WO2016195074A1 - Agent thérapeutique de lecture - Google Patents

Agent thérapeutique de lecture Download PDF

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Publication number
WO2016195074A1
WO2016195074A1 PCT/JP2016/066593 JP2016066593W WO2016195074A1 WO 2016195074 A1 WO2016195074 A1 WO 2016195074A1 JP 2016066593 W JP2016066593 W JP 2016066593W WO 2016195074 A1 WO2016195074 A1 WO 2016195074A1
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WO
WIPO (PCT)
Prior art keywords
administered
read
clindamycin
therapeutic agent
activity
Prior art date
Application number
PCT/JP2016/066593
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English (en)
Japanese (ja)
Inventor
良一 松田
政孝 塩塚
禎昭 野々村
Original Assignee
国立大学法人東京大学
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Application filed by 国立大学法人東京大学 filed Critical 国立大学法人東京大学
Publication of WO2016195074A1 publication Critical patent/WO2016195074A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim

Definitions

  • the present invention relates to a lead-through therapeutic agent.
  • This application claims priority based on provisional application No. 62 / 171,205 filed in the United States on June 4, 2015, the contents of which are incorporated herein by reference.
  • a nonsense mutation-type inherited disease is a disease caused by inhibition of protein expression by an immature stop codon formed by a point mutation on a gene (nonsense mutation).
  • the read-through activity refers to an activity in which, when a specific compound is administered to a patient with a nonsense mutation type inherited disease, the compound acts on the ribosome, and the ribosome reads through the immature stop codon and translates.
  • wild-type normal protein is synthesized, and the symptoms of nonsense mutation-type inherited disease are alleviated.
  • Patent Document 1 describes that arbekacin, which is an aminoglycoside compound, has read-through activity.
  • aminoglycoside compounds need to be administered by intravenous injection.
  • a drug that can be administered orally is desirable in order to maintain compliance.
  • an object of the present invention is to provide a read-through therapeutic agent that can be administered orally.
  • the present invention is as follows. (1) A lead-through therapeutic agent containing a lincomycin-based compound as an active ingredient. (2) The lead-through therapeutic agent according to (1), which is an oral agent. (3) The read-through therapeutic agent according to (1) or (2), which is used for treatment of a nonsense mutation-type inherited disease. (4) The read-through therapeutic agent according to any one of (1) to (3), wherein the nonsense mutation-type inherited disease is muscular dystrophy or cystic fibrosis.
  • a lead-through therapeutic agent that can be administered orally can be provided.
  • Experimental Example 1 it is a graph which shows the measurement result of the read-through activity of each mouse.
  • Experimental Example 2 it is a graph which shows the measurement result of the read-through activity of each mouse
  • (A) to (d) are photographs showing the results of immunostaining in Experimental Example 3.
  • (A) to (d) are photographs showing the results of immunostaining in Experimental Example 3.
  • (A) to (c) are photographs showing the results of immunostaining in Experimental Example 5.
  • Experimental Example 6 it is a graph which shows the measurement result of the creatine kinase activity in the blood of each mouse
  • ⁇ ⁇ Functional protein deficiency due to nonsense mutation causes more than 2,400 lethal diseases (nonsense mutation type inherited disease) including muscular dystrophy.
  • Lead-through treatment is a treatment method that improves the symptoms by administering a drug to a patient, suppressing the inhibition of protein expression due to nonsense mutation, allowing translation to progress, and acquiring a congenitally lacking functional protein. It is.
  • This therapy is not based on gene therapy or nucleic acid medicine, but is based on the concept that comprehensive treatment of nonsense mutation cases is possible. For example, effective and rapid options for nonsense mutation cases accounting for 19% in Duchenne muscular dystrophy patients in Japan. it is conceivable that.
  • the present invention provides a lead-through therapeutic agent containing a lincomycin-based compound as an active ingredient.
  • the read-through therapeutic agent of this embodiment can exhibit read-through activity by oral administration. Therefore, the lead-through therapeutic agent of this embodiment can be used as an oral agent.
  • an intractable nonsense mutation-type inherited disease can be treated using a drug regardless of gene therapy, nucleic acid medicine, stem cell transplantation, and the like.
  • examples of lincomycin compounds include clindamycin, lincomycin, and the like.
  • clindamycin is a drug that has good oral absorbability and tissue permeability, has been used as an antibacterial agent for many years, and a lot of information has been accumulated on safety from the track record of clinical use.
  • the inventors have clarified that clindamycin is also effective as a lead-through therapeutic agent.
  • nonsense mutation hereditary diseases include, for example, cystic fibrosis, retinitis pigmentosa, epidermolysis bullosa, xeroderma pigmentosum, lysosomes, multiple sclerosis, infant neuronal ceroid lipofuscin deposition Disease, Alzheimer's disease, Tay-Sachs disease, neural tissue degeneration, Parkinson's disease, rheumatoid arthritis, graft versus host disease, arthritis, hemophilia, von Willebrand disease, telangiectasia ataxia, thalassemia, kidney stone, Bone dysplasia, cirrhosis, neurofibromatosis, bullous disease, lysosomal storage disease, Harrah's disease, familial cholesterolemia, cerebellar ataxia, tuberous sclerosis, familial erythrocytosis, immunodeficiency
