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.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a divisional of U.S. patent application Ser. No. 11 / 20,582 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 10th 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 ...

AI Technical Summary

Benefits of technology

[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 μg / kg / day—and 200 μg / kg / day.

[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.

[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.

Problems solved by technology

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.

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.

It is currently believed that upregulation of s-flt, which can antagonize VEGF and PIGF activity, shifts the balance of this family toward anti-angiogenic activity, thus interfering with normal vascular development of the placenta.

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