WO2010059245A2 - Compositions et procédés pour traiter ou prévenir les lésions dues à un rayonnement - Google Patents

Compositions et procédés pour traiter ou prévenir les lésions dues à un rayonnement Download PDF

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WO2010059245A2
WO2010059245A2 PCT/US2009/006244 US2009006244W WO2010059245A2 WO 2010059245 A2 WO2010059245 A2 WO 2010059245A2 US 2009006244 W US2009006244 W US 2009006244W WO 2010059245 A2 WO2010059245 A2 WO 2010059245A2
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cell
nrf2
radiation
injury
preventing
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PCT/US2009/006244
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English (en)
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WO2010059245A3 (fr
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Shyam Biswal
Rajesh Kumar Thimmulappa
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The Johns Hopkins University
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Priority to EP09827894A priority Critical patent/EP2362770A4/fr
Priority to CA2744388A priority patent/CA2744388A1/fr
Priority to US13/130,526 priority patent/US20120029071A1/en
Publication of WO2010059245A2 publication Critical patent/WO2010059245A2/fr
Publication of WO2010059245A3 publication Critical patent/WO2010059245A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/121—Ketones acyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • Radiation injury can occur from external irradiation, either when the entire body is irradiated or when only part of the body is irradiated. Radiation injury may occur in connection with radiotherapy, during an accidental exposure to radioactivity, or in connection with a nuclear attack. Accidental exposure or nuclear attack can also cause internal radiation exposure due to widespread radioactive particles released in the environment. Radiation exposure causes short term and/or long term disorders. Clinical components of the acute radiation syndrome include the hematopoietic, gastrointestinal, and cerebrovascular syndromes that occur within days to a few weeks following radiation exposure. Long term disorders, such as lung fibrosis, following radiation exposure are typically associated with tissue damage. At present, there is no effective way to prevent or treat radiation injuries. Thus, improved compositions and methods for the treatment of radiation-associated tissue damage are urgently required.
  • the present invention features compositions and methods for treating or preventing radiation-associated tissue damage.
  • the invention generally provides methods for treating or preventing cell damage associated with radiation exposure, the method involving contacting a cell with an effective amount of a Nrf2 activator (e.g., sulforaphane, triterpenoid).
  • a Nrf2 activator e.g., sulforaphane, triterpenoid
  • the invention generally provides methods of preventing or reducing cell death associated with radiation injury, the method involving contacting a cell at risk of cell death with a Nrf2 activator, thereby preventing or reducing cell death relative to an untreated control cell.
  • the invention generally provides methods of treating or preventing radiation injury in a subject at risk thereof, the method involving administering to the subject an effective amount of a Nrf2 activator.
  • the invention generally provides packaged pharmaceutical comprising a therapeutically effective amount of a Nrf2 activator labeled for use in preventing or treating radiation injury, and instructions for use.
  • the invention generally provides a kit for the amelioration of treating or preventing radiation injury comprising a Nrf2 activator and written instructions for use of the kit.
  • the method prevents or ameliorates hematopoietic syndrome, gastrointestinal syndrome, or cerebrovascular syndrome, pulmonary effects, renal failure, and effects on soft tissues.
  • the method prevents or ameliorates a symptom of hematopoietic damage that is any one or more of hypoplasia or aplasia of the bone marrow, pancytopenia, predisposition to infection, bleeding, and poor wound healing.
  • the method prevents or ameliorates a symptom of gastrointestinal damage that is any one or more of loss of intestinal crypts, breakdown of the mucosal barrier, abdominal pain, diarrhea, and nausea and vomiting.
  • the method treats or prevents cutaneous injury from radiation burns wherein the injury is any one or more ofloss of epidermis, loss of dermis, loss of muscle and loss of bone.
  • the method prevents lung fibrosis or esophageal damage associated with radiotherapy.
  • the method prevents or ameliorates inflammation.
  • the compound is a compound listed in Table IA (e.g., sulforaphane, a triterpenoid, such as Tri terpenoid- 155, Triterpenoid-156, Triterpenoid- 162, and Triterpenoid-225).
  • the radiation injury is associated with a nuclear attack or radiotherapy.
  • the method increases Nrf2 transcription or translation.
