant mammal, the method comprising administering to the pregnant mammal an amount of relaxin effective to reduce the risk or incidence of spontaneous abortion. the relaxin is administered during the first trimester of pregnancy. In related embodiments, the relaxin is administered during the first, second, and/or third trimester of pregnancy. In another related embodiment, the relaxin is administered for at least 2 weeks starting at ovulation. In yet another embodiment, the relaxin is administered before and after ovulation. In yet another embodiment, the relaxin is administered for about a week before ovulation and about four weeks after ovulation. In yet another embodiment, the relaxin is administered in an amount sufficient to maintain a serum concentration of at least about 1 ng/ml. [0015] In another embodiment, the invention provides a method for determining whether a subject has an increased risk for developing a condition associated with placental insufficiency, comprising the steps of measuring the level of relaxin expression in said subject, comparing said measured level of relaxin to a level of relaxin associated with normal placental development in an appropriate control subject, wherein a lower measured level of relaxin correlates with an increased risk of developing said condition. In a related embodiment, the subject is pregnant. In a related embodiment, the placental insufficiency is selected from the group consisting of IUGR, SGR, and preeclampsia. In yet other related embodiments, the relaxin expression is measured in serum or tissue. In yet another embodiment, the level of level of relaxin expression is measured by determining the level of transcription of a gene encoding relaxin. In yet another related embodiment, the subject has previously been diagnosed with intrauterine growth retardation, placental insufficiency, or preeclampsia. In yet another related embodiment, the method further comprises treating said subject with a therapeutic amount of relaxin. In yet another embodiment, the relaxin is human H2 relaxin. In yet another embodiment, the relaxin is selected from the group consisting of H1, H2 or H3 relaxin. In yet another embodiment, the method comprises testing the subject to determine whether levels of HIF-1.alpha. or HGF have increased. [0016] In yet another embodiment, the invention provides a method for determining whether a subject has an increased risk for developing a condition associated with placental insufficiency, comprising determining a nucleotide sequence of at least a portion of a gene encoding relaxin in the subject, wherein the identification of a nucleotide sequence associated with the decreased expression or activity of the relaxin peptide indicates that the subject has an increased risk for developing said condition. In a related embodiment, the subject is pregnant. In a related embodiment, the condition is selected from the group consisting of IUGR, SGR, and preeclampsia. In yet another related embodiment, the subject has previously been diagnosed with intrauterine growth retardation, placental insufficiency, or preeclampsia. In yet another related embodiment, the method further comprises treating said subject with a therapeutic amount of relaxin. In yet another embodiment, the relaxin is human H2 relaxin. In yet another embodiment, the relaxin is selected from the group consisting of H1, H2 or H3 relaxin. In yet another embodiment, the method comprises testing the subject to determine whether levels of IF-1.alpha. or HGF have increased. [0017] In another embodiment, the invention provides a method for determining whether a subject has an increased risk for developing a condition associated with placental insufficiency, comprising determining a nucleotide sequence of at least a portion of a gene encoding an enzyme involved in the post-translational processing of relaxin, wherein the identification of a nucleotide sequence associated with the decreased activity of relaxin indicates that the subject has an increased risk for developing said condition. In a related embodiment, the condition is selected from the group consisting of IUGR, SGR, and preeclampsia. In a related embodiment, the subject is pregnant. In yet another related embodiment, the subject has previously been diagnosed with intrauterine growth retardation, placental insufficiency, or preeclampsia. In yet another related embodiment, the method further comprises treating said subject with a therapeutic amount of relaxin. In yet another embodiment, the relaxin is human H2 relaxin. In yet another embodiment, the relaxin is selected from the group consisting of H1, H2 or H3 relaxin. In yet another embodiment, the method comprises testing the subject to determine whether levels of HIF-1.alpha. or HGF have increased. [0018] In another embodiment, the invention provides a method for treating placental insufficiency in a subject, comprising: diagnosing placental insufficiency in the subject, and administering a therapeutically effective amount of relaxin to treat the placental insufficiency. In yet another related embodiment, the subject has previously been diagnosed with intrauterine growth retardation, placental insufficiency, or preeclampsia. In yet another related embodiment, the method further comprises treating said subject with a therapeutic amount of relaxin. In yet another embodiment, the relaxin is human H2 relaxin. In yet another embodiment, the relaxin is selected from the group consisting of H1, H2 or H3 relaxin. In yet another embodiment, the method comprises testing the subject to determine whether levels of HIF-1.alpha. or HGF have increased. BRIEF DESCRIPTION OF THE DRAWINGS [0019] FIG. 1 shows the change in endometrial thickness between Day 0-Day 7 in vehicle- and relaxin-treated female cynomolgus monkeys. Two endometrial thickness measurements were made in each of the sagittal and transverse planes for each female, and were averaged to yield one thickness measurement for each female on each of Days 0 and 7. Thickness increased in all females in the relaxin group (p=0.003, paired t-test), whereas it increased in five of the seven females in the vehicle-treated group (NS). [0020] FIG. 2 shows the results of real-time quantitative RT-PCR determination of abundance of HIF-1.alpha. transcripts in NHE cells 12 hours and 24 hours after treatment. A rhRLX dose dependent (0.1-100 ng/mL) increase in HIF-1.alpha. mRNA is observed. Data shown represent means .+-.SD; n=3 independent tissue culture experiments; *p<0.05, compared to untreated control, by Bonferroni t-test. Continue reading... Full patent description for Methods and compositions for control of fetal growth via modulation of relaxin Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Methods and compositions for control of fetal growth via modulation of relaxin patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. 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