US20050214294A1 - Diabetic nephropathy therapies - Google Patents

Diabetic nephropathy therapies Download PDF

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US20050214294A1
US20050214294A1 US11/057,323 US5732305A US2005214294A1 US 20050214294 A1 US20050214294 A1 US 20050214294A1 US 5732305 A US5732305 A US 5732305A US 2005214294 A1 US2005214294 A1 US 2005214294A1
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diabetic nephropathy
ctgf
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administering
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Allan Flyvbjerg
Guangjie Guo
David Liu
Thomas Neff
Noelynn Oliver
William Usinger
Qingjian Wang
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Fibrogen Inc
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Assigned to FIBROGEN, INC. reassignment FIBROGEN, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NEFF, THOMAS B., OLIVER, NOELYNN A., WANG, QINGJLAN, GUO, GUANGJLE, LIU, DAVID Y., USINGER, WILLIAM R., FLYVBJERG, ALLAN
Priority to US12/802,373 priority patent/US8314059B2/en
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    • 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
    • A61K38/55—Protease inhibitors
    • A61K38/556—Angiotensin converting enzyme inhibitors
    • 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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention relates to methods and compounds for treating specific early stage aspects and late stage aspects of diabetic nephropathy. Methods and compounds for treating various physiological features associated with early stage and with late stage diabetic nephropathy are also provided.
  • a renal disorder is any alteration in normal physiology and function of the kidney. Renal disorders can result from a wide range of acute and chronic conditions and events, including physical, chemical, or biological injury, insult, or trauma, disease, such as, for example, hypertension, diabetes, congestive heart failure, lupus, sickle cell anemia, and various inflammatory and autoimmune diseases, HIV-associated nephropathies, etc. Renal disorders can lead to reduced kidney function, hypertension, and renal failure, seriously compromising quality of life, sometimes requiring dialysis and in certain circumstances, kidney transplantation.
  • Diabetic nephropathy is a major long-term complication of diabetes mellitus, and is the leading indication for dialysis and kidney transplantation in the United States. (Marks and Raskin, 1998, Med Clin North Am, 82:877-907.) The development of diabetic nephropathy is seen in 25 to 50% of Type I and Type 2 diabetic individuals. Accordingly, diabetic nephropathy is the most common cause of end-stage renal disease and kidney failure in the Western world.
  • TGF ⁇ transforming growth factor-beta
  • IGF-I insulin-like growth factor
  • VEGF-A vascular endothelial growth factor-a
  • CTGF connective tissue growth factor
  • glycemic and blood pressure control therapies significantly decrease the morbidity and mortality associated with diabetic nephropathy by delaying progression of associated pathologies
  • conventional therapies do not adequately halt the progression of the disease and thus fail to provide a complete therapeutic effect.
  • administration of ACE inhibitors or ARBs are not universally effective and only minimally delay, but do not remove, the need for kidney transplantation.
  • VEGF— or TGF ⁇ -targeted therapies may compromise the beneficial activities of these growth factors, such as angiogenesis, tumor suppression, and proper immune system development.
  • TGF ⁇ has been associated with development of fibrosis, it is also an important mediator of immune development and tumor suppression, suggesting that inhibition of TGF ⁇ might have unwanted and potentially adverse secondary effects. Therefore, there is a need in the art for a more selective therapeutic approach for diabetic nephropathy.
  • diabetic nephropathy which is effective at various stages (e.g., early stage and late stage diabetic nephropathy) in the development and progression of the disease.
  • a complete treatment for diabetic nephropathy one effective in treating both early stage features and late stage features of diabetic nephropathy such as, for example, hyperfiltration (early stage), increased glomerular permeability (early stage), increased glomerular filtration rate (early stage), microalbuminuria (early stage), macroalbuminuria (late stage), and decreased glomerular filtration rate (late stage).
  • the present invention addresses these needs by identifying the role of CTGF in various processes associated with the development and progression of renal disorders such as, e.g., diabetic nephropathy, and by providing methods for inhibiting and preventing these processes.
  • the invention further addresses existing needs by providing methods and agents that can be applied to the treatment and prevention of renal diseases, particularly, renal disease associated with diabetes, and most particularly, diabetic nephropathy.
  • FIG. 1 shows anti-CTGF antibody administration reduced kidney weight increase in diabetic db/db mice.
  • FIG. 2 shows anti-CTGF antibody administration reduced creatinine clearance in diabetic db/db mice.
  • FIG. 3 shows anti-CTGF antibody administration reduced urinary albumin excretion in diabetic db/db mice.
  • FIG. 4 shows the correlation between CTGF and VEGF levels in human vitreous.
  • FIG. 5 shows anti-CTGF antibody administration reduced urine volume in diabetic db/db mice.
  • FIG. 6 shows anti-CTGF antibody administration reduced basement membrane thickening in kidneys of diabetic db/db mice.
  • FIG. 7 shows anti-CTGF antibody administration reduced proteinuria in a rat model of diabetic nephropathy.
  • FIG. 8 shows anti-CTGF antibody administration reduced BUN levels in a rat model of diabetic nephropathy.
  • FIG. 9 shows anti-CTGF antibody administration improved glomerular filtration rate in a rat model of diabetic nephropathy.
  • the present invention relates to methods and compounds for treatment or prevention of specific early stage aspects and late stage aspects of diabetic nephropathy, and for treatment or prevention of various physiological features associated with early stage and with late stage diabetic nephropathy are also provided.
  • the preferred subject is a human subject.
  • the present invention provides a method for reducing creatinine clearance in a subject having or at risk for having diabetes or early stage diabetic nephropathy, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF, thereby reducing creatinine clearance in the subject.
  • Normal creatinine clearance levels in humans are typically about 97 to 137 ml/min. (adult males) and 88 to 128 ml/min (in adult females). Therefore, methods of reducing creatinine clearance levels to these levels or to about these levels are specifically contemplated.
  • Methods for reducing glomerular hyperfiltration in a subject having or at risk for having diabetes or early stage diabetic nephropathy comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF, are also provided herein, as are methods for reducing glomerular hyperperfusion.
  • the invention encompasses a method for reducing or preventing kidney weight gain in a subject having or at risk for having diabetes or diabetic nephropathy, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • the invention further provides methods for normalizing glomerular filtration rate in a subject having or at risk for having diabetes or diabetic nephropathy, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • the diabetic nephropathy can be, for example, early stage, late stage, incipient, or overt diabetic nephropathy. In the case that the diabetic nephropathy is early stage or incipient, the normalization will likely be a decrease in glomerular filtration rate, while in the case that the diabetic nephropathy is late stage or overt, the normalization will likely be an increase. Normal GFR in an adult human subject is about 120 ml/min.
  • the invention provides a method for reducing glomerular hypertrophy in a subject having or at risk for having diabetes or diabetic nephropathy, including early stage, late stage, incipient, or overt diabetic nephropathy, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • Methods for reducing proteinuria in a subject having or at risk for having diabetes or diabetic nephropathy are also provided herein, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • the invention additionally encompasses methods for reducing albuminuria in a subject having or at risk for having diabetes or diabetic nephropathy, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • a method for reducing microalbuminuria in a subject having or at risk for having diabetes or diabetic nephropathy, wherein the diabetic nephropathy is early stage or incipient diabetic nephropathy, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF, is additionally contemplated, as is a method for reducing macroalbuminuria in a subject having or at risk for having diabetes or diabetic nephropathy, wherein the diabetic nephropathy is late stage or overt, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • Normal urinary albumin excretion levels in adult humans are typically about 15-30 mg per day.