  • the method prevents cell death of a cell that is any one or more of a pulmonary cell, endothelial cell, pulmonary endothelial cell, smooth muscle cell, epithelial cell, and alveolar cell.
  • the Nrf2 activator is administered before, during , or after radiation injury.
  • the Nrf2 activator is administered within 1-12 (e.g., 1, 2, 3, 6, 9, 12) hours of radiation exposure.
  • the Nrf2 activator is administered prior to radiation exposure.
  • compositions and methods for treating or preventing radiation-associated tissue damage are provided.
  • Compositions and articles defined by the invention were isolated or otherwise manufactured in connection with the examples provided below. Other features and advantages of the invention will be apparent from the detailed description, and from the claims.
  • Nrf2 activator any agent that increases Nrf2 expression or biological activity.
  • exemplary Nrf2 activators include but are not limited to small compounds, polypeptides and fragments thereof, and polynucleotides (e.g., DNA, RNA, microRNAs, siRNAs) and fragments thereof.
  • Nrf2 polypeptide is meant a protein or protein variant, or fragment thereof, that comprises an amino acid sequence substantially identical to at least a portion of GenBank Accession No. NP 006164 (human nuclear factor (erythroid-derived 2)-like 2) and that has a Nrf2 biological activity (e.g., activation of target genes through binding to antioxidant response element (ARE), regulation of expression of antioxidants and xenobiotic metabolism genes).
  • NP 006164 human nuclear factor (erythroid-derived 2)-like 2
  • Nrf2 biological activity e.g., activation of target genes through binding to antioxidant response element (ARE), regulation of expression of antioxidants and xenobiotic metabolism genes.
  • Nrf2 biological activity binding to an antioxidant-response element (ARE), nuclear accumulation, or the transcriptional induction of target genes.
  • ARE antioxidant-response element
  • Nrf2 nucleic acid molecule is meant a polynucleotide encoding an Nrf2 polypeptide or variant, or fragment thereof.
  • Nrf2 nucleic acid molecule is meant a polynucleotide encoding an Nrf2 polypeptide or variant, or fragment thereof.
  • radiation injury is meant cell or tissue damage associated with exposure to ionizing radiation.
  • agent any small molecule chemical compound, antibody, nucleic acid molecule, or polypeptide, or fragments thereof.
  • ameliorate decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease.
  • alteration is meant a change (increase or decrease) in the expression levels or activity of a gene or polypeptide as detected by standard art known methods such as those described herein.
  • an alteration includes a 10% change in expression levels, preferably a 25% change, more preferably a 40% change, and most preferably a 50% or greater change in expression levels.
  • an analog is meant a molecule that is not identical, but has analogous functional or structural features.
  • a polypeptide analog retains the biological activity of a corresponding naturally-occurring polypeptide, while having certain biochemical modifications that enhance the analog's function relative to a naturally occurring polypeptide. Such biochemical modifications could increase the analog's protease resistance, membrane permeability, or half-life, without altering, for example, ligand binding.
  • An analog may include an unnatural amino acid.
  • disease is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
  • diseases include radiation injury, as characterized by any reduction in cell or tissue biological function, including a reduction in hematopoiesis, gastrointestinal morphology or function, immune system function, lung function, renal function, central nervous system function, oral function and skin function.
  • an effective amount is meant the amount of a required to ameliorate the symptoms of a disease relative to an untreated patient.
  • the effective amount of active compound(s) used to practice the present invention for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an "effective" amount.
  • the invention provides a number of targets that are useful for the development of highly specific drugs to treat or a disorder characterized by the methods delineated herein.
  • the methods of the invention provide a facile means to identify therapies that are safe for use in subjects.
  • the methods of the invention provide a route for analyzing virtually any number of compounds for effects on a disease described herein with high-volume throughput, high sensitivity, and low complexity.
  • fragment is meant a portion of a polypeptide or nucleic acid molecule. This portion contains, preferably, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the entire length of the reference nucleic acid molecule or polypeptide.
  • a fragment may contain 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 nucleotides or amino acids.
  • obtaining as in “obtaining an agent” includes synthesizing, purchasing, or otherwise acquiring the agent.
  • radiation injury any cell, tissue, or organ damage associated with radiation exposure.
