WO2016144968A1 - Thérapie par la relaxine pour troubles du diaphragme - Google Patents

Thérapie par la relaxine pour troubles du diaphragme Download PDF

Info

Publication number
WO2016144968A1
WO2016144968A1 PCT/US2016/021389 US2016021389W WO2016144968A1 WO 2016144968 A1 WO2016144968 A1 WO 2016144968A1 US 2016021389 W US2016021389 W US 2016021389W WO 2016144968 A1 WO2016144968 A1 WO 2016144968A1
Authority
WO
WIPO (PCT)
Prior art keywords
relaxin
rxfp1
activator
peptide
diaphragmatic
Prior art date
Application number
PCT/US2016/021389
Other languages
English (en)
Inventor
Jeffrey S. Chamberlain
Niclas Bengtsson
Ronald Berenson
Original Assignee
University Of Washington
Dmd Therapeutics
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University Of Washington, Dmd Therapeutics filed Critical University Of Washington
Publication of WO2016144968A1 publication Critical patent/WO2016144968A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2221—Relaxins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present disclosure relates generally to methods of treating a subject having diaphragmatic weakness or a condition associated with diaphragmatic weakness.
  • the present disclosure also relates to methods of prophylactically treating a subject at risk of developing diaphragmatic weakness or at risk of developing a condition associated with diaphragmatic weakness.
  • the methods may comprise administering an activator of relaxin/insulin-like family peptide receptor 1 (RXFP1 ). More particularly, the methods may comprise administering a relaxin, a relaxin analog, a prorelaxin, a prorelaxin analog, or combinations thereof to the subject.
  • RXFP1 relaxin/insulin-like family peptide receptor 1
  • DMD Duchenne muscular dystrophy
  • Pompe disease metabolic disorders that can cause damage to the diaphragm
  • inflammatory/autoimmune disorders e.g., polymyositis
  • diaphragmatic damage may lead to respiratory compromise resulting in morbidity and mortality.
  • Current treatment is generally limited to supportive care with ventilator devices and/or supplemental oxygen.
  • therapeutics may repair damage of and/or strengthen the diaphragm.
  • therapies designed to treat the underlying disease (e.g., DMD, polymyositis, etc.).
  • these therapies such as anti-inflammatory and immunosuppressive agents (e.g. , corticosteroids), can be associated with side effects that may limit their use.
  • FIG. 1 is a graph depicting specific force measured as maximum produced force at optimal fiber length normalized to muscle cross-sectional area during end- point analysis following 12 weeks of relaxin treatment. Controls consisted of 18- week-old age-matched male siblings. P ⁇ 0.01 (diaphragm: controls vs. HD relaxin). Error bars represent standard error of mean (SEM).
  • FIG. 2 is a graph depicting contractile-induced injury. Contractile performance of diaphragm strips from treated and non-treated control mice was measured ex vivo after consecutive eccentric contractions of progressively increasing strain. Contractile performance was identified as percent beyond optimal muscle length (L 0 ) and expressed in terms of median force relative to respective initial output. Error bars represent SEM.
  • relaxin can improve the muscle strength of a damaged diaphragm in a relevant animal model of diaphragmatic weakness, DMD, a condition in which diaphragmatic weakness can be the leading cause of death. Accordingly, relaxin may provide a therapy for treating disorders characterized by diaphragmatic weakness and/or respiratory compromise.
  • a and “an” denote one or more, unless specifically noted.
  • “about” refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies by as much as about 30%, about 25%, about 20%, about 15%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1 % to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length. In any embodiment discussed in the context of a numerical value used in conjunction with the term "about,” it is specifically contemplated that the term “about” can be omitted.
  • an "increased” or “enhanced” amount is typically a "statistically significant” amount, and may include an increase that is about 1 .1 , about 1 .2, about 1 .3, about 1 .4, about 1 .5, about 1 .6, about 1 .7, about 1 .8, about 1.9, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, or more times (e.g., about 100, about 500, about 1 ,000 times; including all integers and decimal points in between and above 1 , e.g., 2.1 , 2.2, 2.3, 2.4, etc.) an amount or level described herein.
  • times e.g., about 100, about 500, about 1 ,000 times; including all integers and decimal points in between and above 1 , e.g., 2.1 , 2.2, 2.3, 2.4, etc.
  • a “decreased,” “reduced,” or “lesser” amount is typically a “statistically significant” amount, and may include a decrease that is about 1 .1 , about 1 .2, about 1 .3, about 1 .4, about 1 .5, about 1.6 about 1.7, about 1 .8, about 1 .9, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, or more times (e.g., about 100, about 500, about 1 ,000 times; including all integers and decimal points in between and above 1 , e.g. , 3.6, 3.7. 3.8, 3.9, etc.) an amount or level described herein.
  • times e.g., about 100, about 500, about 1 ,000 times; including all integers and decimal points in between and above 1 , e.g. , 3.6, 3.7. 3.8, 3.9, etc.
  • a “longer plasma half-life” refers to an "increase" in the "plasma half-life” as defined herein.
  • a longer plasma half-life refers to statistically significant increases in half-life.
  • longer plasma half-life refers to a half-life that is at least about several hours longer.
  • longer plasma half-life refers to a half-life that is at least about 2 hours longer, or about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 1 1 , about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21 , about 22, or about 23 hours longer, or any integer or decimal in between a half-life value.
  • a longer plasma half-life refers to a half-life that is at least about 1 day longer. In some embodiments, longer plasma half-life refers to a half-life that is at least about 2 days longer, or about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 1 1 , about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, or about 21 days longer, or any integer or decimal in between a half-life value. In some embodiments, longer plasma half-life refers to a half-life that is at least about 3 weeks longer or more than about 4 weeks longer. In some embodiments, a longer plasma half-life is between about 1 and about 5 days longer, about 2 and about 7 days longer, about 1 and about 2 weeks longer, about 2 and about 3 weeks longer, or about 3 and about 4 weeks longer.
  • a "mammal” includes humans, domestic animals such as laboratory animals and household pets (e.g. , cats, dogs, swine, cattle, sheep, goats, horses, and rabbits), and non-domestic animals such as wildlife and the like.
  • relaxin refers to molecules that bind to the RXFP1 receptor.
  • Relaxin includes H2 relaxin, H3 relaxin, and prorelaxin (e.g. , H2 prorelaxin and H3 prorelaxin).
  • Relaxin also includes analogues of these molecules, including, for example, molecules that comprise additional moieties that may be used to prolong half-lives of these molecules.
  • Relaxin may also include molecules that are smaller in size than native molecules. These molecules may include a smaller number of amino acids for the A chain, the B chain, or both chains of these molecules.
  • relaxin includes small molecules, such as chemical compounds, that bind to the RXFP1 receptor.
  • a "subject” includes any animal that exhibits a disease or symptom, or is at risk for exhibiting a disease or symptom, which can be treated with a compound capable of binding and/or activating the RXFP1 receptor.
