Method for treating kidney disease

Abstract

To provide a pharmaceutical preparation for treating a subject who suffers from a kidney disease or has an onset risk of the disease.SOLUTION: A pharmaceutical preparation is directly administered to a kidney of a subject by direct injection on and / or into a kidney tissue to reduce kidney cytoclasis and / or fibrosis and treat a kidney disease, contains stromal cell derived factor 1 alpha (SDF-1α) of an effective therapeutic amount of 10 nanograms to 1000 nanograms per one administration, where the liver disease is an acute renal failure (caused by poison, psychological trauma, shock, infectious disease, obstruction of a kidney stone or the like, cardiac failure or the like for example), a chronic kidney disease (CKD) (gradual loss of renal function caused by aging, inheritance, obstruction of a kidney stone or the like, diabetes mellitus, infectious disease, dental disease, immune disease, hypertension, thyroid disorder, cancer, congenital renal malformation, congenital polycystic kidney disease or the like for example), a terminal kidney disease, or anemia.SELECTED DRAWING: None

Description

[Background technology]

[0001] Chronic kidney disease (CKD), also known as chronic kidney disease or chronic renal failure, can last for several months or more. CKD is the progressive loss of kidney function over a period of several years or more. It can be caused by a number of metabolic disorders and can affect humans as well as other animals, including companion animals. For example, CKD is the most common cause of morbidity and mortality in older cats. This is one of the causes.

[0002] New therapeutic options are needed for the treatment of kidney disease. Summary of the Invention

[0003] As used herein, the present invention relates to a method for treating a subject suffering from or at risk of developing kidney disease. The method includes administering to a subject (e.g., to a kidney of a subject) a therapeutically effective amount of stromal cell-derived factor 1. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of SDF-1. The kidney disease may be acute renal failure, chronic kidney disease, end-stage renal disease, or anemia. In embodiments, the kidney disease is chronic interstitial nephritis.

[0004] In some embodiments, the method further comprises administering to the subject angiogenic growth deficiency syndrome (ADS) in combination with SDF-1. and administering to the subject a factor (e.g., vascular endothelial growth factor (VEGF)). .

[0005] Further, a sterile injectable composition for treating kidney disease comprising SDF-1 and an aqueous carrier. In some embodiments, the composition comprises collagen or gelatin. In some embodiments, the composition comprises an angiogenic growth factor (e.g., vascular endothelial growth factor). The compound further contains VEGF.

[0006] Also disclosed are methods for treating subjects suffering from or at risk of developing kidney disease. or for use in patients suffering from or at risk of developing kidney disease For use in the preparation of a medicament for carrying out a method of treating a subject, SDF-1 or a vector encoding SDF-1 is provided.

[0007] Figures 1A to 1D show histological images of kidney tissues (Masson's trichrome) from different control and treatment groups. Shown are chromatin staining. [Brief description of the drawings]

[0008] [Figure 1A] FIG. 1 shows histology of kidney tissue from a control subject. [Figure 1B] FIG. 1 shows histology of kidney tissue from an injured subject without treatment. [Figure 1C] FIG. 1 shows histology of kidney tissue from an injured subject receiving carrier injection. [Figure 1D] Figure 1 shows histology of kidney tissue from an injured subject receiving an injection of SDF-1 in a carrier.Administration of SDF-1 restores a more normal cortex-medullary structure to the tissue. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The present disclosure relates to a method for the treatment of stromal cell-derived factor 1 (SDF-1), a chemokine protein. Compositions and methods for the treatment of kidney disease are provided.

[0010] The disclosures of all patent documents cited herein are incorporated by reference in their entirety as if they were set forth herein. To the extent consistent with the disclosure set forth herein, the disclosures set forth herein are incorporated by reference. As used herein in the specification and appended claims of the present invention, The singular forms "a," "an," and "the" are used unless the context clearly indicates otherwise. As used herein, "and / or" is intended to include the plural forms as well. and " / " refers to any and all possible combinations of one or more of the associated listed items. refers to the combination, and the absence of a combination when interpreted in another way ("or"); and Includes.