  • radiation injury include, but are not limited to, cerebrospinal injury, lung fibrosis, pneumonitis, hematopoietic injury, gastrointestinal injury, skin injuries and sepsis
  • reduces is meant a negative alteration of at least 10%, 25%, 50%, 75%, or 100%.
  • reference is meant a standard or control condition.
  • subject is meant a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline.
  • Ranges provided herein are understood to be shorthand for all of the values within the range.
  • a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.
  • treat refers to reducing or ameliorating a disorder and/or symptoms associated therewith. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated.
  • the term "about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term about.
  • compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.
  • Figure 2 includes three graphs, which provide proof of concept studies with Nrf2 activator, showing quantitation of TBI induced Mortality in Nrf2-/- mice and Nrf2+/+ mice after CDDO-me (small molecule Nrf2 activator) or vehicle treatment.
  • CDDO-me small molecule Nrf2 activator
  • Figures 3A-3D show TBI induced GI injury in Nrf2+/+ and Nrf2-/- mice after CDDO-me or vehicle treatment.
  • TBI 24 hours mice
  • GI injury was assessed by mucosal damage by histopathalogical analysis ( Figures 3 A and 3B) and crypt cell proliferation by BrdU immunohistochemistry staining ( Figures 3C and 3D).
  • Figures 3A and 3B are micrographs showing CDDO-Me treatment significantly mitigated reduction in gastrointestinal villi while 3C and 3D showing CDDO-Me significantly mitigated loss of crypt cells as indicated by increase proliferation of crypt cells.
  • Figure 4 is a graph quantitating TBI induced HP injury in mice after CDDO-me or vehicle treatment as assessed by bone marrow clonogenic assay.
  • Figure 5 is a table that quantifies Nrf2 regulated antioxidant defenses in multiple tissues of mice treated with CDDO-Me post TBI.
  • the invention features compositions and methods that are useful for the treatment of radiation injury.
  • the invention is based, at least in part, on the discovery that compounds that activate Nrf2 protect against cell and tissue damage associated with radiation exposure, and reduce mortality in response to such injury.
  • Clinical components of acute radiation syndrome include hematopoietic, gastrointestinal, and cerebrovascular syndromes that occur within days or weeks of exposure.
  • the hematopoietic syndrome which is characterized by hypoplasia or aplasia of the bone marrow, occurs in connection with significant partial-body or whole-body radiation exposures. These hematopoietic changes result in pancytopenia, predisposition to infection, bleeding, and poor wound healing. Any one of these effects of radiation on hematopoiesis may be fatal.
  • Gastrointestinal syndrome is characterized by abdominal pain, diarrhea, and nausea and vomiting and predispose patients to infection. Radiation induces loss of intestinal crypts and breakdown of the mucosal barrier. Cutaneous injury from thermal or radiation burns is characterized by loss of epidermis and dermis. Injuries to the skin may cover small areas but extend deep into the soft tissue, even reaching underlying muscle and bone.
  • ROS and electrophiles generated by irradiation are key players in causing acute and chronic pathological injury.
  • ROS induce oxidative damage to biomolecules and causes apoptosis of hematopoietic cells, endothelial cells and epithelial cells.
  • Depletion of hematopoietic cells in a subject results in an impaired immune response and predisposes the subject to secondary infections.
  • the increased death of endothelial cells and epithelial cells results in a loss of mucosal barrier and tissue injury. Loss of intestinal or lung mucosal barrier leads to translocation of bacteria into systemic circulation and causes systemic inflammation and sepsis.
  • Tissue injury causes local inflammation leading to tissue remodeling and fibrosis.
  • irradiation increases oxidative stress, apoptosis, and inflammation leading to multi-organ injury, which is often lethal.
  • Therapies directed towards blocking ROS induced deleterious effects mitigates and treats radiation injury.
  • Nuclear factor erythroid-2 related factor 2 (NRF2), a cap-and-collar basic leucine zipper transcription factor, regulates a transcriptional program that maintains cellular redox homeostasis and protects cells from oxidative insult, including from chemotherapeutic agents (Rangasamy T, et al.,J Clin Invest 114, 1248 (2004); Thimmulappa RK, et al. Cancer Res 62, 5196 (2002); So HS, et al. Cell Death Differ (2006)).
  • NRF2 activates transcription of its target genes through binding specifically to the antioxidant-response element (ARE) found in those gene promoters.