  • Microalbuminuria is typically diagnosed when a subject has a urinary albumin excretion of about 30-300 mg/day.
  • Macroalbuminuria is typically characterized by urinary albumin excretion of greater than about 300 mg/day.
  • the present invention thus specifically provides methods for decreasing urinary albumin excretion in a subject, the method comprising administering to the subject an effective amount of an agent that inhibits CTGF, having elevated urinary albumin excretion, e.g., urinary albumin excretion elevated above normal levels.
  • Embodiments in which the urinary albumin excretion is reduced to under about 300 mg/day, under about 200 mg/day, under about 100 mg/day, under about 50 mg/day, and, most preferably, under about 30 mg/day are specifically contemplated herein.
  • the invention provides a method for reducing BUN levels in a subject having or at risk for having diabetes or diabetic nephropathy, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • Normal BUN levels for adult humans range from 7-20 mg/dL. Therefore, methods for reducing BUN levels to below 20 mg/dL.
  • the invention further provides a method for reducing inulin clearance in a subject having or at risk for having diabetes or diabetic nephropathy, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • the diabetic nephropathy is late stage diabetic nephropathy or overt diabetic nephropathy.
  • the invention provides a method for preventing, reducing the risk of, or delaying the onset of diabetic complications in a subject at risk for developing such complications, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • the diabetic complications include at least one complication selected from the group consisting of increased creatinine clearance, increased or decreased glomerular filtration rate, glomerular basement membrane thickening, glomerular hyperfiltration, glomerular hyperperfusion, glomerular hypertrophy, increased urinary albumin excretion, microalbumnuria, macroalbuminuria, increased BUN levels, increased inulin clearance, kidney weight gain, and impaired kidney function.
  • the invention also encompasses a method for treating incipient diabetic nephropathy in a subject having or at risk for having incipient diabetic nephropathy, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF, and a method for treating early stage diabetic nephropathy in a subject having or at risk for having early stage diabetic nephropathy, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • a method for treating overt diabetic nephropathy in a subject having or at risk for having overt diabetic nephropathy, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF is also contemplated herein.
  • the present invention contemplates the use of the present methods in combination with other therapies.
  • the method is used in combination with another therapy, e.g., to further augment therapeutic effect on certain pathological events, etc.
  • the two treatments may be administered at the same time or consecutively, e.g., during a treatment time course or following disease progression and remission.
  • the method is used in combination with another therapeutic method having a similar or different mode of action, e.g., ACE inhibitors, ARBs, statin, advanced glycation endproduct (AGE) inhibitor, etc.
  • the present invention provides a method for treating diabetic nephropathy in a subject having or at risk for having diabetic nephropathy, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF in combination with an inhibiting amount of an angiotensin converting enzyme inhibitor.
  • the present invention further provides a method for treating diabetic nephropathy in a subject having or at risk for having diabetic nephropathy, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF in combination with an inhibiting amount of angiotensin receptor blocker.
  • Methods for treating progressive renal failure in a subject comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF, are provided in one embodiment.
  • the invention provides a method for reducing the risk or delaying the onset of development of microalbuminuria in a subject, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • a method for reducing the risk or delaying the onset of development of macroalbuminuria in a subject, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF is also provided.
  • the invention relates to the present discovery that CTGF is herein identified as a critical factor in early stage progressive diseases including diabetic kidney complications and vitreoretinal disorders. Therefore, in one aspect, the invention relates to a method for treating or preventing early stage aspects of a progressive disease in a subject having or at risk for having such a disease, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • the progessive disease is associated with a growth factor other than CTGF, and, in a specific aspect, the other growth factor is VEGF.
  • the progressive disease is a renal disease, and, in a particular aspect, the progressive disease is associated with diabetes or with diabetic complications, or is diabetic nephropathy.
  • the invention additionally encompasses a method for improving kidney function in a subject having or at risk for having impaired kidney function, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • the invention relates to the discovery that anti-CTGF therapy is effective in treatment or prevention of various physiological features of early stage and late stagy diabetic nephropathy. Accordingly, it is contemplated that the present invention provides methods for treating or preventing a renal disorder associated with at least one of the features selected from the following: increased creatinine clearance; increased glomerular filtration or glomerular hyperfiltration; proteinuria; increased urine albumin excretion; increased glomerular volume; glomerular hypertrophy; increased kidney weight; glomerular basement membrane thickening; reduced glomerular filtration rate; increased BUN levels; and increased inulin clearance.
  • the methods comprise administering to a subject in need of such treatment an effective amount of an agent that inhibits CTGF. These methods specifically cover administration to a subject of the agent that inhibits CTGF for the express purpose of preventing progression to or development of any one of the above-described complications.
  • the subject is a human subject.
  • the agent that inhibits CTGF may be a polypeptide, polynucleotide, or small molecule; for example, an antibody that binds to CTGF, an antisense molecule, siRNAs, small molecule chemical compounds, etc.
  • inhibiting CTGF can be accomplished by any of the means well-known in the art for modulating the expression and activity of CTGF.
  • Use of anti-CTGF agent, for example, a human monoclonal antibody directed against CTGF is preferred, although any method of inhibiting expression of the gene encoding CTGF, inhibiting production of CTGF, or inhibiting activity of CTGF is contemplated by the present invention.
  • small molecule compounds may be used to inhibit CTGF expression, production, or activity.
  • CTGF expression is inhibited by cyclic nucleotide
  • such a compound may include, e.g., a cyclic nucleotide analog or a phospodiesterase (PDE) inhibitor.
  • PDE phospodiesterase
  • polynucleotides including small interfering ribonucleic acids (siRNAs), micro-RNAs (mRNAs), ribozymes, and anti-sense sequences may be used in the present methods to inhibit expression and/or production of CTGF.
  • CTGF connective tissue growth factor
  • the invention relates in part to the discovery that connective tissue growth factor (CTGF) plays a key role in specific early stage aspects of renal disease including, e.g., glomerular hyperfiltration, increased glomerular permeability, increased glomerular filtration rate, microalbuminuria, etc.
  • CTGF had previously been associated with specific late stage aspects of kidney disease, e.g., glomerulosclerosis and tubulointerstitial fibrosis, but had not been identified as a critical target for affecting various features of early stage renal pathologies.
  • Methods for treating or preventing renal disorders including, e.g., diabetic nephropathy, and methods for treating or preventing associated pathologies are specifically contemplated.
  • the present invention provides methods and compositions for reducing or ameliorating in a subject complications associated with multiple, distinct pathological processes associated with renal disorders, e.g., diabetic nephropathy, by inhibiting CTGF.
  • the subject is an animal, more preferably a mammal, and most preferably a human.
  • compositions for use in the methods described herein may include small molecule compounds; peptides and proteins including antibodies or functionally active fragments thereof; and polynucleotides including small interfering ribonucleic acids (siRNAs), micro-RNAs (mRNAs), ribozymes, and anti-sense sequences.
  • siRNAs small interfering ribonucleic acids
  • mRNAs micro-RNAs
  • ribozymes ribozymes
  • anti-sense sequences See, e.g., Zeng (2003) Proc Natl Acad Sci USA 100:9779-9784; and Kurreck (2003) Eur J. Biochem 270:1628-1644.
  • the present invention is based in part on the discovery of unexpected benefits of inhibition of CTGF in treatment of multiple and specific aspects of renal disorders, e.g., diabetic nephropathy.