[0011] As used herein, "treat" refers to any action that provides a benefit to a subject or patient. In particular, the improvement of renal function, renal insufficiency or signs or symptoms thereof, It refers to delay or retardation of onset, progression, or worsening.

[0012] As used herein, "pharmaceutical acceptable" means that a compound or composition is suitable for use in treating a disease. The drug is suitable for administration to a subject without excessively harmful side effects, taking into account the severity of the disease and the need for treatment. This means that it is appropriate for

[0013] "Kidney disease" includes, but is not limited to, acute renal failure (e.g., due to poisoning, trauma, etc.) , shock, infection, blockages such as kidney stones, heart failure, etc.), chronic Kidney disease (CKD) (e.g., aging, genetics, blockages such as kidney stones, diabetes, infections, dental Disease, immune disorders, hypertension, thyroid disorders, cancer, congenital kidney malformations, congenital polycystic kidney disease gradual loss of kidney function due to factors such as diabetes, end-stage renal disease, and anemia. Refers to any type of disease or disorder that can impair multiple kidney functions. Examples include interstitial nephritis (inflammation of the interstitium of the kidney surrounding the renal tubules) can be acute interstitial nephritis or chronic interstitial nephritis. This can eventually lead to kidney failure.

[0014] As used herein, generally, a "subject" or "patient" refers to a research or veterinary For purposes, human subjects and non-human animal subjects (e.g., dogs, cats, horses, birds, etc.) The term "renal disease" refers to an animal subject that is susceptible to renal disease, including both males and females. Any appropriate age group may be studied, including neonatal, infant, child, adolescent, adult, and elderly subjects. It could be an elephant.

[0015] 1. Active compounds As used herein, the active compound is a stromal cell chemokine protein. The compound is a CXC motif chemokine 12 (C Also known as CXCL12, in humans it is produced by the CXCL12 gene. SDF-1 is encoded by the nucleotide sequence described in, for example, M. D'Apuzzo et al., The Chemistry of kine SDF-1, stromal cell-derived factor 1 ,attracts early stage B cell precursors via the chemokine receptor CXCR4, Eur.JI Muno., vol. 27, pp. 1788-1793 (1997); Y. Tabata, R. No. 8,435,953, and Penn et al., U.S. Pat. No. 8,513,213. and U.S. Pat. No. 8,513,007; and S. Itescu, U.S. Pat. No. 62,392, the disclosures of which are hereby incorporated by reference. The entire contents of which are incorporated herein by reference. See also Publication No. 2015 / 171417.

[0016] As used herein, SDF-1 includes, in addition to SDF-1α or its mature form. , e.g., SDF-1β, SDF-1γ, SDF-1δ, SDF-1ε and SDF-1 φ and its mature form, or a mixture of these in any ratio. In the present invention, SDF-1 may be SDF-1α, SDF-1β, or any and mixtures thereof in the ratio of 1 to 10. See U.S. Patent No. 8,435,953. and.

[0017] In the present invention, as long as SDF-1 has activity as a chemokine, Substitution, deletion and / or deletion of one or more amino acids in the amino acid sequence Similarly, SDF-1 may be modified by glycan substitutions, deletions and / or additions. SDF-1 may be added to a physiologically acceptable acid (e.g., an inorganic acid or Form a salt (preferably an acid addition salt) with an organic acid) or a base (e.g., an alkali metal salt). Examples of salts include those formed from inorganic acids (e.g., hydrochloric acid, phosphoric acid, hydrobromic acid, or sulfuric acid), and organic acids (e.g., acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, Acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid or benzenesulfonic acid).

[0018] The SDF-1 used in the present invention may be derived from human, monkey, sheep, bovine, equine, or porcine. Derived from mammals such as dogs, cats, rabbits, rats, or non-human animals such as mice For example, in some embodiments, the compositions of the invention may be For use, the compositions of the invention contain human SDF-1 (e.g., SDF-1α(G GeneBank accession number NP_954637) or SDF-1β (GeneBank accession number As another example, some In an embodiment, when the composition is for use in domestic cats, the composition of the present invention feline SDF-1 (e.g., GeneBank accession number NP_001009847 ( As a further example, the genus Felis catus may be used. In some embodiments, when the composition is for use in a pet dog, The compositions of the invention may be derived from canine SDF-1 (e.g., GeneBank Accession No. AAU89475 (Canis lupus familiaris or GeneBank deposit) Number NP_001121569 (Dog (Canis lupus familiaris) ))).