  • ARE antioxidant-response element
  • Nrf2 is a redox sensitive transcription factor that regulates a battery of cellular antioxidant defenses that protect organisms from reactive oxygen species, inflammatory mediators and proapoptotic factors. Radiation injury is predominantly mediated by oxidative stress and inflammation. Radiation induces excess generation of reactive oxygen species and electrophiles that causes massive cell loss (e.g., loss of bone marrow stem cells, immune cells, epithelial cells and endothelial cells) in radiosensitive tissues (e.g., gut, liver, lung, brain, and kidney) due to apoptosis.
  • massive cell loss e.g., loss of bone marrow stem cells, immune cells, epithelial cells and endothelial cells
  • radiosensitive tissues e.g., gut, liver, lung, brain, and kidney
  • Nrf2 as a novel drug target that can induce most powerful and efficient cellular antioxidant defense. Activation of Nrf2 prior to radiation exposure will help in preventing radiation injuries while postradiation activiation of Nrf2 mitigates and treats radiation injuries.
  • the Nrf2 pathway can be manipulated to generate engineered stem cells.
  • Nrf2 activators include pharmacological drugs (natural or synthetic), nucleic acid molecules (siRNA, miRNA)) that activate Nrf2 for the treatment or prevention of radiation induced disorders.
  • the NRF2-regulated transcriptional program includes a broad spectrum of genes, including antioxidants [ ⁇ -glutamyl cysteine synthetase modifier subunit (GCLm), ⁇ -glutamyl cysteine synthetase catalytic subunit (GCLc), heme oxygenase- 1, superoxide dismutase, glutathione reductase (GSR), glutathione peroxidase, thioredoxin, thioredoxin reductase, peroxiredoxins (PRDX), cysteine/glutamate transporter (SLC7A11) (7, 8)], phase II detoxification enzymes [NADP(H) quinone oxidoreductase 1 (NQOl), GST, UDP- glucuronosyltransferase (Rangasamy T, et al.
  • antioxidants [ ⁇ -glutamyl cysteine synthetase modifier subunit (GCLm), ⁇ -g
  • Nrf2 activating compounds include the class of compounds known as tricyclic bis-enones (TBEs) that are structurally related to synthetic tri terpenoids, including RTA401 and RTA 402.
  • TBEs tricyclic bis-enones
  • Compounds useful in the methods of the invention include those described in U.S. Patent Publication No. 2004/002463, as well as those listed in Table IA (below).
  • the invention provides therapeutic compositions that increase Nrf2 expression in a cell, tissue, or organ, such as skin, lung, esophagus, or a gastrointestinal tissue.
  • Nrf2 expression or biological activity may be administered within a pharmaceutically-acceptable diluents, carrier, or excipient, in unit dosage form.
  • Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer the compounds to patients suffering from a disease that is associated with radiation injury and radiation-related cellular damage. Administration may begin before, during or after radiation exposure.
  • a Nrf2 activating agent is administered before, during or after radiotherapy (e.g., radiotherapy for the treatment of neoplasia).
  • a Nrf2 activating agent is administered after a nuclear attack (e.g., within 1, 2, 3, 4, 5, 6, 8, 10, 12 or 24 hours of exposure.
  • administration may be by inhalation, or parenteral, intravenous, intraarterial, subcutaneous, intratumoral, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intrahepatic, intracapsular, intrathecal, intracisternal, intraperitoneal, intranasal, aerosol, suppository, or oral administration.
  • therapeutic formulations may be in the form of liquid solutions or suspensions; for oral administration, formulations may be in the form of tablets or capsules; and for intranasal formulations, in the form of powders, nasal drops, or aerosols.
  • Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes.
  • Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene- polyoxypropylene copolymers may be used to control the release of the compounds.
  • Nrf2 activators include ethylene- vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.
  • the formulations can be administered to human patients in therapeutically effective amounts (e.g., amounts which prevent, eliminate, or reduce a pathological condition) to provide therapy for radiation injury.
  • therapeutically effective amounts e.g., amounts which prevent, eliminate, or reduce a pathological condition
  • the preferred dosage of a Nrf2 activator of the invention is likely to depend on such variables as the type and extent of the disorder, the overall health status of the particular patient, the formulation of the compound excipients, and its route of administration.