  • the present invention provides data demonstrating that inhibition of CTGF reduced various pathological aspects of renal disease not previously associated with CTGF.
  • the present invention provides evidence that inhibition of CTGF provides a therapeutic approach to treat or prevent specific physiological aspects of diabetic nephropathy previously associated with biological and pathological activities of VEGF, such as, for example, glomerular hyperfiltration and hyperperfusion.
  • Diabetes is a major cause of morbidity and mortality worldwide, with approximately 40% of all individuals with diabetes developing diabetic nephropathy, requiring either kidney dialysis or transplantation. Diabetes is the leading cause of end stage renal disease, and therefore, any individual diagnosed with diabetes is at risk for the development of diabetic nephropathy.
  • Progression of diabetic nephropathy is characterized by a fairly predictable pattern of events.
  • the time course of development of diabetic nephropathy is as follows.
  • Glomerular hyperfiltration and renal hypertrophy occur in the first years after the onset of diabetes and are reflected by increased glomerular filtration rate (e.g., from a normal glomerular filtration rate of about 120 ml/min to about 150 ml/min in humans).
  • pathological changes such as glomerular hypertrophy, thickening of the glomerular basement membrane, and glomerular mesangial volume expansion, are observed.
  • Glomerular filtration rate gradually returns to normal.
  • Microalbuminuria diabetic individuals with microalbuminuria are referred to as having incipient diabetic nephropathy
  • overt diabetic nephropathy characterized, in part, by macroalbuminuria or overt proteinuria.
  • the basement membrane thickening and glomerular volume expansion seen in early stages of the disease can accumulate in late stage diabetic nephropathy, leading to obliteration of the capillary lumen, and, eventually, to glomerulosclerosis.
  • overt diabetic nephropathy is present, a steady decline in the glomerular filtration rate occurs, and approximately half of individuals reach end-stage renal disease in 7 to 10 years.
  • Stage I diabetic nephropathy is associated with increased kidney (i.e., glormerular) filtration (i.e., hyperfiltration, resulting from increased blood flow through the kidneys and glomeruli), increased glomerular filtration rate, glomerular hypertrophy, and enlarged kidneys.
  • Stage II diabetic nephropathy is a clinically silent phase associated with continued hyperfiltration and kidney hypertrophy. Thickening of the glomerular basement membrane and mesangial expansion occurs.
  • Stage III diabetic nephropathy also known as incipient diabetic nephropathy is associated with microalbuminuria and micro proteinuria.
  • Microalbuminuria is defined as 30 to 300 mg/day urinary albumin in a 24-hour collection, 20-200 ⁇ g/min urinary albumin, or 30 to 300 ⁇ g/mg creatinine in a spot collection.
  • the kidneys progressively lose the ability to filter waste and blood levels of creatinine and urea-nitrogen increase. Glomerular basement membrane thickening and mesangial expansion continue to occur with increasing severity.
  • Stage IV diabetic nephropathy also known as overt diabetic nephropathy
  • macroalbuminuria i.e., clinical albuminuria
  • BUN blood urea-nitrogen
  • Macroalbuminuria is defined as greater than 300 mg/day urinary albumin in a 24-hour collection, greater than 200 ⁇ g/min urinary albumin, or greater than 300 ⁇ g/mg creatinine spot collection.
  • Glomerular hyperfiltration is a glomerular adaptation to nephron loss associated with hyperglycemia and diabetes. With loss of functioning nephron mass, the remaining functional nephrons hypertrophy and take on an increased workload, thereby attempting to minimize the overall loss of renal function. As a result, glomerular hyperfiltration and hyperperfusion occur.
  • Glomerular hyperfiltration and hyperperfusion are reflected as increased glomerular filtration rate.
  • Glomerular filtration rate is a measurement of the volume of filtrate made by the kidneys per minute. Measurement of glomerular filtration rate in human subjects has been accepted as the best overall index of kidney function in health and disease. (Smith, Diseases of the kidney and urinary tract, In: Structure and Function in Health and Disease, New York; Oxford Univ. Press, 1951:836-887.) Glomerular filtration rate can be determined by various methods, such as by measuring the urinary clearance of a filtration marker, such as inulin, iothalamate, or iohexol.
  • a filtration marker such as inulin, iothalamate, or iohexol.
  • glomerular filtration rate is estimated by determining clearance of creatinine, a protein produced by muscle and released into the blood.
  • Creatinine clearance (often expressed as ml/min) can be determined by comparing the level of creatinine collected in urine over a given period of time, e.g., 12 or 24 hours, with the creatinine level in blood.
  • a typical creatinine clearance rate is about 97 to 137 ml/min in adult males, and about 88 to 128 ml/min in adult females.
  • creatinine clearance is most often estimated from the serum creatinine concentration. Creatinine clearance is related directly to the urine creatinine excretion and inversely to serum creatinine concentration.
  • Various formulas that provide estimates of creatinine clearance, and therefore estimates of glomerular filtration rate, using parameters such as serum creatinine concentration, age, sex, and body size, have been developed and are standard in the art. (See, e.g., Cockcroft and Gault (1976) Nephron 16:3141; Levey et al (1999) Annals of Internal Medicine 130:462-470; Rule et al (2004) Ann Intern Med 141:929-937.)
  • Methods and compounds of the present invention reduced creatinine clearance in an animal model of diabetes. (See, e.g., Example 1.) Therefore, the present invention provides methods and compounds for reducing creatinine clearance in a subject with increased or elevated creatinine clearance or in which creatinine clearance is elevated above normal levels.
  • the present invention demonstrates that inhibition of CTGF (e.g., by administration of an antibody to CTGF) reduces creatinine clearance associated with nephropathy, and in particular, diabetic nephropathy.
  • Increased creatinine clearance is associated with glomerular hyperfiltration, hyperperfusion, hypertrophy, and increased glomerular filtration rate, and is indicative of altered or impaired renal function in early stages of developing nephropathy, e.g., diabetic nephropathy.
  • the present invention provides methods and compounds for reducing creatinine clearance by inhibiting CTGF. In another aspect, the present invention provides methods and compounds for reducing glomerular creatinine permeability and restoring glomerular selectivity and function by inhibiting CTGF. In another aspect, methods and compounds are provided for treating or preventing glomerular hypertrophy, hyperfiltration, and hyperperfusion associated with hyperglycemia or diabetes by inhibiting CTGF. In yet another aspect, methods and compounds are provided for treating or preventing glomerular hypertrophy, hyperfiltration, and hyperperfusion associated with renal diseases, and, in particular, diabetic nephropathy, by inhibiting CTGF. In one aspect, the renal disease is early stage diabetic nephropathy.
  • the present invention provides methods and compounds for reducing glomerular filtration rate in a subject with an increased glomerular filtration rate by inhibiting CTGF.
  • the present invention provides methods and compounds for reducing glomerular filtration rate by administering to a subject having or at risk for having an impaired or increased glomerular filtration rate an agent that inhibits CTGF.
  • the impaired glomerular filtration and increased glomerular filtration rate are associated with early stage kidney disease.
  • the present invention provides methods and compounds for treating a renal disorder associated with or characterized by increased creatinine clearance by administering to a subject having or at risk for having the disorder an agent that inhibits CTGF, thus treating or preventing the disorder.
  • the present invention provides methods and compounds for treating a renal disorder associated with or characterized by increased glomerular filtration or glomerular hyperfiltration by administering to a subject having or at risk for having the disorder an agent that inhibits CTGF, thus treating or preventing the disorder.