  • Suitable subjects include laboratory animals (e.g. , mice, rats, rabbits, and guinea pigs), farm animals, and domestic animals or pets (e.g. , cats or dogs).
  • Non-human primates and human patients are also included.
  • substantially refers to an ample or a considerable amount, quantity, or size (e.g. , nearly totally or completely). For example, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, or more of some given quantity.
  • a “therapeutic agent” refers to any compound that, when administered to a subject (e.g. , a mammal such as a human) in a therapeutically effective amount is capable of effecting treatment of a disease and/or a condition.
  • a “therapeutically effective amount” or a “therapeutically effective dose” refers to an amount of a compound that, when administered to a subject, is sufficient to effect treatment of a disease or condition in the subject.
  • the amount of a compound that constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, the manner of administration, and/or the age of the subject to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his or her own knowledge and to this disclosure. Accordingly, when a compound is said to possess “therapeutic efficacy,” this is intended to mean that the compound is capable of effecting treatment of a disease or condition in a subject, provided a "therapeutically effective amount" of the compound is administered under appropriate conditions.
  • treating refers to the treatment of a disease or condition of interest in a subject (e.g., a human) having the disease or condition of interest, and includes: (i) preventing or inhibiting the disease or condition from occurring in the subject, for example, when the subject is predisposed to the condition but has not yet been diagnosed as having the condition; (ii) inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; and/or (iv) relieving the symptoms resulting from the disease or condition.
  • disease As used herein, "disease,” “disorder,” and “condition” may be used interchangeably or may be different in that the particular malady, injury, or condition may not have a known causative agent (so that etiology has not yet been determined), and it is, therefore, not yet recognized as an injury or disease but only as a condition or a syndrome (e.g., an undesirable condition or syndrome), wherein a more or less specific set of symptoms has been identified by clinicians.
  • a syndrome e.g., an undesirable condition or syndrome
  • the diaphragm is a ventilator muscle that can function to displace chest wall structures (e.g. , a ventilatory pump apparatus).
  • the diaphragm/ventilatory pump apparatus can adjust ventilation to meet a variety of physiologic and pathophysiologic conditions.
  • the diaphragm is a primary muscle of inspiration, and as such, substantially uncompromised function of the diaphragm can support the ventilatory and gas exchange demands of a subject's body.
  • the diaphragm can contract, which may increase the volume and reduce the pressure of the thoracic cavity. This can allow the lungs to expand and take in air.
  • the diaphragm can relax and elastic recoil can allow air to be drawn out of the lungs.
  • Diaphragm dysfunction can be the result of either acute injury or chronic injury. Acute injuries can be to the diaphragm itself. For example, blunt trauma or paralysis from damage to the phrenic nerve or spinal cord can compromise diaphragm function. There are also chronic conditions in which the diaphragm may be a site of damage resulting in compromised respiratory function that can eventually lead to pulmonary failure and/or death. Such chronic conditions can be characterized by inflammation and thus are generally referred to as inflammatory myopathies.
  • the muscle itself is damaged, and these conditions may be referred to as primary myopathies.
  • inflammation can lead to muscle damage and/or death.
  • abnormalities in metabolism can lead to accumulation of toxic substances that may destroy diaphragmatic muscle.
  • Conditions or disorders that can be associated with diaphragmatic weakness include, but are not limited to, muscular dystrophy (e.g., myotonic muscular dystrophy, DMD, Becker muscular dystrophy, limb-girdle muscular dystrophy, facioscapulohumeral muscular dystrophy, congenital muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, and Emery-Dreifuss muscular dystrophy), primary myopathies (e.g., Nemaline myopathy), autoimmune diseases (e.g., polymyositis, dermatomyositis, inclusion body myositis, and systemic lupus erythematosus), metabolic disorders (e.g., glycogen storage disease type II (Pompe disease) and glycogen
  • Damage to the diaphragm can lead to a reduction in specific force and/or increased muscle fatigue. This can result in reduced transdiaphragmatic pressure, peak inspiratory flow, and forced vital capacity and tidal volume. Furthermore, this can lead to ventilator failure, chronic hypoxia, and/or chronic hypercapnia. Diaphragmatic damage can be characterized by muscle injury and/or loss, as well as increased inflammation. [0028] Weakness of the diaphragm can be manifested by shortness of breath, either at rest or with exercise. Measurements of lung function can be made by functional tests measuring total lung capacity, vital capacity, forced expiratory volume, peak inspiratory flow, forced residual capacity, etc.
  • Reduction in one or more of these parameters may be found in patients with diaphragmatic weakness.
  • Measurement of arterial oxygen saturation which is generally decreased in subjects having diaphragmatic weakness, can be determined by sampling arterial blood.
  • fluoroscopy can be performed; however, this may not be required in conditions characterized by diaphragmatic weakness such as muscular dystrophies.
  • Relaxin has been demonstrated as a potential therapeutic for muscle-related disorders (i.e. , disorders associated with damaged limb skeletal muscle), including involuntary muscle dysfunctions and chronic fatigue syndrome (CFS) (see, e.g., U.S. Patent No. 5,612,051 , which is incorporated herein in its entirety), fibromyalgia (see, e.g., U.S. Patent No. 5,707,642, which is incorporated herein in its entirety), and myofacial pain syndrome (see, e.g., U.S. Patent No. 5,863,552, which is incorporated herein in its entirety).
  • CFS chronic fatigue syndrome
  • use of relaxin in these muscle- related disorders may be due to anti-fibrotic properties of relaxin.
  • the diaphragm and limb skeletal muscle can differ.
  • the diaphragm in contrast to limb skeletal muscles, which are generally only intermittently used for specific activities (e.g., walking), the diaphragm is generally subject to continuous contraction and relaxation in order to carry out inspiration and exhalation with each breath. Consequently, the diaphragm has structural and biochemical differences from limb skeletal muscle to meet these increased demands.
  • the diaphragm has increased metabolic and energy requirements in comparison to limb skeletal muscle, the diaphragm is generally more susceptible to fatigue and injury than limb skeletal muscle and the diaphragm may be potentially more difficult to treat than limb skeletal muscle.
  • Muscle is categorized into two general categories: smooth muscle (present in internal organs such as the small and large bowel as well as lining blood vessels) and striated muscle (present in the diaphragm, heart, and limb skeletal muscle). Although the diaphragm, limb skeletal muscle, and the heart are composed of striated muscle, there are many differences between them. Without being bound by any one particular theory, the differences between the diaphragm and limb skeletal muscle may account, at least in part, for the different therapeutic effects shown herein that can be induced by relaxin in these two types of muscle.