  • the lead-through therapeutic agent of this embodiment greatly contributes as a direct reduction to human welfare, and can provide great hope to patients suffering from intractable diseases. Furthermore, by specifying drug candidates from existing drugs, it is possible to omit non-clinical / phase I clinical trials, and it can be put to practical use quickly. For this reason, contributing to the early treatment of progressive serious diseases and increasing the opportunity to provide useful pharmaceuticals will greatly contribute to society. In addition to shortening the development period, it is also possible to reduce development risks and development costs.
  • the lead-through therapeutic agent of this embodiment may be a pharmaceutical composition containing a lincomycin-based compound and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be formulated into an orally used dosage form or a parenterally used dosage form, but it is formulated into an orally used dosage form from the viewpoint of maintaining compliance. It is preferable that
  • Examples of the dosage form used orally include tablets, capsules, elixirs, microcapsules and the like.
  • Examples of dosage forms used parenterally include injections.
  • binders such as gelatin, corn starch, tragacanth and gum arabic
  • excipients such as crystalline cellulose
  • corn starch Swelling agents such as gelatin, alginic acid, etc .
  • lubricants such as magnesium stearate
  • sweeteners such as sucrose, lactose, saccharin
  • flavoring agents such as peppermint, red mono oil, cherry
  • fats and oils water for injection, vegetable oil (eg, sesame oil, coconut oil, soybean oil), liquid carriers such as buffer (for example, phosphate buffer, sodium acetate buffer); solubilizer (for example, ethanol, propylene glycol, polyethylene glycol, benzyl benzoate, benzyl alcohol);
  • Nonionic surfactant eg, Polysorbate 80 TM, HCO-50
  • a soothing agent e.g., benzalkonium chloride, procaine hydrochloride
  • stabilizers e.g., benzalkonium chloride, pro
  • water for injection examples include physiological saline; isotonic solutions containing glucose, D-sorbitol, D-mannitol, sodium chloride and the like.
  • Administration of the pharmaceutical composition to a patient can be performed by methods known to those skilled in the art, such as oral administration, intraarterial injection, intravenous injection, and subcutaneous injection.
  • the dose of the lincomycin-based compound varies depending on the weight and age of the patient, the administration method, etc., but those skilled in the art can appropriately select an appropriate dose.
  • 100 to 500 mg (titer) is generally administered every 6 hours.
  • 600 to 2400 mg (titer) is generally administered 2 to 4 times a day.
  • the present invention provides a method for reducing the dose of an amide glycoside compound comprising the step of administering an amide glycoside compound and a lincomycin compound in combination.
  • the reduction method of the present embodiment by using a lincomycin-based compound in combination, the dose of the amide glycoside compound can be reduced while exhibiting the same degree of lead-through therapeutic effect. As a result, effects such as reduction of side effects caused by administration of the amide glycoside compound can be obtained.
  • the present invention provides a method for reducing the dose of a lincomycin compound, comprising the step of administering a combination of an amide glycoside compound and a lincomycin compound.
  • the reduction method of the present embodiment by using an amide glycoside compound in combination, the dose of the lincomycin compound can be reduced while exhibiting the same degree of lead-through treatment effect. As a result, effects such as reduction of side effects caused by administration of the lincomycin-based compound can be obtained.
  • the present invention provides a kit for treating a nonsense mutant genetic disease, comprising an injection containing an amide glycoside compound as an active ingredient and an oral preparation containing a lincomycin compound as an active ingredient. provide.
  • the present invention provides a method for treating a nonsense mutant genetic disease, comprising the steps of administering an amide glycoside compound to a patient and administering a lincomycin compound to the patient.
  • the present invention provides a method for treating a nonsense mutant genetic disease, comprising the step of administering an effective amount of a lincomycin-based compound to a patient in need of treatment.
  • the present invention provides a lincomycin-based compound for the treatment of a nonsense mutant genetic disease.
  • the present invention provides the use of a lincomycin-based compound for the manufacture of a therapeutic agent for a nonsense mutant genetic disease.
  • the lincomycin-based compound is preferably administered orally.
  • the nonsense mutation-type inherited disease may be muscular dystrophy or cystic fibrosis.
  • Example 1 Use a transgenic mouse for detection of read-through activity (Readthrough Evaluation and Assessment by Dual-reporter, International Publication No. 2008/004610, hereinafter referred to as “READ mouse”).