  • the present invention provides methods and compounds for increasing or normalizing glomerular filtration rate in a subject with a reduced or impaired glomerular filtration rate or in which the glomerular filtration rate is below normal by inhibiting CTGF.
  • the present invention provides methods and compounds for increasing or normalizing the glomerular filtration rate by administering to a subject having or at risk for having an impaired or reduced glomerular filtration rate an agent that inhibits CTGF.
  • the impaired glomerular filtration rate and reduced glomerular filtration rate are associated with late stage kidney disease or overt diabetic nephropathy.
  • the present invention provides methods and compounds for treating or preventing a renal disorder associated with impaired glomerular filtration rate and reduced glomerular filtration rate by administering to a subject having or at risk for having the disorder an agent that inhibits CTGF, thus treating or preventing the disorder.
  • the impaired glomerular filtration rate and reduced glomerular filtration rate are associated with late stage kidney disease.
  • the present methods can be applied to improving renal function, normalizing glomerular filtration rate, reducing glomerular hyperfiltration and hyperperfusion, or reducing creatinine clearance in a subject with any clinically accepted standard of measurement indicative of nephropathy or renal disease, or a subject at risk for developing such a renal disorder.
  • the subject has diabetic kidney disease.
  • the subject has stage I kidney disease, stage II kidney disease, stage III kidney disease, stage IV kidney disease, or stage V kidney disease.
  • the present methods are applied to preventing, reducing, or delaying the onset of renal complications associated with early stage kidney disease in a subject at risk for developing such complications, or to manufacture of a medicament for a subject, preferably a human subject, having any of the disorders and features associated with early stage kidney disease discussed herein.
  • the subject has diabetes. Diabetes can be determined by any measure accepted and utilized by those of skill in the art.
  • a human subject would be diagnosed with diabetes with a blood glucose level above about 200 mg/dL (as determined in a fasting blood glucose test, an oral glucose tolerance test, or a random blood glucose test). Therefore, in certain aspects, it is contemplated that a human subject having a blood glucose level above about 200 mg/dL is a suitable subject for treatment with the methods or use of medicaments provided by the present invention.
  • the human subject has a glomerular filtration rate above normal glomerular filtration rate, e.g., above about 120 ml/min. Therefore, it is contemplated that a human subject having a glomerular filtration rate above about 120 ml/min, above about 130 ml/min, above about 140 ml/min, or above about 150 ml/min is a suitable subject for treatment with the methods or use of medicaments provided by the present invention.
  • the methods for reducing glomerular filtration rate in a subject with increased glomerular filtration rate can be applied to reducing glomerular filtration rate in a human subject to a level below about 150 ml/min, below about 140 ml/min, below about 130 ml/min, or to a level of about 120 ml/min.
  • Methods and compounds of the present invention reduced the increase in kidney weight associated with diabetes and early stage diabetic nephropathy in an animal model of diabetes. (See Example 1.) Therefore, a method for treating or preventing a renal disorder associated with increased kidney weight, the method comprising administering to a subject having or at risk for having the disorder an agent that inhibits CTGF, thus treating or preventing the disorder, is contemplated by the present invention.
  • the invention further contemplates a method for treating or preventing a renal disorder associated with increased glomerular volume, the method comprising administering to a subject having or suspected of having the disorder an agent that inhibits CTGF, thus treating or preventing the disorder.
  • the present methods and compounds are also applied to preventing, reducing, or delaying the onset of renal complications associated with late stage kidney disease in a subject at risk for developing such complications, or manufacture of a medicament for a subject, preferably a human subject, having any of the disorder and conditions associated with late stage kidney disease discussed herein.
  • the human subject has a glomerular filtration rate below a normal glomerular filtration rate, e.g., below about 120 ml/min.
  • a human subject having a glomerular filtration rate below about 120 ml/min, below about 90 ml/min, below about 60 ml/min, below about 30 ml/min, or below about 15 ml/min is a suitable subject for treatment with the methods or use of medicaments provided by the present invention.
  • the methods for increasing glomerular filtration rate in a human subject with reduced or impaired glomerular filtration rate can be applied to increase glomerular filtration rate to a level above about 15 ml/min, above about 30 ml/min, above about 60 ml/min, above about 90 ml/min, and to a level of about 120 m/min.
  • the renal disorder is associated with Type 1 or Type 2 diabetes. In other embodiments, the renal disorder is diabetic nephropathy.
  • nephropathy including diabetic nephropathy
  • microalbunimuria Early clinical evidence of nephropathy, including diabetic nephropathy, is the appearance of low but abnormal levels of albumin in the urine, a condition referred to as microalbunimuria.
  • Individuals with microalbuminuria are referred to as having incipient nephropathy, or, if associated with diabetes, incipient diabetic nephropathy.
  • Diabetic individuals with microalbuminuria have a 42% increased risk of progression to overt diabetic nephropathy compared to those with normoalbuminuria (Bruno et al, 2003, Diabetes Care 26:2150-2155).
  • microalbuminuria in individuals with diabetes is associated with a greatly-increased risk of progression to overt diabetic nephropathy (i.e., macroalbuminuria) and eventual end-stage renal disease and kidney failure.
  • overt diabetic nephropathy i.e., macroalbuminuria
  • end-stage renal disease and kidney failure See, e.g., Mogensen and Christensen (1984) N Engl J. Med 311:89-93; Mogensen et al (1983) Diabetes 32 [Suppl 2 ]: 64 - 78 ; Viberti et al (1982) Lancet 1:1430-1432.
  • Microalbuminuria can be determined by various methods, including: (1) measurement of the albumin-to-creatinine ratio in a random spot urine collection; (2) 24-hour urine collection with creatinine, allowing the simultaneous measurement of creatinine clearance; and (3) timed (e.g., 4-hour or overnight) collection.
  • Normal urinary albumin excretion in humans is less than 30 ⁇ g/mg creatinine (spot collection), less than 30 mg/24-hours (24-hour collection), or less than 20 ⁇ g/min (timed collection).
  • Microalbuminuria in humans is having urinary albumin excretion of 30 to 299 ⁇ g/mg creatinine (spot collection), 30 to 299 mg/24-hours (24-hour collection), or 20 to 199 ⁇ g/min (timed collection).
  • Macroalbuminuria (e.g., clinical albuminuria) in humans is having urinary albumin excretion of greater than or equal to 300 ⁇ g/mg creatinine (spot collection), greater than or equal to 300 mg/24-hours (24-hour collection), or greater than or equal to 200 ⁇ g/min (timed collection).
  • the present invention demonstrates for the first time that inhibition of CTGF (e.g., by administration of an antibody to CTGF) reduces urinary albumin excretion associated with nephropathy, and in particular, diabetic nephropathy.
  • CTGF e.g., by administration of an antibody to CTGF
  • Increased urinary albumin excretion is associated with changes in glomerular albumin permeability and selectivity, and is indicative of altered or impaired renal function in early stages of developing nephropathy.
  • the present invention provides methods for reducing urinary albumin excretion by inhibiting CTGF.
  • the present invention provides methods for reducing glomerular albumin permeability and restoring glomerular selectivity by inhibiting CTGF.
  • the present invention provides methods for reducing microalbuminuria by inhibiting CTGF.
  • the present methods therefore, provide a means for treating early stage kidney disease and incipient nephropathy.