  • the diaphragm and limb skeletal muscle are subject to different types of stress. Limb skeletal muscle is generally activated episodically to allow movement of limbs. The diaphragm, however, is generally subject to continuous contraction and relaxation in order to support the breathing process. To support its generally continuous activity, the diaphragm is characterized by a number of physiological, structural, and metabolic differences in comparison to limb skeletal muscle.
  • regulation of ionic conductance can differ between the diaphragm and limb skeletal muscles.
  • diaphragm muscle and limb skeletal muscle are generally different.
  • the duration of the action potential can influence muscle contractile performance by regulating the mechanically effective contractile period. Longer duration of action potentials can increase calcium release from the sarcoplasmic reticulum and enhance muscle contractile force.
  • the speed with which the membrane repolarizes, and hence the duration of the action potential can in turn be regulated by the rapidity and degree to which potassium conductance increases. Alteration of this conductance can affect contractility.
  • differences in ion conductance between diaphragm muscle and limb skeletal muscle can help to support the different physiologic purposes of these muscle types.
  • Conductance is generally regulated by potassium channels (two such channels are inward rectifier channels and delayed rectifier channels).
  • potassium channels two such channels are inward rectifier channels and delayed rectifier channels.
  • the diaphragm can also differ from limb skeletal muscle in the regulation of potassium channels, and this difference can be independent of the composition of muscle fibers present in the two muscle types.
  • Delayed rectifier potassium channels generally control action potential and thus muscle force and the duration of tension.
  • Inward potassium rectifier channels generally control membrane potential depolarization and thus muscle force alone.
  • the relative differences of these two types of channels in diaphragm muscle versus limb skeletal muscle may explain, at least in part, the differential effects of relaxin as disclosed herein on these types of muscle, given that relaxin can reduce the potassium channel associated with depolarization, and thus may have a predominant effect on the diaphragm in regulating diaphragmatic force, which could reduce muscle damage.
  • a number of other differences have also been documented between diaphragmatic muscle and limb skeletal muscle. These include, but are not limited to: differences in response to acetylcholine receptor inhibitors; the expression of different types of ryanodine receptors, which can play roles in calcium homeostasis; and differences in the expression of the developmental protein MRF3 and the expression of Pax3, a myogenic protein, both of which are expressed in the diaphragm but not limb skeletal muscle. These differences may also contribute to the differential response of relaxin treatment in the diaphragm versus limb skeletal muscle.
  • Muscle fibers are generally classified as: 1 ) type 1 , which are slow twitch fibers that are resistant to fatigue; 2) type 2b fibers, which are fast twitch fibers that are subject to fatigue; and 3) type 2a fibers, which are intermediate between type 1 and type 2b fibers. Isometric contraction is generally lower in slow type 1 fibers than in fast type 2 fibers.
  • the diaphragm generally includes a higher proportion of the more fatigue resistant type fibers, which is consistent with its requirement for continuous activity. Without being bound by any one particular theory, these differences may be related to the increased therapeutic effects of relaxin on the diaphragm in muscular dystrophies.
  • Dystroglycan can be found in the diaphragmatic cell membrane but not the limb skeletal cell membrane.
  • dystroglycan can be reduced in limb skeletal muscle but not diaphragm muscle of mdx mice.
  • a small form of utrophin known as U71 along with C-terminal utrophin can be expressed at higher levels in the diaphragm than in limb skeletal muscle. Without being bound by any one particular theory, these differences may also influence the therapeutic effects of relaxin.
  • Certain embodiments are provided herein, which may relate to administering a pharmaceutically relevant dose of one or more compounds capable of binding and/or activating the RXFP1 receptor to an appropriate subject prior to, concurrent with, and/or following the clinical manifestation, diagnosis, and/or induction of a disease, condition, and/or injury treatable with a compound capable of binding and/or activating the RXFP1 receptor.
  • compositions e.g., pharmaceutical compositions
  • the disclosure provides compositions comprising one or more compounds configured to bind and/or activate the RXFP1 receptor in a pharmacologically acceptable vehicle.
  • the disclosure provides compositions including one or more compounds capable of binding to and/or activating the RXFP1 receptor, alone or in combination with at least one other agent, such as a stabilizing compound, which may be administered in any sterile, biocompatible pharmaceutical carrier, including, but not limited to, saline, buffered saline, dextrose, and water.
  • compositions including relaxin can be lyophilized. Any of the compositions including compounds capable of binding and activating the RXFP1 receptor can be administered to a patient alone, or in combination with other agents, drugs, and/or hormones; and/or in compositions wherein the compounds are mixed with one or more excipients and/or pharmaceutically acceptable carriers.
  • compositions comprising one or more compounds capable of binding to and/or activating the RXFP1 receptor include a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is pharmaceutically inert.
  • the composition may prevent and/or treat disorders and/or diseases in a subject. In various other embodiments, the composition may be configured for diagnostic purposes.
  • the compound capable of binding and/or activating the RXFP1 receptor may be in a soluble form.
  • the composition may include suitable pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that may facilitate processing of the compounds into preparations, which can be used pharmaceutically.
  • Pharmaceutically acceptable carriers can include basal buffers to control the pH of a composition or formulation, stabilizers (e.g. , neutral, acidic, or basic amino acids), lyophilization agents and cryoprotectants (e.g. , sugars), solubilizing agents (e.g. , ionic and/or non-ionic detergents), and miscellaneous solubility and stability imparting agents (e.g. , inorganic salts, sugars, and glycols).
  • stabilizers e.g. , neutral, acidic, or basic amino acids
  • cryoprotectants e.g. , sugars
  • solubilizing agents e.g. , ionic and/or non-ionic detergents
  • the formulations disclosed herein can be depot preparations.
  • Agents that can be incorporated into the depot preparations include polymers, gelatins, oils, fatty acids, and/or hydrogels. In some embodiments, these may include beeswax, Evan's Blue, and benzopurpurin.
  • the formulations may comprise one or more pH- buffering agents, i.e., buffers.
  • buffers include histidine (e.g. , L-histidine and D-histidine), citrate buffers (e.g. , sodium citrate, citric acid, and mixtures thereof), and phosphate buffers (e.g. , sodium phosphate and phosphate buffered saline (PBS)).
  • histidine e.g. , L-histidine and D-histidine
  • citrate buffers e.g. , sodium citrate, citric acid, and mixtures thereof
  • phosphate buffers e.g. , sodium phosphate and phosphate buffered saline (PBS)
  • the formulations can be prepared in pharmaceutically acceptable, physiologically acceptable, and/or pharmaceutical-grade solutions for administration to a cell or a subject (e.g. , an animal), either alone, or in combination with one or more other modalities of therapy.