[0019] In some embodiments, SDF-1 is used to prevent the action of SDF-1 from being compromised by other contaminants. Preferably, SDF-1 is administered in a pharmaceutical preparation. The compound may be purified so as to be usable as such.

[0020] In the present invention, SDF-1 may be obtained from natural sources or by genetic engineering techniques. When obtained from a natural source, SDF-1 may be produced by the addition of a soluble form of SDF-1. Human or non-human animals (e.g., monkeys, sheep, cows, horses, dogs, cats, Extracted from various organs such as the spleen of mammals (rabbit, rat or mouse). Specific examples of organs in which SDF-1 is known to exist include SDF-1 1 is a tumor-specific marker for SDF-1 in organs where tumor cells expressing CXCR4, a receptor for SDF-1, frequently metastasize. On the other hand, it is known that it exists in large quantities in the human body through genetic engineering techniques. In the case of humans or non-human animals (e.g., monkeys, sheep, cows, horses, pigs, dogs, cats, The gene encoding SDF-1 from a mammal (e.g., eg, heron, rat or mouse) is suitably The vector is then introduced into a suitable host cell for transformation, thereby By using the above method, it is possible to obtain the target recombinant SDF-1 from the culture supernatant of the transformant. The host cell in the present specification is not limited, and may be any of E. coli, which is commonly used in genetic engineering technology. Various host cells such as E. coli, yeast cells, and various insect cells such as silkworm cells Insect cells, as well as a variety of animal cells, may be used.

[0021] The active compounds disclosed herein, as described above, may be administered in the form of their pharma- ceutically acceptable salts. Pharmaceutically acceptable salts can be prepared in any form that retains the desired biological activity of the parent compound and, if desired, is Examples of such salts are: (a) salts of inorganic acids, e.g. , acid addition salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc., and organic acids, e.g. For example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid Acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, poly Liglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, (b) Salts formed with naphthalenedisulfonic acid, polygalacturonic acid, etc.; (c) Salts formed with chlorine, bromine and and iodine, and (c) salts such as ammonium salts. salts derived from the aryl group, alkali metal salts such as sodium and potassium salts, calcium and and magnesium salts, as well as dicyclohexylamine and It is a salt with an organic base such as N-methyl-D-glucamine.

[0022] In some embodiments, SDF-1 is delivered directly onto and / or into renal tissue. or in kidney tissue, for example, by injection, Nucleic acid vectors (e.g., integrating, and non-integrating viral vectors, retroviral vectors, plasmid vectors, linear The method is to administer the gene to the host (e.g., by injection) a DNA vector that is capable of expressing the gene. Generally, such vectors contain a promoter that is operable in the tissue (e.g., C A nucleic acid segment encoding SDF-1 as described above operably associated with a MV promoter. Suitable vectors, including plasmid vectors, are known or can be found in the literature. Based on the disclosure, it will be clear to a person skilled in the art, and the following disclosures, for example and without limitation, are cited: No. 8,535,293, issued to Penn et al., the disclosures of which are incorporated herein by reference. 13,213 and U.S. Pat. No. 8,513,007, under accession number PT The plasmids deposited at the American Type Culture Collection under the number A-13320 are listed below. can be.

[0023] 2. Pharmaceutical preparations The active compounds described above can be formulated in a pharmaceutical carrier for administration in accordance with known techniques. For example, Remington, The Science and Prac See, for example, The Book of Pharmacy (9th ed., 1995). In the manufacture of pharmaceutical formulations, the active compound (including its physiologically acceptable salts) is typically The pharmaceutical composition is, inter alia, mixed with an acceptable carrier. Of course, the carrier may be any other suitable component in the formulation. It must be acceptable in the sense of being compatible with the ingredients of the product and not harmful to the patient. The carrier may be a solid or a liquid, or both, and is preferably a unit-sized The compound may be formulated as a dosage form, for example as a tablet, which may contain 0.01% by weight or 0. They may contain from 5% to 95% or 99% by weight of active compound. Multiple active compounds may be incorporated into the formulations of the present invention, which may include one or more It may contain a number of accessory ingredients, and may be prepared by mixing the ingredients in a manner well known in the art of pharmacy. It can be prepared by either