  • R. E. A. D. The mouse comprises a construct (27mer including a 12mer peripheral sequence before and after the immature stop codon of exon 23 of mdx mouse) in which a ⁇ -galactosidase gene and a luciferase gene are linked and an immature stop codon (TGA) is inserted into the joint.
  • TGA immature stop codon
  • An expression vector (pCAGGS) having a cytomegalovirus enhancer / chicken ⁇ -actin hybrid promoter is incorporated into the germline.
  • R. E. A. D. Mice normally express only ⁇ -galactosidase, and luciferase when read through the premature stop codon.
  • R. E. A. D. Expression of ⁇ -galactosidase has been confirmed in all muscle tissues including mouse myocardium and diaphragm.
  • R.D. E. A. D. Arbekacin 1 mg / day, lincomycin 3 mg / day, lincomycin 10 mg / day, and clindamycin 6 mg / day were subcutaneously administered to mice for 7 days. Subsequently, the read-through activity in each mouse was measured. The read-through activity was measured by quantifying the luciferase activity and ⁇ -galactosidase activity in the thigh / crus skeletal muscle tissue extract at the end of drug administration with a luminometer.
  • FIG. 1 is a graph showing the measurement results of the read-through activity of each mouse. As a result, it was clarified that by administering lincomycin or clindamycin subcutaneously, the same level of read-through activity as that obtained by subcutaneous administration of arbekacin known to have read-through activity was exhibited. .
  • FIG. 2 is a graph showing the measurement results of the read-through activity of each mouse.
  • mdx mice which are model mice of Duchenne muscular dystrophy, and the expression of dystrophin protein was examined. Note that mdx mice have a nonsense mutation in the dystrophin gene and lack the dystrophin protein.
  • Mdx mice were administered clindamycin 6 mg / day for 4 consecutive days. Clindamycin was administered subcutaneously or orally. Subsequently, the lower leg muscle tissue of each mouse was collected to prepare a sliced section, and the expression of dystrophin protein was examined by immunostaining. For comparison, B10 mice, which are normal mice, and mdx mice that were not administered with clindamycin were also subjected to the same immunostaining by collecting crus muscle tissue and preparing sliced sections.
  • FIG. 3 (a) to 3 (d) are photographs showing the results of immunostaining.
  • FIG. 3 (a) shows the results of B10 mice
  • FIG. 3 (b) shows the results of mdx mice not administered with clindamycin
  • FIG. 3 (c) shows mdx administered with clindamycin by subcutaneous administration.
  • mouth is shown
  • FIG.3 (d) shows the result of the mdx mouse
  • dystrophin protein was not detected in the tissue of mdx mice not administered with clindamycin (FIG. 3 (b)).
  • B10 mice FIGG. 3A
  • mdx mice administered with clindamycin by subcutaneous administration FIG. 3C
  • mdx mice administered with clindamycin by oral administration FIG. 3D
  • the expression of full-length dystrophin protein was detected.
  • dystrophin protein can be expressed in tissues of mdx mice having a nonsense mutation in the dystrophin gene by subcutaneous administration or oral administration of clindamycin.
  • Creatine kinase is a clinical marker for muscular dystrophy. Creatine kinase is an enzyme contained in muscle fibers and leaks into the blood when the muscle is destroyed. For this reason, it shows that muscle collapse progresses, so that the creatine kinase activity in blood is high.
  • Mdx mice were administered clindamycin 6 mg / day for 4 consecutive days. Clindamycin was administered subcutaneously or orally. For comparison, a group in which normal saline was administered to B10 mice and mdx mice, which were normal mice, and a group in which arbekacin 1 mg / day was subcutaneously administered to mdx mice every day for 4 weeks were prepared.
  • FIG. 4 is a graph showing measurement results of creatine kinase activity.
  • Arbekacin 1 mg / day was subcutaneously administered to mdx mice every day for 3 weeks. Moreover, arbekacin 0.5 mg / day was subcutaneously administered to mdx mice every day for 3 weeks, and clindamycin 3 mg / day was orally administered. Subsequently, the lower leg muscle tissue of each mouse was collected in the same manner as in Experimental Example 3, thin slices were prepared, and the expression of dystrophin protein was examined by immunostaining. As a control, muscular tissue was collected from mdx mice subcutaneously administered daily for 3 weeks, and the crus muscle tissue was collected and sliced, and the same immunostaining was performed.
  • FIG. 5 (a) to (c) are photographs showing the results of immunostaining.
  • Fig. 5 (a) shows the results of control mdx mice
  • Fig. 5 (b) shows the results of mdx mice administered with arbekacin
  • Fig. 5 (c) shows mdx administered with arbekacin and clindamycin in combination. Mouse results are shown.
  • dystrophin protein was not detected in the tissue of mdx mice administered with physiological saline (FIG. 5 (a)).
  • mdx mice administered subcutaneously with arbekacin 1 mg / day FIG. 5B
  • mdx mice administered subcutaneously with arbekacin 0.5 mg / day FIG. 3 (c)
  • the expression of dystrophin protein was detected to the same extent from the tissue of)).
  • a lead-through therapeutic agent that can be administered orally can be provided.
  • the lead-through therapeutic agent it is possible to treat an intractable nonsense mutated hereditary disease using a drug regardless of gene therapy, nucleic acid medicine, stem cell transplantation and the like.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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Abstract