  • the formulations may be administered in combination with other agents, such as other proteins, polypeptides, pharmaceutically active agents, etc.
  • compositions can be administered via any suitable route, including but not limited to, locally, orally, subcutaneously, systemically, intravenously, intramuscularly, mucosally, transdermal ⁇ (e.g. , via a patch), or via a bolus.
  • the composition may be administered via a mode selected from the group consisting of, but not limited to: parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intratumoral, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, intravaginal, buccal, sublingual, and intranasal, and via administration to the central nervous system.
  • parenteral subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intraca
  • compositions may be encapsulated in liposomes, microparticles, microcapsules, nanoparticles, and the like.
  • Techniques for formulating and administering therapeutically useful polypeptides are also disclosed in Remington: The Science and Practice of Pharmacy (Alfonso R. Gennaro, et al. eds. Philadelphia College of Pharmacy and Science 2000), which is incorporated herein in its entirety.
  • the compositions may be administered at a dose ranging from about 1 g/kg to about 1 ,000 pg/kg, from about 1 g/kg to about 500 pg/kg, from about 1 g/kg to about 250 pg/kg, from about 1 g/kg to about 100 pg/kg, from about 5 g/kg to about 50 pg/kg, or from about 10 g/kg to 40 g/kg.
  • the compositions of the present disclosure may be administered via a schedule including continuous administration or intermittent administration. Accordingly, in addition to these general schedules, in some embodiments, the composition may be administered twice a day, once a day, once every other day, once a week, once a month, or another suitable period of administration.
  • Relaxin can ameliorate diaphragmatic damage (e.g., due to chronic conditions, such as DMD) by increasing the strength and/or the size of diaphragmatic muscle and/or by reducing susceptibility of diaphragmatic muscle to injury.
  • These effects on diaphragmatic muscle may result in enhanced or improved respiratory function in subjects having a condition or conditions associated with diaphragmatic injury.
  • these effects on diaphragmatic muscle may be due, at least in part, to the effects of relaxin on at least two pathways.
  • relaxin can induce the production of nitric oxide, which can act on the diaphragm to increase the contractility and vascular supply of the diaphragm.
  • relaxin can inhibit the activity of TGF- ⁇ , which can play a role in chronic inflammation and/or fibrosis.
  • the relaxin family may comprise endocrine and autocrine/paracrine peptide hormones that are part of the insulin superfamily.
  • H2 relaxin also referred to as relaxin 2
  • other types of relaxins such as H1 relaxin and H3 relaxin, can also bind to and/or activate the RXFP1 receptor, albeit generally with lower affinity than H2 relaxin.
  • Precursor forms of relaxin referred to as prorelaxin, can also bind to and activate the RXFP1 receptor.
  • Non-natural forms of relaxin molecules or other compounds that bind to and activate the RXFP1 receptor are also within the scope of this disclosure. Chemical or biological modifications that may result in either increasing or decreasing the size of relaxin molecules have been generated that can also bind to and activate the RXFP1 receptor. Additionally, covalent addition to relaxin molecules of moieties (e.g., albumin, hetastarch, sugars, additional amino acids, glycosylated peptides, polyethylene glycol (PEG), and/or the Fc portion of immunoglobulins, which may be used to extend plasma half-lives of compounds) can also bind to and activate the RXFP1 receptor.
  • moieties e.g., albumin, hetastarch, sugars, additional amino acids, glycosylated peptides, polyethylene glycol (PEG), and/or the Fc portion of immunoglobulins, which may be used to extend plasma half-lives of compounds
  • H2 relaxin can be produced in nature as a prohormone comprising (from N-terminus to C-terminus): a B chain, a C chain, and an A chain.
  • the C chain can be cleaved, generating mature relaxin, which may include an A chain and a B chain bound together by two inter-chain disulfide bonds, wherein the A chain further comprises one intra-chain disulfide bond (see Reddy, et al. (1992), Arch. Biochem. Biophys. 294(2), 579-585).
  • a cognate relaxin-2 receptor is RXFP1 , which is a G protein-coupled receptor (GPCR) that can be activated when bound by relaxin.
  • GPCR G protein-coupled receptor
  • Relaxin and relaxin receptors can be found in many organs and tissues, including, but not limited to, heart, muscle (e.g., smooth muscle), endothelium, kidney, corpus luteum, and ovaries.
  • a first aspect of the disclosure relates to methods for treating, or methods for therapeutic treatment of, a subject or patient having diaphragmatic weakness and/or a condition associated with diaphragmatic weakness.
  • the methods for treating the subject may include identifying the subject having the diaphragmatic weakness and/or the condition associated with diaphragmatic weakness.
  • the subject may be a mouse, a rat, a rabbit, a guinea pig, a swine, a cattle, a sheep, a goat, a horse, a cat, a dog, a non-human primate, a human, or another suitable subject.
  • this disclosure provides methods of treating a subject having diaphragmatic weakness and/or a condition associated with diaphragmatic weakness including administering to the subject a therapeutically effective amount of a pharmaceutical composition.
  • the pharmaceutical composition may be an activator of relaxin/insulin-like family peptide receptor 1 (RXFP1 ).
  • the pharmaceutical composition may bind or be configured to bind RXFP1 .
  • the activator of RXFP1 may be a relaxin, a relaxin analog, a prorelaxin, and/or a prorelaxin analog.
  • the activator of RXFP1 may be a human H1 relaxin, a human H1 relaxin analog, a human H2 relaxin, a human H2 relaxin analog, a human H3 relaxin, a human H3 relaxin analog, a human prorelaxin, a human prorelaxin analog, or another suitable activator of RXFP1 .
  • the activator of RXFP1 may be an A-chain- truncated peptide of a human H2 relaxin and/or a B-chain-truncated peptide of a human H2 relaxin.
  • the activator of RXFP1 may be a relaxin analog comprising a modified relaxin B chain peptide, for example, wherein the modified relaxin B chain peptide is longer or substantially longer than a B chain peptide of a corresponding native relaxin.
  • the activator of RXFP1 may be a relaxin comprising at least one chemical modification.
  • the relaxin may be coupled to or covalently bound to a moiety selected from at least one of an albumin, a hetastarch, a sugar, an additional amino acid, a glycosylated peptide, a PEG, and/or a fragment crystallizable (F c ) region of an immunoglobulin.
  • the activator of RXFP1 may include at least two, at least three, at least four, or more chemical modifications.
  • the activator of RXFP1 may be modified to include one or more half-life prolonging moieties (HPMs).
  • the HPM may be coupled to or conjugated to (i.e. , genetically conjugated to) the activator of RXFP1 and the HPM may be disposed within the activator of RXFP1 at any suitable position.
  • the HPM may be chemically coupled to or conjugated to the activator of RXFP1 (e.g. , via synthetic attachment within the activator of RXFP1 during chemical synthesis or via post-synthesis chemical conjugation to the activator of RXFP1 ) and the HPM may be disposed within the activator of RXFP1 at any suitable position.