[0024] Formulations of the present invention suitable for parenteral administration include sterile aqueous and non-aqueous injections of the active compound. Injections contain intravenous fluids, and the preparations are preferably isotonic with the blood of the intended recipient. These preparations contain antioxidants, buffers, bacteriostats, and other ingredients that are intended for the formulation and intended recipient. They may contain solutes which render them isotonic with blood. Aqueous and non-aqueous sterile suspensions are prepared by suspending The formulations may contain, in unit dose or multi-dose containers, For example, it may be present in sealed ampoules and vials and immediately prior to use, A liquid carrier for the bacteria, such as a freeze-dried liquid that requires only the addition of saline or water for injection. Stored in a freeze-dried (lyophilized) state. Extemporaneous injection solutions and suspensions may be prepared in the form of sterile powders, granules and tablets of the kind previously described. It may also be prepared from

[0025] For example, in one embodiment of the present invention, the active compound or a salt thereof is contained in a sealed container in a unit amount. The compound or salt is preferably administered to a subject in an injectable, stable, sterile composition comprising the compound or salt in a dosage form. In order to form a liquid composition suitable for injection, a suitable pharma- ceutically acceptable carrier is added. The unit dosage form is typically provided in a lyophilized form that can be reconstituted using , about 10 mg to about 10 grams of the compound or salt. If water-insoluble, a sufficient amount of a physiologically acceptable emulsifying agent is added to the compound in an aqueous carrier. or in an amount sufficient to emulsify the salt. One such useful emulsifier is , phosphatidylcholine.

[0026] Non-limiting examples of sterile carriers include those that are endotoxin-free or pyrogen-free. Examples of the water or saline include water and saline.

[0027] In addition to the active compound, the pharmaceutical composition may contain other additives, such as pH-adjusting additives. Particularly useful pH adjusting additives include acids such as hydrochloric acid, sodium lactate, and sodium acetate. Thorium, sodium phosphate, sodium citrate, sodium borate or gluconate The composition may further comprise a base or buffer, such as sodium chloride. Useful microbial preservatives include methylparaben, propylparaben, Microbial preservatives are typically used when the formulation is used multiple times. It is used when the drug is contained in a vial designed for administration. As indicated, the pharmaceutical compositions of the present invention can be frozen and packaged using techniques well known in the art. It may be dried.

[0028] The pharmaceutical compositions can be used for immediate and / or sustained release of SDF-1, e.g., Hydrogels using modified gelatin having carboxyl and / or sulfo groups For example, U.S. Patent No. 8,331,633 to Tabata may be formulated into a sustained release composition. In some embodiments, the composition comprises a collagen The composition may contain glycerin and / or gelatin.

[0029] 3. Dosage and route of administration As mentioned above, the present invention relates to a method for the parenteral administration of an active compound (including a pharma- ceutically acceptable salt thereof). In accordance with another aspect of the present invention, a pharmaceutical formulation is provided comprising the compound of formula (I) in a pharma- ceutically acceptable carrier for administration.

[0030] Direct administration to an organ (e.g., directly onto and / or into one or more parts of the kidney) Intravenous injection (intravenous injection) may be administered by any suitable technique. Administration by injection may be by continuous infusion. This may be done by single or multiple boluses. See U.S. Patent Application Publication No. 2009 / 0306625 to Ira-Kamath et al. This is what I mean.

[0031] In some embodiments, administration directly to an organ can be visualized by imaging techniques, e.g., ultrasonography. In some embodiments, administration is via ultrasound guidance. Some or more sites in (e.g., 1, 2, or 3 to 7, 8, 9, or 10 sites) By direct administration (e.g., direct injection or infusion) into the Administration is by intra-arterial infusion into the kidney.

