Methods of treatment of spontaneous preterm birth
Inventors
Sirota, Marina • Le, Brian • Wong, Ronald • Stevenson, David
Assignees
University of California San Diego UCSD • Leland Stanford Junior University
Publication Number
US-12310934-B2
Publication Date
2025-05-27
Expiration Date
2040-03-20
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Abstract
Spontaneous preterm birth (sPTB) is premature delivery prior to 37 weeks of pregnancy and is a leading cause of infant mortality worldwide. sPTB is associated with a unique gene expression profile. Identified herein are numerous safe and proven therapeutic compositions used for unrelated indications that have the biological effect of reversing, in part, the gene expression profile of sPTB and which can be used in preventative or interventional treatments to prevent, delay, or ameliorate sPTB. The repurposed drugs include several Class A and Class B therapeutics that are regarded as safe or low risk in pregnant subjects.
Core Innovation
The invention provides novel therapeutic methods for preventing or treating spontaneous preterm birth (sPTB) by administering repurposed drugs that partially reverse the gene expression profile associated with sPTB in pregnant subjects. These therapeutic compositions consist of one or more agents, including various drugs currently approved and used for unrelated indications, but which have been computationally identified to yield a gene expression signature that opposes that seen in sPTB. The agents are administered in therapeutically effective amounts to subjects at risk or suffering from sPTB, including for preventative or interventional treatment.
The problem addressed is that sPTB is the leading cause of infant mortality worldwide, with limited pharmacological options to prevent its occurrence. Existing treatments such as progesterone supplementation or surgical methods offer only partial efficacy or involve invasive procedures. There is a critical need for new, safe, and effective drugs to prevent or ameliorate sPTB, especially those with proven safety in pregnancy.
The method uses computational drug repositioning to compare gene expression profiles of known drugs with the gene expression signature characteristic of sPTB, identifying drugs with opposing gene effects as potential therapeutics. From this approach, a set of drugs with pregnancy category A or B safety designations, and which demonstrate significant reversal of sPTB-associated gene expression, were selected as candidate agents. These agents can be administered singly or in combination and via various routes, to reduce risk, delay or prevent preterm birth, or reduce associated fetal morbidity or mortality.
Claims Coverage
The patent contains one independent claim with several dependent claims, capturing the key inventive features of the invention.
Method of treating spontaneous preterm birth with agents that partially reverse the gene expression profile associated with spontaneous preterm birth
A method for treating spontaneous preterm birth in a subject in need of such treatment, involving administering a therapeutic composition that contains a therapeutically effective amount of one or more agents that partially reverse the gene expression profile associated with spontaneous preterm birth. - The claimed method is applicable to subjects at any stage of pregnancy. - The therapeutic composition can include agents selected from a defined group of repurposed drugs—including, but not limited to, naproxen, cefotaxime, levopropoxyphene, prednisone, vorinostat, brompheniramine, genistein, valproic acid, cefoperazone, alprostadil, lansoprazole, iopamidol, letrozole, molindone, fluticasone, estradiol, isoxicam, thiamphenicol, guanabenz, isometheptene, isoniazid, sulfadimethoxine, ribavirin, pioglitazone, benzocaine, pentoxifylline, meclofenamic acid, rosiglitazone, methotrexate, domperidone, amitriptyline, vinblastine, naringenin, fulvestrant, sodium phenylbutyrate, haloperidol, zalcitabine, zuclopenthixol, iohexol, adenosine phosphate, iodixanol, viomycin, nimodipine, ciclosporin, rifabutin, podophyllotoxin, ceforanide, sirolimus, ajmaline, diloxanide, chlortalidone, trimethobenzamide, timolol, tenoxicam, ketotifen, geldanamycin, dantrolene, dapsone, streptozocin, raloxifene, ambroxol, benzathine benzylpenicillin, finasteride, trifluoperazine, vanoxerine, thiamazole, homosalate, levomepromazine, co-dergocrine mesilate, oxyphenbutazone, promazine, carisoprodol, niclosamide, methoxamine, tocainide, cefotiam, maprotiline, resveratrol, and nadolol. - Embodiments are provided in which the therapeutic composition comprises a specific one of these agents, such as lansoprazole, cefotaxime, rifabutin, chlortalidone, benzathine benzylpenicillin, maprotiline, or naproxen. The core inventive feature centers on utilizing gene-expression signature reversal to select and administer safe, repurposed drugs for sPTB treatment or prevention.
The inventive features are centered on the novel use of existing drugs, each with a demonstrated effect in reversing sPTB-associated gene expression, to treat or prevent spontaneous preterm birth in pregnant subjects through pharmaceutical compositions that may include a wide range of specified agents.
Stated Advantages
The invention identifies numerous therapeutic compositions regarded as safe or low risk in pregnant subjects for preventing, delaying, or ameliorating spontaneous preterm birth.
The use of repurposed existing drugs allows for reduced development time and costs due to already established safety and pharmacokinetic profiles.
The approach provides new therapies and preventative medicines for spontaneous preterm birth beyond the limited and only partially effective options previously available.
The treatments can reduce the risk of sPTB, delay delivery, decrease fetal morbidity or mortality, and improve post-birth outcomes by allowing for further fetal development.
Documented Applications
Preventative treatment of pregnant subjects at risk of spontaneous preterm birth to reduce the risk or severity of sPTB.
Interventional treatment applied to subjects undergoing premature delivery to inhibit or delay delivery, or decrease fetal morbidity or mortality.
Administration of sPTB-reversing agents to pre-pregnancy subjects to reduce the risk of spontaneous preterm birth in subsequent pregnancies.
Therapeutic use in a wide range of pregnant mammals, including humans and non-human animals such as test animals, domestic animals, and livestock.
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