  • an activator of RXFP1 comprising one or more HPMs may retain relaxin activity (e.g., relaxin bioactivity), while exhibiting increased half-life in plasma as compared to a similar activator of RXFP1 lacking an HPM.
  • relaxin activity e.g., relaxin bioactivity
  • the activator of RXFP1 may be coupled to or conjugated to one or more proteinaceous HPMs.
  • the activator of RXFP1 may be coupled to or conjugated to one or more portions or regions of an immunoglobulin (e.g., the F c region), an albumin, a random amino acid sequence, and/or a polypeptide including repeating glycan acceptor motifs.
  • the activator of RXFP1 may be coupled to or conjugated to one or more nonproteinaceous HPMs.
  • the activator of RXFP1 may be coupled to or conjugated to one or more hetastarch motifs and/or PEG polymers (including, e.g., branched and/or linear chains).
  • a C * chain may refer to any type of C chain between the A chain and the C chains.
  • the C * chain may include a natural C chain or a non-natural C chain (e.g., a C chain that is truncated and/or a C chain that has amino acid substitutions, deletions, and/or additions).
  • a proteinaceous HPM may be coupled to or conjugated to the activator of RXFP1 via genetic fusion to the N- or C-terminus of the C * chain.
  • such fusions may be disposed or located at a junction between the C * chain and the retained B or A chain portion, such that the activator of RXFP1 includes a primary chain coupled to or fused to an HPM that is in turn coupled to or fused to the C * chain.
  • such fusions may be additionally, or alternatively, fused to the C * chain such that the HPM is not additionally fused to a primary chain.
  • a proteinaceous HPM may be coupled to or conjugated to the activator of RXFP1 via genetic fusion to the N- or C-terminus of the A chain.
  • the HPM in such an A chain HPM fusion may be disposed or located between the A chain and the C * chain.
  • the HPMs in such an A chain HPM fusion may be disposed or located at an A chain terminus, such that the HPM is not bound directly to the C * chain.
  • a proteinaceous HPM may be coupled to or conjugated to the activator of RXFP1 via genetic fusion to the N- or C-terminus of the B chain.
  • the HPM in such a B chain HPM fusion may be disposed or located between the B chain and the C * chain.
  • the HPM in such a B chain HPM fusion may be disposed or located at a B chain terminus, such that the HPM is not bound directly to the C * chain.
  • the activator of RXFP1 may comprise an HPM fused to the A chain, B chain, and/or C * chain of the activator of RXFP1 .
  • the HPM may be coupled via a polypeptide linker.
  • a suitable polypeptide linker may be a flexible linker (e.g. , a (GGGGS)n-type linker).
  • the activator of RXFP1 may comprise an HPM fused to the A chain, B chain, and/or C * chain of the activator of RXFP1 .
  • the HPM may be coupled via a cleavable linker.
  • the cleavable linker may allow, or be configured to allow, in vitro and/or in vivo cleavage of the HPM from the activator of RXFP1.
  • Such cleavably-linked HPMs may include the HPMs described in International Patent Application Publication No. WO 2013/007563, which is incorporated herein by reference in its entirety.
  • an HPM may be coupled to (e.g. , chemically coupled to) the activator of RXFP1 (e.g. , a PEG moiety or a hetastarch moiety).
  • HPMs such as PEG moieties and hetastarch moieties may be coupled to the activator of RXFP1 via covalent coupling to natural or unnatural amino acids of the activator of RXFP1 .
  • activators of RXFP1 comprising chemically coupled HPMs may also be linked by a linker portion.
  • the chemically coupled HPM may be coupled to the activator of RXFP1 via a cleavable linker such that in vitro or in vivo cleavage of the HPM from the activator of RXFP1 may occur.
  • the HPM is chemically coupled or attached at an internal position of the activator of RXFP1 (e.g. , within the A chain, the B chain, and/or the C * chain of the activator of RXFP1 ).
  • the HPM may be chemically coupled or attached at a terminal position (e.g. , the HPM may be conjugated to the N- or C-terminus of an A chain, a B chain, and/or a C * chain of the activator of RXFP1 ).
  • a PEG and/or a hetastarch moiety may be coupled (e.g. , by a covalent linkage) to an amino, carboxyl, or thiol group of an amino acid side chain.
  • the PEG and/or the hetastarch may be coupled to the thiol group of a cysteine (Cys) residue, the epsilon amino group of a lysine (Lys) residue, and/or the carboxyl group of an aspartic acid (Asp) residue or a glutamic acid (Glu) residue.
  • a PEG moiety having a methoxy group can be coupled to a Cys thiol group by a maleimido linkage using commercially available reagents (e.g., from NEKTAR ® ).
  • Other methods of coupling an HPM to an activator of RXFP1 are also within the scope of this disclosure (see, e.g.
  • a maleimide-functionalized PEG may also be coupled to or conjugated to the side-chain sulfhydryl group of a Cys residue.
  • Other methods of coupling or conjugating PEG and/or hetastarch moieties to the side chains of amino acids disposed in polypeptides are also within the scope of this disclosure.
  • other methods of coupling or conjugating PEG and/or hetastarch moieties to an activator of RXFP1 are also within the scope of this disclosure.
  • Albumin HPMs can be derived from albumins cloned from any species. Human albumin, fragments of human albumin, and analogs thereof may reduce the risk of immunogenicity in humans.
  • Human serum albumin (HSA) includes a single non-glycosylated polypeptide chain of 585 amino acids with a formula molecular weight of 66,500. The amino acid sequence of HSA has been described, e.g., in Eloun, et al. (1975); Behrens, et al., (1975) Fed. Proc. Fed. Am. Soc. Exp. Biol. 34, 591 ; Lawn, et al., (1981 ) Nucleic Acids Res.
  • Activators of RXFP1 of the present disclosure may include compounds capable of binding and/or activating the RXFP1 receptor, which are fused to any albumin protein including albumin fragments, albumin analogs, and/or albumin derivatives, wherein such fusion proteins can be biologically active and can have a longer plasma half-life than corresponding wild-type relaxins or activators of RXFP1 alone (i.e., relaxins and/or activators of RXFP1 that are not fused to an albumin protein). Accordingly, the albumin portion of the fusion protein may not have a plasma half-life equal or substantially equal to that of a native human albumin.
  • Fragments, analogs, and/or derivatives may be isolated and/or generated that have longer half-lives or that have half-lives intermediate to that of native human albumin and/or the activator of RXFP1 (see, e.g., International Publication No. WO 2001/077137).
  • the activator of RXFP1 may be a relaxin analog comprising a relaxin A chain peptide and a relaxin B chain peptide, wherein the relaxin A chain peptide may have at least 80% sequence identity to the amino acid sequence of SEQ ID NO:1 , and wherein the relaxin B chain peptide may have at least 80% sequence identity to the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:3.
  • the relaxin A chain peptide may have at least 50%, at least 60%, at least 70%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to the amino acid sequence of SEQ ID NO: 1 .
  • the relaxin A chain peptide may have another suitable percent sequence identity to the amino acid sequence of SEQ ID NO: 1 .
  • residue 1 of the relaxin A chain peptide of the relaxin analog may be modified in comparison to residue 1 of a relaxin A chain peptide of a corresponding native relaxin.