  • microalbuminuria i.e., incipient nephropathy
  • incipient nephropathy i.e., incipient nephropathy
  • Methods and compositions of the present invention are also applied to preventing, reducing, or delaying the onset of or reduce the risk of developing renal complications associated with late stage kidney disease, including macroalbuminuia, overt nephropathy, end stage renal disease, and kidney failure, in a subject at risk for developing such complications.
  • the present invention demonstrates that inhibition of CTGF (e.g., by administration of an antibody to CTGF) reduces proteinuria, BUN levels, and creatinine clearance associated with nephropathy. Increased proteinuria, BUN levels, and creatinine clearance are indicative of altered or impaired renal function and development of nephropathy.
  • CTGF e.g., by administration of an antibody to CTGF
  • Increased proteinuria, BUN levels, and creatinine clearance are indicative of altered or impaired renal function and development of nephropathy.
  • the present invention provides methods and compounds for reducing proteinuria by inhibiting CTGF.
  • the present invention provides methods and compounds for reducing BUN levels by inhibiting CTGF.
  • methods and compounds are provided for reducing creatinine clearance by inhibiting CTGF.
  • the present invention demonstrates that inhibition of CTGF (e.g., by administration of an antibody to CTGF) improves kidney function. As diabetic nephropathy progresses to late stage kidney disease, glomerular filtration rate decline, as measured, for example, by decreased inulin clearance, is indicative of altered or impaired kidney function.
  • the present invention further demonstrates that inhibition of CTGF (e.g., by administration of an antibody to CTGF) improved the impaired or reduced glomerular filtration rate associated with late stage kidney disease. (See Example 3.)
  • the present invention provides methods and compounds for increasing glomerular filtration rate by inhibiting CTGF. In another aspect, the present invention provides methods and compounds for decreasing inulin clearance by inhibiting CTGF.
  • methods and compounds are provided for treating or preventing impaired kidney function, in particular impaired kidney function associated with nephropathy, such as diabetic nephropathy, by inhibiting CTGF.
  • the nephropathy is associated with decreased glomerular filtration rate, macroalbuminuria, or overt nephropathy.
  • Late stage diabetic nephropathy is associated with various pathological and morphological changes in the kidney. Such changes include mesangial expansion, associated with increased matrix production and accumulation of mesangial extracellular matrix; mesangial cell expansion; glomerular basement membrane thickening, which in late stage diabetic nephropathy is associated with glomerulosclerosis; and development of tubulointerstitial fibrosis.
  • Glomerulosclerosis and tubulointerstitial fibrosis are the structural late stage kidney disease hallmarks of advanced diabetic nephropathy with renal insufficiency, resulting in reduction in glomerular filtration rate and, possibly, end stage renal disease and kidney failure.
  • CTGF had been associated with features of late stages of renal pathology, specifically, production of excess extracellular matrix, excess mesangial matrix expansion, and development of glomeruloscleorsis and tubulointerstitial fibrosis.
  • VEGF vascular endothelial growth factor
  • the present invention provides data demonstrating that it is CTGF that plays a key role in the development and progression of early stage as well as late stage aspects of nephropathy, and thus represents an ideal target for a complete and effective therapeutic approach to diabetic nephropathy.
  • the present invention provides methods for treating and preventing various clinical and pathological aspects of early stage as well as late stage diabetic nephropathy. Specifically, methods and compositions of the present invention are useful for treating or preventing glomerular hyperfiltration and mesangial matrix expansion. Therefore, the present invention contemplates methods for treating various aspects of renal disease, including features of early stage diabetic kidney disease, such as, e.g., renal and glomerular hypertrophy and hyperfiltration (measured as increased creatinine clearance, increased urinary albumin excretion, increased glomerular filtration rate, etc.), and features of late stage diabetic kidney disease (decreased glomerular filtration rate, mesangial matrix expansion, basement membrane thickening, etc.).
  • features of early stage diabetic kidney disease such as, e.g., renal and glomerular hypertrophy and hyperfiltration (measured as increased creatinine clearance, increased urinary albumin excretion, increased glomerular filtration rate, etc.)
  • features of late stage diabetic kidney disease decreased glomerular
  • CTGF connective tissue growth factor
  • CTGF-associated disorders have been described in the literature; however, until the present invention, CTGF was primarily associated with fibroproliferative conditions, particularly those associated with TGF ⁇ . Although numerous disorders involve fibroproliferative processes, and the treatment of these disorders using therapeutics directed at providing or preventing CTGF activity have been suggested, the present invention extends the understanding and, thus, the use of CTGF-directed therapies to treatment of various non-fibroproliferative conditions and complications associated with diabetic nephropathy and renal disorders.
  • the methods of the present invention e.g., inhibiting CTGF, effectively reduce hyperfiltration by the kidney and normalize or restore kidney function as measured, e.g., by glomerular filtration rate, urinary albumin excretion, albuminuria, and/or proteinuria.
  • the methods and compositions of the present invention can be used to treat patients at risk for diabetic nephropathy, including, for example, early stage diabetic nephropathy and incipient diabetic nephropathy.
  • Such subjects include individuals diagnosed with hyperglycemia, hypertension, and/or diabetes.
  • the methods of the present invention can be used to treat patients diagnosed with a kidney disorder such as glomeruloscerosis, glomerulamephritis, or diabetic nephropathy.
  • the methods of the present invention e.g., inhibiting CTGF, reduce mesangial matrix expansion and glomerular basement membrane thickening.
  • the methods of the present invention can be used to treat patients at risk for diabetic nephropathy to prevent albuminuria, reduced glomerular filtration rate, and the like.
  • Such subjects include individuals diagnosed with hyperglycemia, hypertension, and/or diabetes.
  • the methods of the present invention can be used to treat patients having overt diabetic nephropathy or another renal disorder such as glomeruloscerosis, glomerularnephritis, etc.
  • the present invention contemplates methods of treating or preventing processes associated with early stage renal disease or late stage renal disease by inhibiting CTGF.
  • pathological conditions include, for example, hyperfiltration, albuminuria, proteinuria, glomerular hypertrophy, and mesangial volume expansion.
  • Use of the present methods to treat or prevent aspects of early stage and of late stage renal disease previously associated with VEGF and TGF ⁇ is specifically contemplated.
  • the methods can be used to treat patients at risk for diabetic nephropathy or an associated pathology, and to treat patients having a renal disorder such as glomeruloscerosis, glomerulonephritis, diabetic nephropathy, etc.
  • the present invention contemplates the use of the present methods in combination with other therapies.
  • the method is used in combination with another therapy, e.g., to further augment therapeutic effect on certain pathological events, etc.
  • the two treatments may be administered at the same time or consecutively, e.g., during a treatment time course or following disease progression and remission.
  • the method is used in combination with another therapeutic method having a similar or different mode of action, e.g., an ACE inhibitor, ARBs, statin, advanced glycation endproduct (AGE) inhibitor, etc.
  • ACE inhibitors include, for example, ACE inhibitors, angiotensin receptor blockers, statins, advanced glycation endproduct inhibitors, hepatocyte growth factor gene therapy, pyridoxamine, Enapril, PPAR antagonists, sulfonylureas, matrix metalloproteinase inhibitors, COX-2 inhibitors, pirfenidone, sulodexide, high-dose thiamine and Benfotiamine, calcium channel blockers, etc.
  • ACE inhibitors include, for example, ACE inhibitors, angiotensin receptor blockers, statins, advanced glycation endproduct inhibitors, hepatocyte growth factor gene therapy, pyridoxamine, Enapril, PPAR antagonists, sulfonylureas, matrix metalloproteinase inhibitors, COX-2 inhibitors, pirfenidone, sulodexide, high-dose thiamine and Benfotiamine, calcium
  • the present invention represents the first time therapeutic efficacy of two distinct pathological aspects associated with renal disease (for example, early stage features and late stage features of diabetic nephropathy) has been demonstrated.