  • an effective amount is sufficient to increase Nrf2 expression or biological activity, increase antioxidant activity or reduce oxidative stress, or protect a cell, tissue or organism from damage or death.
  • doses of Nrf2 activators would be from about 0.01 mg/kg per day to about 1000 mg/kg per day. It is expected that doses ranging from about 50 to about 2000 mg/kg will be suitable. Lower doses will result from certain forms of administration, such as intravenous administration. In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of the compositions of the present invention.
  • a variety of administration routes are available.
  • the methods of the invention may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects.
  • Other modes of administration include oral, rectal, topical, intraocular, buccal, intravaginal, intracisternal, intracerebroventricular, intratracheal, nasal, transdermal, within/on implants, e.g., fibers such as collagen, osmotic pumps, or grafts comprising appropriately transformed cells, etc., or parenteral routes.
  • the present invention provides methods of treating radiation injury and radiation- related cellular damage or symptoms thereof which comprise administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of the formulae herein to a subject (e.g., a mammal such as a human).
  • a subject e.g., a mammal such as a human
  • one embodiment is a method of treating a subject suffering from or susceptible to a radiation injury and radiation-related cellular damageor symptom thereof.
  • the method includes the step of administering to the mammal a therapeutic amount of an amount of a compound herein sufficient to treat the disease or disorder or symptom thereof, under conditions such that the disease or disorder is treated.
  • the methods herein include administering to the subject (including a subject identified as in need of such treatment) an effective amount of a compound described herein (e.g., Nrf2 activator), or a composition described herein to produce such effect. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).
  • a compound described herein e.g., Nrf2 activator
  • Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).
  • treat refers to reducing or ameliorating a disorder and/or symptoms associated therewith. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated.
  • the terms "prevent,” “preventing,” “prevention,” “prophylactic treatment” and the like refer to reducing the probability of developing a disorder or condition in a subject, who does not have, but is at risk of or susceptible to developing a disorder or condition.
  • the therapeutic methods of the invention in general comprise administration of a therapeutically effective amount of the compounds herein, such as a compound of the formulae herein to a subject (e.g., animal, human) in need thereof, including a mammal, particularly a human.
  • a subject e.g., animal, human
  • Such treatment will be suitably administered to subjects, particularly humans, suffering from, having, susceptible to, or at risk for a disease, disorder, or symptom thereof.
  • Determination of those subjects "at risk” can be made by any objective or subjective determination by a diagnostic test or opinion of a subject or health care provider (e.g., genetic test, enzyme or protein marker, Marker (as defined herein), family history, and the like).
  • a diagnostic test or opinion of a subject or health care provider e.g., genetic test, enzyme or protein marker, Marker (as defined herein), family history, and the like.
  • the compounds herein may be also used in the treatment of any other disorders in which radiation injury and radiation-related cellular damage may be implicated.
  • the invention provides a method of monitoring treatment progress.
  • the method includes the step of determining a level of diagnostic marker (Marker) (e.g., any target delineated herein modulated by a compound herein, a protein or indicator thereof, etc.) or diagnostic measurement (e.g., screen, assay) in a subject suffering from or susceptible to a disorder or symptoms thereof associated with radiation injury and radiation- related cellular damage, in which the subject has been administered a therapeutic amount of a compound herein sufficient to treat the disease or symptoms thereof.
  • the level of Marker determined in the method can be compared to known levels of Marker in either healthy normal controls or in other afflicted patients to establish the subject's disease status.
  • a second level of Marker in the subject is determined at a time point later than the determination of the first level, and the two levels are compared to monitor the course of disease or the efficacy of the therapy.
  • a pre- treatment level of Marker in the subject is determined prior to beginning treatment according to this invention; this pre-treatment level of Marker can then be compared to the level of Marker in the subject after the treatment commences, to determine the efficacy of the treatment.
  • kits for preventing or treating radiation injury and/or radiation-related cellular damage e.g., lung fibrosis
  • the kit comprises a sterile container that contains a Nrf2 activator; such containers can be boxes, ampoules, bottles, vials, tubes, bags, pouches, blister-packs, or other suitable container form known in the art.
  • Such containers can be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holding nucleic acids.
  • the instructions will generally include information about the use of the Nrf2 activator in treating or preventing oxidative stress or cellular damage associated with radiation injury and radiation-related cellular damage.