  • the relaxin B chain peptide may have at least 50%, at least 60%, at least 70%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to the amino acid sequence of SEQ ID NO:2. In some other embodiments, the relaxin B chain peptide may have another suitable percent sequence identity to the amino acid sequence of SEQ ID NO:2. In certain embodiments, the relaxin B chain peptide may have at least 50%, at least 60%, at least 70%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to the amino acid sequence of SEQ ID NO:3. In certain other embodiments, the relaxin B chain peptide may have another suitable percent sequence identity to the amino acid sequence of SEQ ID NO:3.
  • the modified relaxin polypeptide may be encoded by a non-natural or synthetic amino acid sequence, wherein the relaxin polypeptide includes a relaxin A chain polypeptide and a relaxin B chain polypeptide, wherein said relaxin A chain polypeptide has a sequence at least 95% identical to SEQ ID NO: 1 , and said relaxin B chain polypeptide has a sequence at least 95% identical to SEQ ID NO:2 or SEQ ID NO:3, and said non-naturally encoded amino acid is substituted in said A chain polypeptide at residue 1 as described in U.S. Patent No. 8,735,539, which is incorporated herein by reference in its entirety.
  • a fusion polypeptide having relaxin activity may include a relaxin B chain polypeptide or a functional variant thereof, a relaxin A chain polypeptide or a functional variant thereof, and a linker polypeptide as described in U.S. Patent Publication No. 2014/0187491 , which is incorporated herein by reference in its entirety.
  • the relaxin A chain amino acid sequence is QLYSALANKCCHVGCTKRSLARFC (SEQ ID NO: 1 )
  • the relaxin B chain amino acid sequence is DSWMEEVIKLCGRELVRAQIAICGMSTWS (SEQ ID NO:2)
  • the relaxin B chain amino acid sequence with B1 Ala 7 is ASWMEEVIKLCGRELVRAQIAICGMSTWS (SEQ ID NO:3).
  • the activator of RXFP1 may be a fusion peptide, wherein the fusion peptide has relaxin activity.
  • the fusion peptide may comprise a relaxin B chain peptide, or a functional variant of the relaxin B chain peptide, and a relaxin A chain peptide, or a functional variant of the relaxin A chain peptide.
  • Relaxin activity can be measured using any suitable method known in the art.
  • relaxin activity may be measured by treating THP-1 cells with one or more of the following test polypeptides or test compounds: a native relaxin polypeptide, a modified relaxin polypeptide, and/or a compound of the present disclosure.
  • the ability of the test polypeptide or test compound to bind to and/or to activate the RXFP1 receptor may then be determined, for example, by measuring increases in cAMP production or cAMP accumulation that may be induced by the test polypeptide or test compound.
  • the THP-1 cell line is a human acute monocytic leukemia cell line that was derived from peripheral blood cells isolated from a 1 -year-old boy with monocytic leukemia. These cells generally express the cognate relaxin-2 receptor RXFP1 , a G protein-coupled receptor (GPCR) that is activated when bound by relaxin, inducing adenylyl cyclase activation and subsequent cAMP production and/or signal transduction.
  • RXFP1 a G protein-coupled receptor
  • Relaxin activity may also be determined by assaying other measureable relaxin-induced changes, such as Gs mediated activation of PI3K as measured by assaying for phosphorylated PI3K or other downstream signal transduction activities such as the phosphorylation of Akt.
  • the activator of the RXFP1 receptor may be an H2 relaxin or an H2 relaxin analog selected from the group consisting of H2 (acid), H2-(B3-29), H2-(B5-29), H2-(B7-29), H2-(B9-29), H2-(B1-28), H2-(B1-27), H2- (B1-26), H2-(B1-25), H2-(B1-24), H2-(B1-23), H2-(B7-25), H2-(B8-25), H2-(B7- 24), H2-(B8-24), H2-(A2-24)(B7-24), H2-(A3-24)(B7-24), H2-(A4-24)(B7-24), H2- (A5-24)(B7-24), H2-(A7-24)(B7-24), H2-(A9-24)(B7-24), H2-(A-Z-5-24)(B7-24), H2-(A-Z-5-24)(B7-24), H2-(A-Z-7-24)(B
  • the activator of the RXFP1 receptor may be a modified H2 or H3 relaxin polypeptide including a relaxin B chain and a modified A- chain-truncated peptide selected from the group consisting of A-(5-24) H3, A-(7-24) H3, A-(8-24) H3, A-(9-24) H3, A-(10-24) H3, Ala-4A-(9-24) H3, Ala-5 A-(9-24) H3, A-(5-24) H2, A-(7-24) H2, A-(9-24) H2, Ala-4 A-(9-24) H2, and/or Ala-5 A-(9-24) H2 (see Hossain, et al., (2008) J. Biol. Chem. 283(25), 17287-17297, which is incorporated herein by reference in its entirety).
  • the activator of the RXFP1 receptor may have the amino acid sequence DSWMEEVIKLCGRELVRAQIAICGMSTWSKRSL (SEQ ID NO:4; see Tang, et al., (2003) Biochemistry 42(9), 2731 -2739, which is incorporated herein by reference in its entirety).
  • this disclosure provides methods of treating a subject having diaphragmatic weakness and/or a condition associated with diaphragmatic weakness including administering to the subject a therapeutically effective amount of a pharmaceutical composition including an activator of RXFP1 and one or more steroids.
  • the pharmaceutical composition may further include a steroid such as prednisone, prednisolone, triamcinolone, dexamethasone, deflazacort, and/or another suitable steroid.
  • the pharmaceutical composition may include an activator of RXFP1 and one or more compounds that are configured to improve respiratory function.
  • the pharmaceutical composition may also comprise a bronchodilator.
  • the bronchodilator may be selected from at least one of a beta-adrenoreceptor agonist, an anticholinergic, theophylline, albuterol, levalbuterol, pirbuterol, epinephrine, ephedrine, terbutaline, salmeterol, clenbuterol, formoterol, bambuterol, indacaterol, ipratropium, umeclidinium, tiotropium, olodaterol, vilanterol, aclidinium, formoterol, fluticasone, budesonide, and/or another suitable bronchodilator.
  • a beta-adrenoreceptor agonist an anticholinergic
  • theophylline albuterol
  • levalbuterol pirbuterol
  • epinephrine ephedrine
  • terbutaline salmeterol
  • clenbuterol formoterol
  • the methods of treating a subject having diaphragmatic weakness and/or a condition associated with diaphragmatic weakness may further include administering to the subject a therapeutically effective amount of a steroid.
  • the methods may include administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an activator of RXFP1 and further include administering to the subject a therapeutically effective amount of a steroid.
  • the steroid may be prednisone, prednisolone, triamcinolone, dexamethasone, deflazacort, and/or another suitable steroid.
  • the methods of treating a subject having diaphragmatic weakness and/or a condition associated with diaphragmatic weakness may further include administering to the subject a therapeutically effective amount of one or more compounds that are configured to improve respiratory function.
  • the methods of treating a subject having diaphragmatic weakness and/or a condition associated with diaphragmatic weakness may further include administering to the subject a therapeutically effective amount of one or more compounds that are configured to improve respiratory function.
  • the methods of treating a subject having diaphragmatic weakness and/or a condition associated with diaphragmatic weakness may further include administering to the subject a therapeutically effective amount of a bronchodilator.
  • the pharmaceutical composition may reduce or be configured to reduce a pathological effect and/or symptom of diaphragmatic weakness and/or a condition associated with diaphragmatic weakness.
  • the pathological effect and/or symptom of the diaphragmatic weakness and/or the condition associated with diaphragmatic weakness may include diaphragmatic weakness, dyspnea, decreased forced expiratory volume, decreased forced expiratory velocity, decreased forced vital capacity, decreased muscle mass, muscle wasting, inflammation, pulmonary hypertension, right-sided heart failure, bronchiectasis, and/or pneumonia.