  • anti-CTGF therapy is exemplified herein using a human monoclonal antibody directed against CTGF
  • any method of inhibiting expression of the gene encoding CTGF, inhibiting production of CTGF, or inhibiting activity of CTGF is contemplated by the present invention.
  • small molecule compounds may be used to inhibit CTGF expression, production, or activity.
  • cyclic nucleotide such a compound may include, e.g., a cyclic nucleotide analog or a phospodiesterase (PDE) inhibitor.
  • PDE phospodiesterase
  • polynucleotides including small interfering ribonucleic acids (siRNAs), micro-RNAs (mRNAs), ribozymes, and anti-sense sequences may be used in the present methods to inhibit expression and/or production of CTGF.
  • siRNAs small interfering ribonucleic acids
  • mRNAs micro-RNAs
  • ribozymes ribozymes
  • anti-sense sequences may be used in the present methods to inhibit expression and/or production of CTGF.
  • the present invention provides exemplary evidence that the methods described herein, using an anti-CTGF monoclonal antibody in animal models of diabetes, provide improvement in creatinine clearance and glomerular hypertrophy, and a decrease in kidney weight, an indicator of TGF ⁇ -induced and CTGF-mediated glomerular fibrosis and mesangial expansion.
  • the methods of the present invention ameliorate two pathologies contributing to diabetic nephropathy, i.e., mesangial expansion and glomerular filtration.
  • the present invention provides methods and compositions for treating a disorder associated with TGF ⁇ by inhibiting CTGF. In other aspects, the present invention provides methods and compositions for treating a disorder associated with VEGF by inhibiting CTGF. In yet other aspects, the present invention provides methods and compositions for treating a disorder associated with TGF ⁇ and VEGF by inhibiting CTGF. It is further contemplated in the present invention methods and compositions for treating a disorder associated with other growth factors, e.g., IGF-1, endothelin, etc.
  • other growth factors e.g., IGF-1, endothelin, etc.
  • the present invention provides a method for treating or preventing a renal disorder associated with increased creatinine clearance, the method comprising administering to a subject having or at risk for having the disorder an agent that inhibits CTGF (e.g., inhibits or reduces CTGF expression or CTGF activity), thus treating or preventing the renal disorder.
  • an agent that inhibits CTGF e.g., inhibits or reduces CTGF expression or CTGF activity
  • the present invention provides methods for treating or preventing a renal disorder associated with increased glomerular filtration and hyperfiltration by administering to a subject having or at risk for having the disorder an agent that inhibits CTGF, thus treating or preventing the disorder.
  • the present invention provides methods for treating or preventing a renal disorder associated with basement membrane thickening by administering to a subject having or at risk for having the disorder an agent that inhibits CTGF, thus treating or preventing the disorder.
  • the present invention provides methods for treating or preventing a renal disorder associated with increased urine volume by administering to a subject having or at risk for having the disorder an agent that inhibits CTGF, thus treating or preventing the disorder.
  • a method for treating a renal disorder associated with increased urinary albumin excretion by administering to a subject having the disorder or at risk for having the disorder an agent that inhibits CTGF, thus treating or preventing the renal disorder is also provided.
  • the present invention provides methods for reducing creatinine clearance in a subject in need of such treatment, the method comprising administering to the subject an agent that inhibits CTGF.
  • Methods for reducing urinary albumin excretion, reducing glomerular filtration and hyperfiltration, reducing glomerular volume expansion, or reducing kidney weight increase in a subject in need of such treatment are also provided, the methods comprising administering to the subject an agent that inhibits CTGF.
  • the present invention provides a method for treating or preventing proteinuria associated with renal disease, the method comprising administering to a subject having or at risk for having the renal disease an agent that inhibits CTGF.
  • the proteinuria is albuminuria.
  • the albuminuria is microalbumnuria or macroalbuminuria.
  • the present invention provides a method for treating or preventing basement membrane thickening in the kidney, the method comprising administering to a subject having or as risk for having basement membrane thickening in the kidney an agent that inhibits CTGF.
  • the present invention provides a method for reducing or preventing increased urine volume by administering to a subject having or at risk for having increased urine volume an agent that inhibits CTGF.
  • Methods of the present invention include administering to a subject in need a therapeutically effective amount of an agent that inhibits CTGF (e.g., reduces CTGF expression or activity).
  • the agent is an antibody to CTGF.
  • the antibody is a monoclonal antibody to CTGF.
  • the antibody is a human or humanized antibody to CTGF.
  • the agent is a small molecule.
  • the agent is an antisense oligonucleotide.
  • Such agents can be used to reduce expression of CTGF and thereby ameliorate or prevent the pathological processes induced by CTGF in joint disorders.
  • Such compounds can be formulated and administered according to established procedures within the art.
  • Antisense technologies including small interfering ribonucleic acids (siRNAs), micro-RNAs (mRNAs), ribozymes, and anti-sense sequences directed to CTGF expression may also be used to treat joint disorders.
  • siRNAs small interfering ribonucleic acids
  • mRNAs micro-RNAs
  • ribozymes ribozymes
  • anti-sense sequences directed to CTGF expression may also be used to treat joint disorders.
  • Antisense constructs that target CTGF expression have been described and utilized to reduce CTGF expression in various cell types.
  • Such antisense constructs can be used to reduce expression of CTGF and thereby ameliorate or prevent the pathological processes induced by CTGF in joint disorders.
  • Such constructs can be designed using appropriate vectors and expressional regulators for cell- or tissue-specific expression and constitutive or inducible expression.
  • Such genetic constructs can be formulated and administered according to established procedures within the art.
  • compositions of the present invention can be delivered directly or in pharmaceutical compositions containing excipients, as is well known in the art.
  • Present methods of treatment can comprise administration of an effective amount of a compound of the present invention to a subject having or at risk for diabetic nephropathy; particularly a disorder associated with, for example, glomerular hyperfiltration and hyperperfusion, microalbuminuria, incipient diabetic nephropathy, macroalbuminuria, overt nephropathy, etc.
  • the subject is a mammalian subject, and in a most preferred embodiment, the subject is a human subject.
  • an effective amount, e.g., dose, of compound or drug can readily be determined by routine experimentation, as can an effective and convenient route of administration and an appropriate formulation.
  • Various formulations and drug delivery systems are available in the art. (See, e.g., Gennaro, ed. (2000) Remington's Pharmaceutical Sciences, supra; and Hardman, Limbird, and Gilman, eds. (2001) The Pharmacological Basis of Therapeutics, supra.)
  • Suitable routes of administration may, for example, include oral, rectal, topical, nasal, pulmonary, ocular, intestinal, and parenteral administration.
  • Primary routes for parenteral administration include intravenous, intramuscular, and subcutaneous administration.
  • Secondary routes of administration include intraperitoneal, intra-arterial, intra-articular, intracardiac, intracistemal, intradermal, intralesional, intraocular, intrapleural, intrathecal, intrauterine, and intraventricular administration.
  • Pharmaceutical dosage forms of a compound of the invention may be provided in an instant release, controlled release, sustained release, or target drug-delivery system.
  • Commonly used dosage forms include, for example, solutions and suspensions, (micro-) emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants; amorphous or crystalline powders, aerosols, and lyophilized formulations.