[0032] The therapeutically effective dose of any particular compound, the use of which is within the scope of the present invention, may vary between compounds. and may vary somewhat between patients, depending on the patient's condition and the route of delivery. For direct injection of SDF-1 into an organ, a subject (e.g., a human subject or a companion animal) Depending on the animal subject, the dose ranges from approximately 10 or 50 nanograms to 400, 80, or 100 nanograms. 00 or 1000 nanogram amounts, or about 10 or 50 micrograms per dose Amounts from 1 g to 400, 800 or 1000 micrograms may be appropriate, and therapeutic One injection into organ tissue per session or different injections into organ tissues per session of treatment Sites (e.g., sites distributed around the periphery of an organ or part thereof (e.g., around the dorsal pole of the kidney) Each subject may receive multiple injections (e.g., 2, 3, 4, 5, 6) into the nascent nascent pleura.

[0033] Treatment sessions may be repeated periodically (e.g., every 2 Once every month or once every four months). If a nucleic acid vector is administered, the vector is administered at the injection site. or in the vicinity thereof in an amount effective to achieve a corresponding level of expression of SDF-1. It is possible.

[0034] 4. Combination Therapy In some embodiments, SDF-1 is an angiogenic growth factor (e.g., vascular endothelial growth factor). For example, Schreiner et al. U.S. Patent No. 6,352,975 to Chade et al., Reversal of rena l dysfunction by targeted administration of VEGF into the stenotic kidney:a nove l potential therapeutic approach, Am J Ph ysiol Renal Physiol, May 15, 2012, Volume 302 (Issue 10) , pp. F1342-50; U.S. Patent Application Publication No. 2016 / 07761 to Chade et al. See issue 8.

[0035] Administration of two or more agents, such as SDF-1 and VEGF, in "combination" means administering two The drugs are administered close enough in time that the presence of one alters the biological effects of the other The two drugs may be applied simultaneously (concomitantly or contemporaneously) or sequentially. Administration according to some embodiments may be administered within minutes (e.g., as needed for effective treatment). For example, 1, 5, 10, 30, 60 or 90 minutes or more) to several days (for example, 1, 2, 5, 8 or 10 days or more).

[0036] Simultaneous, concomitant, or contemporaneous administration means that the agents are mixed in the same composition prior to administration. or by administering drugs at the same time but in different parts of the body or organs. This may be done by administering the same or different types of doses, or by observing the results achieved are substantially the same as those achieved when the agent is administered at the same time may be applied close enough.

[0037] Sequential application of drugs allows one drug to be administered sequentially, such that the earlier administration potentiates the effect of the subsequent administration. This may be accomplished by administering the agent at the same time before another agent is administered.

[0038] SDF-1, which may be combined with VEGF, may also be used in combination with one or more treatments, e.g. IV fluid therapy to treat dehydration, surgery to remove the blockage, and surgery to treat the infection. Antibiotics to control hypertension, angiotensin-converting enzyme (ACE) inhibitors to control high blood pressure, diet Food restriction (e.g., diet low in protein, phosphorus, calcium and / or sodium) ) and / or supplements (e.g., phosphorus binders, vitamin D supplements, etc.) For example, supplements such as antioxidants and mitochondrial cofactors may be administered in combination. Reagents may be provided in food compositions. See, for example, U.S. Pat. See No. 8,859,613. EXAMPLES

[0039] The invention is described in further detail in the following non-limiting examples.

[0040] [Example 1] Chronic kidney disease (CKD) affects an estimated 1% to 3% of all cats. The prevalence of CKD in cats increases with age, occurring in 30% to 50% of cats aged 15 years or older. Many patients with CKD have a history of CKD, and the prevalence of CKD appears to be increasing.