  • the condition associated with diaphragmatic weakness may be a respiratory condition, for example, dyspnea, decreased forced expiratory volume, decreased forced expiratory velocity, decreased forced vital capacity, and/or below normal arterial blood oxygen saturation.
  • the condition associated with diaphragmatic weakness may be a diaphragmatic disease with inflammation, for example, an inflammatory myopathy, a muscular dystrophy, and/or a primary inflammatory muscle disease.
  • the primary inflammatory muscle disease may be polymyositis, dermatomyositis, inclusion body myositis, systemic lupus erythematosus, and/or an inherited disease characterized by diaphragmatic weakness (e.g. , glycogen storage disease type II (Pompe disease), glycogen storage disease type III, a collagen VI myopathy, and nemaline myopathy).
  • the condition associated with diaphragmatic weakness may be a muscular dystrophy, for example, myotonic muscular dystrophy, DMD, Becker muscular dystrophy, limb-girdle muscular dystrophy, facioscapulohumeral muscular dystrophy, congenital muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, and/or Emery- Dreifuss muscular dystrophy.
  • a muscular dystrophy for example, myotonic muscular dystrophy, DMD, Becker muscular dystrophy, limb-girdle muscular dystrophy, facioscapulohumeral muscular dystrophy, congenital muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, and/or Emery- Dreifuss muscular dystrophy.
  • the pharmaceutical composition may be administered to the subject via mechanical ventilation.
  • the pharmaceutical composition may be administered to the subject intranasally, intrabronchially, via injection or intermittent injection (e.g. , subcutaneous, intravenous, intramuscular, and/or intraperitoneal injection), and/or via infusion (e.g., continuous infusion).
  • the pharmaceutical composition may be administered to the subject via a continuous administration schedule or an intermittent administration schedule.
  • the pharmaceutical composition may be administered at a dose ranging from between about 1 g/kg and about 1 ,000 pg/kg, about 1 g/kg and about 500 pg/kg, about 1 g/kg and about 250 g/kg, about 1 g/kg and about 100 pg/kg, about 5 g/kg and about 50 pg/kg, about 10 g/kg and about 40 pg/kg, or another suitable dose.
  • Another aspect of the disclosure relates to methods for prophylactically treating a subject or patient at risk of developing diaphragmatic weakness and/or at risk of developing a condition associated with diaphragmatic weakness.
  • the methods for prophylactically treating the subject may include identifying the subject at risk of developing the diaphragmatic weakness and/or at risk of developing the condition associated with diaphragmatic weakness.
  • the methods for treating a subject having diaphragmatic weakness and/or a condition associated with diaphragmatic weakness as discussed above, may be adapted as methods for prophylactically treating a subject at risk of developing diaphragmatic weakness and/or at risk of developing a condition associated with diaphragmatic weakness.
  • methods for prophylactically treating a subject at risk of developing diaphragmatic weakness and/or at risk of developing a condition associated with diaphragmatic weakness may include administering to the subject a therapeutically effective amount of a pharmaceutical composition.
  • the pharmaceutical composition may reduce or be configured to reduce the risk of developing diaphragmatic weakness or a pathological effect or symptom of a condition associated with diaphragmatic weakness.
  • the pharmaceutical composition may be an activator of RXFP1 .
  • Another aspect of the disclosure relates to methods for treating a subject having diaphragmatic weakness and/or a condition associated with diaphragmatic weakness.
  • the methods may include administering to the subject a therapeutically effective amount of a pharmaceutical composition, wherein the pharmaceutical composition includes one or more gene therapy expression vectors encoding one or more peptides that activate, or that are configured to activate, RXFP1.
  • Another aspect of the disclosure relates to uses of an activator of RXFP1 in the manufacture of a medicament for the treatment of diaphragmatic weakness and/or conditions associated with diaphragmatic weakness.
  • the disclosure also relates to the manufacture of a medicament for the prophylactic treatment of diaphragmatic weakness and/or a condition associated with diaphragmatic weakness.
  • compositions for the treatment of diaphragmatic weakness and/or conditions associated with diaphragmatic weakness relate to pharmaceutical compositions for the treatment of diaphragmatic weakness and/or conditions associated with diaphragmatic weakness.
  • the disclosure also relates to pharmaceutical compositions for the prophylactic treatment of diaphragmatic weakness and/or conditions associated with diaphragmatic weakness.
  • the pharmaceutical compositions may include one or more activators of RXFP1.
  • the pharmaceutical compositions may also include one or more pharmaceutically acceptable carriers.
  • Another aspect of the disclosure relates to activators of RXFP1 for use in the treatment of a condition associated with diaphragmatic weakness.
  • the disclosure also related to activators of RXFP1 for use in the prophylactic treatment of a condition associated with diaphragmatic weakness.
  • compositions comprising an activator of RXFP1 for use in the treatment of a condition associated with diaphragmatic weakness.
  • the disclosure also relates to pharmaceutical compositions comprising an activator of RXFP1 for use in the prophylactic treatment of a condition associated with diaphragmatic weakness.
  • the pharmaceutical composition may comprise a pharmaceutically acceptable carrier.
  • MDL Muscular dystrophy
  • DMD muscular dystrophy
  • Becker muscular dystrophy limb-girdle muscular dystrophy
  • facioscapulohumeral muscular dystrophy congenital muscular dystrophy
  • oculopharyngeal muscular dystrophy distal muscular dystrophy
  • Emery-Dreifuss muscular dystrophy is a group of several muscle diseases that can lead to a progressive weakening of the musculoskeletal system and eventual death of muscle cells and tissues and loss or decrease in locomotor ability.
  • Different forms of MD include: myotonic muscular dystrophy, DMD, Becker muscular dystrophy, limb-girdle muscular dystrophy, facioscapulohumeral muscular dystrophy, congenital muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, and Emery-Dreifuss muscular dystrophy.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Endocrinology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des procédés pour traiter un sujet présentant une faiblesse diaphragmatique ou une pathologie associée à une faiblesse diaphragmatique. L'invention concerne également des procédés de traitement prophylactique d'un sujet présentant un risque de développer une faiblesse diaphragmatique ou un risque de développer une pathologie associée à une faiblesse diaphragmatique. Les procédés de traitement d'un sujet présentant, ou ayant un risque de développer, une faiblesse diaphragmatique ou une pathologie associée à une faiblesse diaphragmatique peuvent comprendre l'administration d'un activateur du récepteur peptidique de la famille de type relaxine/insuline 1 (RXFP1) pour le sujet. Les procédés de traitement d'un sujet présentant, ou ayant un risque de développer, une faiblesse diaphragmatique ou une pathologie associée à une faiblesse diaphragmatique peuvent également comprendre l'administration au sujet d'une relaxine, d'un analogue de la relaxine, d'une prorelaxine, d'un analogue de la prorelaxine, ou des combinaisons de ces derniers.
PCT/US2016/021389 2015-03-09 2016-03-08 Thérapie par la relaxine pour troubles du diaphragme WO2016144968A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562130448P 2015-03-09 2015-03-09
US62/130,448 2015-03-09