  • the kit further comprises any one or more of the reagents described in the assays described herein.
  • the instructions include at least one of the following: description of the Nrf2 activator; methods for using the enclosed materials for the treatment or prevention of a radiation injury and radiation-related cellular damage; precautions; warnings; indications; clinical or research studies; and/or references.
  • the instructions may be printed directly on the container (when present), or as a label applied to the container, or as a separate sheet, pamphlet, card, or folder supplied in or with the container.
  • Nrf2 is a primary regulator of antioxidant genes.
  • Nrf2 regulates a network of cytoprotective genes including antioxidants in different organs (lung, intestine, liver, brain) in response to chemical activators or stressors.
  • the antioxidant associated genes regulated by Nrf2 include direct antioxidants (SODl, heme oxygenase- 1 (Hmoxl), NQOl) and genes associated with glutathione pathway (glutathione peroxidase (Gpx), glutathione reductase, glutamate cystiene ligase (catalytic and modifier subunit), thioredoxin pathway (thioredoxin reductase (Txnrdl), peroxiredoxin (Prdx)), as well as NADPH-regenerating enzymes (glucose 6-phosphate dehydrogenase (G6PD), phosphogluconate dehydrogenase (Pgd), and maleic enzyme 1 (MeI)) and xenobiotic detoxification enzymes (such as glutathione S-transfera
  • Nrf2 protects tissues from TBI induced mortality.
  • Nrf2 lethal total body irradiation
  • wild-type (Nrf2+/+) and Nrf2-deficient (Nrf2-/-) mice were exposed to 9 Gy.
  • TBI induced early and greater mortality in Nrf2-/- mice when compared to Nrf2+/+ mice.
  • These results indicate that Nrf2 improved survival following TBI ( Figure 1).
  • Example 3 Small molecule Nrf2 activator significantly mitigates TBI induced mortality in NrO+/+ mice, but not in NrO-/- mice.
  • Nrf2+/+ and Nrf2-/- were treated with the small molecule, CDDO-Me, a potent Nrf2 activator 1 hour and 24 hours after TBI. 100% mortality was observed in vehicle treated Nrf2+/+ mice. In contrast, CDDO-Me markedly inhibited TBI induced mortality in Nrf2+/+ mice. Mice treated with CDDO-Me 1 hour or 24 hours post-TBI showed 0% and 25% mortality, respectively. In contrast, CDDO-me treatment in Nrf2-/- mice 1 hour post-TBI failed to improve survival following TBI ( Figure 2).
  • Example 4 NrO activation by CDDO-me mitigates TBI induced Gastrointestinal (GI) injury.
  • Example 5 Activation of NrO by small molecule mitigates TBI induced hematopoietic (HP) injury.
  • CDDO-Me treatment markedly protected hematopoietic stem cells and progenitors cell, as shown by the preservation of granulocyte/macrophage colony forming cells as shown in Figure 4.

Abstract

La présente invention concerne des compositions et des procédés comprenant des activateurs de Nrf2 pour traiter ou prévenir des dommages tissulaires associés à un rayonnement.
PCT/US2009/006244 2008-11-21 2009-11-23 Compositions et procédés pour traiter ou prévenir les lésions dues à un rayonnement WO2010059245A2 (fr)

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US13/130,526 US20120029071A1 (en) 2008-11-21 2009-11-23 Compositions and methods for treating or preventing radiation injury

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CN103027910A (zh) * 2012-12-04 2013-04-10 苏州中药研究所 吲哚-3-原醇在制备防治实验性肺纤维化药物中的应用
WO2014183068A3 (fr) * 2013-05-10 2015-01-08 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Traitement de troubles pulmonaires et d'autres troubles
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US9701709B2 (en) 2012-04-27 2017-07-11 Reata Pharmaceuticals, Inc. 2,2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof
US9757359B2 (en) 2008-01-11 2017-09-12 Reata Pharmaceuticals, Inc. Synthetic triterpenoids and methods of use in the treatment of disease
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WO2012068454A3 (fr) * 2010-11-19 2012-07-12 University Of Rochester Influence d'une déficience en nrf2 sur la sensibilité à la résistance aux stéroïdes par le biais d'une diminution de la concentration en hdac2
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