  • special devices may be required for application or administration of the drug, such as, for example, syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks.
  • Pharmaceutical dosage forms are often composed of the drug, an excipient(s), and a container/closure system.
  • One or multiple excipients also referred to as inactive ingredients, can be added to a compound of the invention to improve or facilitate manufacturing, stability, administration, and safety of the drug, and can provide a means to achieve a desired drug release profile. Therefore, the type of excipient(s) to be added to the drug can depend on various factors, such as, for example, the physical and chemical properties of the drug, the route of administration, and the manufacturing procedure.
  • Pharmaceutically acceptable excipients are available in the art, and include those listed in various pharmacopoeias.
  • compositions of the present invention can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.
  • the composition may be formulated in aqueous solution, if necessary using physiologically compatible buffers, including, for example, phosphate, histidine, or citrate for adjustment of the formulation pH, and a tonicity agent, such as, for example, sodium chloride or dextrose.
  • physiologically compatible buffers including, for example, phosphate, histidine, or citrate for adjustment of the formulation pH
  • a tonicity agent such as, for example, sodium chloride or dextrose.
  • semisolid, liquid formulations, or patches may be preferred, possibly containing penetration enhancers.
  • penetration enhancers are generally known in the art.
  • the compounds can be formulated in liquid or solid dosage forms and as instant or controlled/sustained release formulations.
  • Suitable dosage forms for oral ingestion by a subject include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, slurries, suspensions, and emulsions.
  • the compounds may also be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • Solid oral dosage forms can be obtained using excipients, which may include, fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, antiadherants, cationic exchange resins, wetting agents, antioxidants, preservatives, coloring, and flavoring agents.
  • excipients may include, fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, antiadherants, cationic exchange resins, wetting agents, antioxidants, preservatives, coloring, and flavoring agents.
  • excipients can be of synthetic or natural source.
  • excipients examples include cellulose derivatives, citric acid, dicalcium phosphate, gelatine, magnesium carbonate, magnesium/sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinyl pyrrolidone, silicates, silicium dioxide, sodium benzoate, sorbitol, starches, stearic acid or a salt thereof, sugars (i.e. dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, vegetable oils (hydrogenated), and waxes. Ethanol and water may serve as granulation aides.
  • coating of tablets with, for example, a taste-masking film, a stomach acid resistant film, or a release-retarding film is desirable.
  • Natural and synthetic polymers, in combination with colorants, sugars, and organic solvents or water, are often used to coat tablets, resulting in dragees.
  • the drug powder, suspension, or solution thereof can be delivered in a compatible hard or soft shell capsule.
  • the compounds of the present invention can be administered topically, such as through a skin patch, a semi-solid or a liquid formulation, for example a gel, a (micro-) emulsion, an ointment, a solution, a (nano/micro)-suspension, or a foam.
  • the penetration of the drug into the skin and underlying tissues can be regulated, for example, using penetration enhancers; the appropriate choice and combination of lipophilic, hydrophilic, and amphiphilic excipients, including water, organic solvents, waxes, oils, synthetic and natural polymers, surfactants, emulsifiers; by pH adjustment; and use of complexing agents.
  • Other techniques, such as iontophoresis may be used to regulate skin penetration of a compound of the invention. Transdermal or topical administration would be preferred, for example, in situations in which local delivery with minimal systemic exposure is desired.
  • the compounds for use according to the present invention are conveniently delivered in the form of a solution, suspension, emulsion, or semisolid aerosol from pressurized packs, or a nebuliser, usually with the use of a propellant, e.g., halogenated carbons dervided from methan and ethan, carbon dioxide, or any other suitable gas.
  • a propellant e.g., halogenated carbons dervided from methan and ethan, carbon dioxide, or any other suitable gas.
  • hydrocarbons like butane, isobutene, and pentane are useful.
  • the appropriate dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, for example, gelatin, for use in an inhaler or insufflator may be formulated. These typically contain a powder mix of the compound and a suitable powder base such as lactose or starch.
  • compositions formulated for parenteral administration by injection are usually sterile and, can be presented in unit dosage forms, e.g., in ampoules, syringes, injection pens, or in multi-dose containers, the latter usually containing a preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents, such as buffers, tonicity agents, viscosity enhancing agents, surfactants, suspending and dispersing agents, antioxidants, biocompatible polymers, chelating agents, and preservatives.
  • the vehicle may contain water, a synthetic or vegetable oil, and/or organic co-solvents.
  • the parenteral formulation would be reconstituted or diluted prior to administration.
  • Depot formulations providing controlled or sustained release of a compound of the invention, may include injectable suspensions of nano/micro particles or nano/micro or non-micronized crystals.
  • Polymers such as poly(lactic acid), poly(glycolic acid), or copolymers thereof, can serve as controlled/sustained release matrices, in addition to others well known in the art.
  • Other depot delivery systems may be presented in form of implants and pumps requiring incision.
  • Suitable carriers for intravenous injection for the molecules of the invention are well-known in the art and include water-based solutions containing a base, such as, for example, sodium hydroxide, to form an ionized compound, sucrose or sodium chloride as a tonicity agent, for example, the buffer contains phosphate or histidine.
  • a base such as, for example, sodium hydroxide
  • sucrose or sodium chloride as a tonicity agent
  • the buffer contains phosphate or histidine.
  • Co-solvents such as, for example, polyethylene glycols, may be added.
  • These water-based systems are effective at dissolving compounds of the invention and produce low toxicity upon systemic administration.
  • the proportions of the components of a solution system may be varied considerably, without destroying solubility and toxicity characteristics.
  • the identity of the components may be varied.
  • low-toxicity surfactants such as polysorbates or poloxamers
  • polyethylene glycol or other co-solvents polyethylene glycol or other co-solvents
  • biocompatible polymers such as polyvinyl pyrrolidone may be added, and other sugars and polyols may substitute for dextrose.
  • composition useful for the present methods of treatment a therapeutically effective dose can be estimated initially using a variety of techniques well-known in the art. Initial doses used in animal studies may be based on effective concentrations established in cell culture assays. Dosage ranges appropriate for human subjects can be determined, for example, using data obtained from animal studies and cell culture assays.
  • a therapeutically effective dose or amount of a compound, agent, or drug of the present invention refers to an amount or dose of the compound, agent, or drug that results in amelioration of symptoms or a prolongation of survival in a subject.
  • Toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50/ED50. Agents that exhibit high therapeutic indices are preferred.
  • the effective amount or therapeutically effective amount is the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician, e.g., reducing creatinine clearance, glomerular hyperfiltration and hyperperfusion, urine albumin excretion, or microalbuminuria, or treatment of early or late stage diabetic nephropathy, etc.
  • Dosages preferably fall within a range of circulating concentrations that includes the ED50 with little or no toxicity. Dosages may vary within this range depending upon the dosage form employed and/or the route of administration utilized. The exact formulation, route of administration, dosage, and dosage interval should be chosen according to methods known in the art, in view of the specifics of a subject's condition.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety that are sufficient to achieve the desired effects, e.g., regulation of glucose metabolism, decrease in blood glucose levels, etc., i.e., minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from, for example, in vitro data and animal experiments. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
  • the amount of agent or composition administered may be dependent on a variety of factors, including the sex, age, and weight of the subject being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.
  • compositions may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient.