[0041] Treatment for CKD in cats is largely symptomatic. Early stages of CKD Therefore, dietary changes that reduce serum phosphorus concentrations are effective in restoring serum markers of CKD. (Polzin et al., Dietary management of feline hronic renal failure.Where are we now?In what direction are we headed?, J Feline Med Surg, 2000, vol. 2, pp. 75-82). As the disease progresses, Tensin-converting enzyme inhibitors and calcium channel blockers reduce proteinuria and reduce total It is used to normalize intracellular and intraglomerular blood pressure (Chakrabarti et al., Clinicopathological variables predicting progression of azotemia in cats with ch ronic kidney disease, J Vet Intern Med, 20 12, vol. 26, pp. 275-281; ​​King et al., Tolerability and efficacy of benazepril in cats with chloro nic kidney disease, J Vet Intern Med, 2006 , vol. 20, pp. 1054-1064; Mizutani et al., Evaluation of the clinical efficacy of benazepril in the treatment of chronic renal insufficiency ency in cats, J Vet Intern Med, 2006, Vol. 20, pp. 1074-1079; Jepson et al., Effect of control of systolic blood pressure on survival in c ats with systemic hypertension, J Vet Int. In the later stages of CKD, Treatments tend to focus on limiting the clinical signs associated with declining kidney function. can extend life span and provide a higher quality of life, but these , does not provide a cure.

[0042] The chemokine CXCL12 (often called stromal-derived factor-1 or SDF-1) The CXCR4 / CXCR7 receptor-mediated mechanism mediates the recruitment of progenitor cells to the site of injury. Provides cell trafficking and homing and enhances cell survival when at the site of injury (Na gasawa, CXC chemokine ligand 12 (CXCL12) a nd its receptor CXCR4, J Mol Med (Berl), (2 014) Volume 92 (No. 5), pp. 433-9; Lau et al., Stromal cell-de driven factor-1(SDF-1): homing factor for engineered regenerative medicine, Expert Opin Biol Ther., (2011) Volume 11 (No. 2), pp. 189-97;H erberg et al., Stromal cell-derived factor-1β m edits cell survival through enhancing autophagy in bone marrow-derived mesench ymal stem cells, PLoS One, (2013) Vol. 8(No. 3), e Page 58207; Ara et al., Long-term hematopoietic stem cells require stromal cell-derived fact or-1 for colonizing bone marrow during o ntogeny, Immunity, (2003) Volume 19 (No. 2), pp. 257-67; Zisa et al., Intramuscular VEGF activates an SD F1-dependent progenitor cell cascade and an SDF1-independent muscle paracrine ca scade for cardiac repair, Am J Physiol He art Circ Physiol, (2011) 6, 2422-243). group showed that CXCL12 inhibits the renal function of bone marrow cells in a mouse model of acute kidney injury. They have reported that the government is involved in mobilizing

[0043] [method] CXCL12 is administered directly into the kidneys of cats with experimentally induced chronic kidney disease. .

[0044] Safety and feasibility study. This study involved six adult female cats. Three cats were , 5 locations (each 0 These injections were administered in a 10-mL (0.25 ml) 3-well plate. The other three cats received 200 ng of CXCL12 in total at the level of the mesonephric cortex. 40 ng / mL of human recombinant CXCL12 (in saline as a carrier solution) was injected into the same site. The mice receive the same injection except that the injection is ultrasound guided and is injected into the mesonephric cortex.

[0045] CBC, BUN, Creatinine, Urine test, IDEXX SDMA test kit (Glomerular To test filtration and renal function, a GFR ( It is used as a surrogate for GFR (filtration fraction) and is highly correlated with standard GFR (filtration fraction). These measurements are repeated 4 weeks after injection and then again 4 weeks later.

[0046] Efficacy Study. This study included 14 adult female cats. Two were control animals. 1) Unilateral CKD induction / no treatment (n=4); 2) CKD induction / vehicle injection (n= 4); and 3) CKD induction / vehicle and CXCL12 injection (n=4). be.

[0047] Induction of ischemia / reperfusion injury to the left kidney. The kidney was then transplanted as described above for safety studies. When the mice were injected with 100 mg / kg of ethanol, blood and urine evaluations were repeated 4 and 8 weeks after injury. Blood and urine analyses were repeated 4 and 8 weeks after injection. CBC, BUN , creatinine, urinalysis, SDMA (to test glomerular filtration and kidney function) evaluate.

[0048] Creation of CKD in cats. Using the procedure published by Schmiedt et al. Unilateral Renal Ischemia as a Model of Acute Kidney Injury and Renal Fibrosis i n Cats, Vet Pathol., January 2016, Volume 53 (Issue 1), 87~10 (p. 1). Injections are performed at the level of the mesonephric cortex as described above.