Publications (1)

Publication Number Publication Date
WO2016144968A1 true WO2016144968A1 (fr) 2016-09-15

Family

ID=56879751

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/021389 WO2016144968A1 (fr) 2015-03-09 2016-03-08 Thérapie par la relaxine pour troubles du diaphragme

Country Status (1)

Country Link
WO (1) WO2016144968A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130040901A1 (en) * 2010-02-26 2013-02-14 University Of Florida Research Foundation Inc. Mitochondrial-targeted antioxidants protect against mechanical ventilation-induced diaphragm dysfunction and skeletal muscle atrophy
WO2014022294A1 (fr) * 2012-07-31 2014-02-06 Novartis Ag Traitement de l'inflammation à l'aide de la sérélaxine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130040901A1 (en) * 2010-02-26 2013-02-14 University Of Florida Research Foundation Inc. Mitochondrial-targeted antioxidants protect against mechanical ventilation-induced diaphragm dysfunction and skeletal muscle atrophy
WO2014022294A1 (fr) * 2012-07-31 2014-02-06 Novartis Ag Traitement de l'inflammation à l'aide de la sérélaxine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SASSER ET AL.: "Serelaxin reduces oxidative stress and asymmetric dimethylarginine in angiotensin II-induced hypertension", AM J PHYSIOL RENAL PHYSIOL., vol. 307, no. 12, 15 December 2014 (2014-12-15), pages F1355 - F1362, XP055310686 *

Similar Documents

Publication Publication Date Title
JP2828250B2 (ja) 真性糖尿病の治療
JP2020040979A (ja) Ｇｉｐ−ｇｌｐ−１デュアルアゴニスト化合物及び方法
KR102253597B1 (ko) 듀켄씨 근이영양증의 치료에서의 폴리스타틴
KR102504200B1 (ko) 글루카곤-유사-펩티드-2 (glp-2) 유사체의 투여를 위한 용량요법
TWI754225B (zh) 治療低血壓之方法
JP2017537894A (ja) Ｇｌｐ−１ｒおよびｇｌｐ−２ｒ二重アゴニスト活性を有する組成物及びペプチド
BR112012017348B1 (pt) análogo de peptídeo de oxintomodulina, seu uso, bem como composição farmacêutica
AU2015261786B2 (en) Method and composition for treating heart failure with preserved ejection fraction
EP3135296A1 (fr) Médicament contre des troubles de croissance induits par l'administration d'un stéroïde
JPWO2015141819A1 (ja) 長時間作用型アドレノメデュリン誘導体
KR20120103606A (ko) 스트레스코핀-유사 펩타이드를 이용해 심부전을 치료하는 방법
CA2638065C (fr) Combinaison d'analogues de la somatostatine presentant une selectivite differente pour chacun des sous-types de recepteurs de la somatostatine humaine
JP6824888B2 (ja) 筋肉の疾患および障害を治療するための方法および組成物
JP2010527989A (ja) 半減期が延長されたｃｒｆ複合体
AU2018318672A1 (en) Acylated oxyntomodulin peptide analog
US10016482B2 (en) Insulin independence among patients with diabetes utilizing an optimized hamster REG3 gamma peptide
WO2016144968A1 (fr) Thérapie par la relaxine pour troubles du diaphragme
US20170333530A1 (en) Methods and materials for reducing cysts and kidney weight in mammals with polycystic kidney disease
EP2911686B1 (fr) Peptides de prévention d'une lésion tissulaire ischémique
KR20170069997A (ko) 미리스토일화된 렙틴-관련된 펩티드 및 이들의 용도

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16762349

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16762349

Country of ref document: EP

Kind code of ref document: A1