La présente invention concerne un agent thérapeutique de lecture renfermant un composé de lincomycine en tant qu'ingrédient actif.
PCT/JP2016/066593 2015-06-04 2016-06-03 Agent thérapeutique de lecture WO2016195074A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562171205P 2015-06-04 2015-06-04
US62/171,205 2015-06-04

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WO2016195074A1 true WO2016195074A1 (fr) 2016-12-08

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108665954A (zh) * 2018-05-22 2018-10-16 王含 帕金森综合征疗效管理方法及管理装置

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008004610A1 (fr) * 2006-07-05 2008-01-10 The University Of Tokyo Méthode de traitement de maladie génétique provoquée par une mutation non sens

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008004610A1 (fr) * 2006-07-05 2008-01-10 The University Of Tokyo Méthode de traitement de maladie génétique provoquée par une mutation non sens

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JAPANESE PHARMACOPOEIA CLINDAMYCIN HYDROCHLORIDE CAPSULE DALACIN (REGISTERED TRADEMARK) CAPSULE 75MG DALACIN (REGISTERED TRADEMARK) CAPSULE 150MG TENPU BUNSHO, 2013 *
LINCOCIN (REGISTERED TRADEMARK) CAPSULE 250MG TENPU BUNSHO, 2009, pages 1 - 2 *
NAVEH A. ET AL.: "Determination of misreading effect of antibiotics with the aid of luminous bacteria.", JOURNAL OF MICROBIOLOGICAL METHODS, vol. 4, 1986, pages 241 - 249, XP023699114 *
THOMPSON J. ET AL.: "Effects of a number of classes of 50S inhibitors on stop codon readthrough during protein synthesis.", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 48, no. 12, 2004, pages 4889 - 4891, XP055332317 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108665954A (zh) * 2018-05-22 2018-10-16 王含 帕金森综合征疗效管理方法及管理装置

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