[0049] [Example 2] Four groups were tested: SDF-1 (4), vehicle (4), no Tx (4), and control (1). CK The D model was surgically created in cats (n=12) as described above. A total dose of 66.7, 00 ng was administered retroperitoneally into the left renal cortex under ultrasound guidance. Three injections of ng were given to the left kidney (n=6).

[0050] [result]

[0051] [Table 1]

[0052] [Table 2]

[0053] [Table 3]

[0054] [Conclusion] There was a beneficial effect of CXCL12 on kidney volume, and blood and urinary measures However, the injection of a collagen-containing carrier (WO 2015 / 171417 (see item 1) may cause some renal pathology and / or This may cause some adverse changes in these measures. Histological analysis showed that injury resulted in renal cortex-medulla, fibrosis and cell damage, and SDF- Our results demonstrate that CXCL12 restores a more normal cortico-medullary structure. While promising, the results are not yet statistically significant due to small numbers of animals tested.

[0055] The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents to the claims being included herein. Included in the invention.

Claims

1. A method of treating a subject suffering from or at risk of developing kidney disease, comprising: The method includes administering to the subject's kidney a therapeutically effective amount of stromal cell-derived factor 1 (SDF-1). Hmm, a method.

2. 4. The method of claim 1, wherein the kidney disease is acute renal failure, chronic kidney disease, end stage renal disease, or anemia.

2. The method according to claim 1.

3. The method of claim 1 or claim 2, wherein the subject is a human subject.

4. The method of claim 1 or claim 2, wherein the subject is a non-human mammalian subject.

5. 3. The method of claim 1 or claim 2, wherein the subject is a cat, dog or horse.

6. The method of claim 1 or claim 2, wherein the subject is a domestic cat.

7. 7. The method according to any one of claims 1 to 6, wherein the kidney disease is chronic interstitial nephritis. 。

8. 8. Any of claims 1 to 7, wherein the SDF-1 is provided in a pharma- ceutically acceptable carrier.

2. The method according to claim 1.

9. The pharma- ceutically acceptable carrier is sterile (e.g., endotoxin-free or Pyrogen-free water, or endotoxin-free and pyrogen-free water 9. The method of claim 8 .

10. wherein the administering step is performed by direct administration of SDF-1 to the kidney. Item 10. The method according to any one of items 1 to 9.

11. 11. The method of claim 10, wherein the direct administration is by injection onto or into the kidney tissue. How to.

12. 11. The method of claim 10, wherein the direct administration is by injection into the kidney tissue. 。

13. 11. The method of claim 10, wherein the direct administration is performed at multiple sites on and / or in the kidney. Or the method according to claim 12.

14. 14. The method of claim 11, wherein the direct administration is into the mesonephric cortex. Law.

15. wherein said administration results in reduced cell destruction and / or reduced fibrosis in said kidney. Item 15. The method according to any one of items 1 to 14.

16. 16. The method according to claim 1, wherein the SDF-1 is a mammalian SDF-1. The method described.

17. The method according to claim 16, wherein the SDF-1 is human SDF-1α or human SDF-1β. Method of posting.

18. 17. The method of claim 16, wherein the SDF-1 is feline SDF-1 or canine SDF-1. method.

19. The administering step comprises injecting a nucleic acid vector encoding SDF-1 into the kidney. and the vector expresses the encoded SDF-1.

19. The method according to any one of claims 1 to 18.

20. The vector according to claim 19, wherein the vector is a plasmid vector or a viral vector. Method of posting.

21. In combination with the SDF-1, angiogenic growth factors (e.g., vascular endothelial growth factor (VEGF) 21. The method of claim 1 , further comprising administering to the subject How to.

22. A sterile injectable composition for treating kidney disease comprising SDF-1 and an aqueous carrier.

23. 23. The sterile injectable composition of claim 22, comprising collagen or gelatin.

24. 24. The sterile injectable composition of claim 22 or claim 23, further comprising VEGF.

25. In carrying out the method of treating a subject suffering from or at risk of developing kidney disease, or for use in treating subjects suffering from or at risk of developing kidney disease. The SDF described herein for use in the preparation of a medicament for carrying out a method of treating A vector encoding SDF-1 or SDF-1.

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