  • a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass and rubber stoppers such as in vials.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the methods of the invention were used to demonstrate broad-spectrum efficacy in an animal model for certain aspects of early stage diabetic nephropathy as follows. Eight-week-old mice having a loss-of-function mutation in the leptin receptor (Ob-R; encoded by the db gene) were obtained from Harlan, Indianapolis Ind. These db/db mice serve as an animal model of obese type 2 diabetes, and, in particular, a model of obese type 2 diabetic nephropathy characterized by early aspects of diabetic nephropathy, including, for example, kidney hyperfiltration and proteinuria with minimal development of interstitial fibrosis.
  • Ob-R leptin receptor
  • Homozygous db/db are hyperglycemic at 8 weeks of age.
  • Homozygous db/db (diabetic) and heterozygous db/+(non-diabetic) animals were treated (intraperitoneal injection) with either anti-CTGF monoclonal antibody ( ⁇ CTGF) (prepared as described in International Publication No. WO 2004/108764 or by the cell line identified by ATCC Accession No. PTA-6006, deposited 20 May 2004) or control human IgG (cIgG).
  • ⁇ CTGF anti-CTGF monoclonal antibody
  • cIgG control human IgG
  • Table 1 below shows the mean body weight (BW), blood glucose level (BG), and food consumption (FC) at day 0 and day 60 in cIgG-treated db/+mice, ⁇ CTGF-treated dbl+mice, cIgG-treated diabetic db/db mice, and aCTGF-treated db/db mice. All data are expressed as Mean ⁇ SEM. The number of mice per group (n) ranged from 9 to 15. Non-diabetic (db/+) animals that presented with polycystic kidneys were excluded from the analysis.
  • kidney weight ⁇ CTGF-treated db/+mice
  • UAE urinary albumin excretion
  • db/db mice exhibited hyperfunctioning kidneys as indicated by renal enlargement (i.e., increased kidney weight) ( FIG. 1 ), increased creatinine clearance ( FIG. 2 ), and increased urinary albumin excretion ( FIG. 3 , *P ⁇ 0.01 vs. anti-CTGF-treated db/+).
  • Diabetic animals treated with anti-CTGF antibody showed reduced kidney weight gain compared to diabetic animals treated with cIgG.
  • Creatinine clearance in cIgG-treated db/db animals was approximately twice the value observed in db/+animals, indicating impaired renal function, hypertrophy, and hyperfiltration in diabetic animals.
  • the urinary albumin excretion was also increased in diabetic db/db animals compared to the urinary albumin excretion observed in non-diabetic dbl+animals.
  • the db/db animals treated with anti-CTGF antibody had creatinine clearance and urinary albumin excretion levels markedly lower than those observed in the cIgG-treated db/db animals.
  • the anti-CTGF treated diabetic mice had creatinine clearance levels 82% below that seen in the cIgG-treated diabetic mice.
  • the anti-CTGF treated diabetic mice had urinary albumin excretion levels 69% below that seen in the cIgG-treated diabetic mice. These results provide evidence of a dramatic improvement in kidney function in the anti-CTGF antibody treated mice. Treatment of non-diabetic animals using methods of the invention showed no adverse effects on kidney weight or function. These data showed that administration of anti-CTGF antibody to diabetic animals resulted in reduced kidney weight gain, creatinine clearance, and urinary albumin excretion.
  • diabetic (db/db) mice showed increased urine volume compared to non-diabetic-(db/+) mice.
  • Administration of anti-CTGF antibody as described above reduced urine volume in diabetic (db/db) mice.
  • FIG. 5 *P ⁇ 0.01 vs. anti-CTGF-treated db/+
  • This data indicated that administration of anti-CTGF antibody to diabetic animals reduced urinary volume.
  • inhibition of CTGF provides a method for reducing increased urinary volume associated with diabetic nephropathy, and therefore provides a method for improving kidney function.
  • Neovascularization associated with all retinal disorders was graded as follows: grade 0 , no neovascularization; grade 1 , quiescent neovascularization, with only non-perfused, gliotic vessels present; and grade 2 , active neovascularization, with perfused preretinal capillaries. (See Aiello et al. (1994) N Engl J. Med 331:1480-1487.)
  • CTGF and VEGF levels in vitreous samples were measured by ELISA. Briefly, vitreous samples were centrifuged at 14,000 rpm for 15 minutes at 4° C. and the supernatant collected. CTGF levels were measured by sandwich ELISA using two monoclonal antibodies to human CTGF, each of which specifically recognizes a distinct region of the N-terminal portion of CTGF as follows. Microtiter plates were coated overnight at 4° C. with capture anti-CTGF monoclonal antibody (10 ⁇ g/ml) in coating buffer (50 mM sodium borate, pH 9.6).
  • the plates were blocked with 100 ⁇ l 1% BSA in phosphate buffered saline for 2 hours at room temperature and then washed with wash buffer (phosphate buffered saline containing 0.05% Tween 20).
  • Vitreous samples were diluted 5 times in assay buffer (50 mM TRIS, pH 7.7, 0.1% BSA, 4 mM MgCl 2 , 400 mM ZnCl 2 , 0.05% NaN 3 , 50 mg/L sodium heparin, and 0.1% Triton X-100).
  • assay buffer 50 mM TRIS, pH 7.7, 0.1% BSA, 4 mM MgCl 2 , 400 mM ZnCl 2 , 0.05% NaN 3 , 50 mg/L sodium heparin, and 0.1% Triton X-100.
  • To each well was added 50 ⁇ l of diluted vitreous sample together with 50 mM of biotinylated monoclonal anti-human CTGF detection
  • the plates were incubated for 2 hours at 37° C., washed with wash buffer, and incubated with 100 ⁇ l/well streptavidin-conjugated alkaline phosphatase (1 ⁇ g/ml diluted in assay buffer) (Jackson Immunoresearch Laboratories) for 1 hour at room temperature. Following this incubation, the plates were washed with wash buffer and 100 ⁇ l of substrate solution (1 mg/ml, p-nitrophenyl phosphate, Sigma Chemical Co.) in diethanolamine buffer (1 M diethanolamine, 0.5 mM MgCl 2 , 0.02% NaN 3 , pH 9.8) was added to each well. Absorbance was read at 405 nm on a Bio-Rad microplate reader. Purified recombinant human CTGF was used as a standard. Vitreous levels of VEGF-165 were determined by a commercially available sandwich ELISA according to the manufacturer's instructions (R&D Systems).
  • CTGF is present in human vitreous and its concentration significantly and strongly correlated with the presence and degree of neovascularization and that vitreous levels of CTGF strongly correlated with vitreous levels of VEGF. While it has been established that CTGF is associated with the development and progression of ocular fibrosis and other late-stage aspects of retinal disease, the present results taken together with the results shown in Example 1 and Example 3 herein, implicate CTGF as well as VEGF as a critical factor in early stage development of progressive disease, including diabetic nephropathy and various vitreoretinal disorders. Therefore, the present invention provides methods for treating both early (e.g., neovascularization) and late (e.g., fibrosis) stages of retinopathies, such as, PVR, PDR, etc.
  • Diabetes mellitus was induced in male Sprague Dawley rats by a single i.v. dose of streptozotocin (STZ) (50 mg/kg).
  • Unilateral renal ischemia reperfusion 1 R was achieved in one kidney by clamping the left renal artery for 30 minutes, thereby preventing blood flow to the left kidney.
  • Treatment with anti-CTGF monoclonal antibody i.p. 5 mg/kg was initiated 1 day before renal ischemia reperfusion (i.e., 2 weeks after the development of diabetes) and continued 3 times per week for 10 weeks.
  • Control animals not receiving anti-CTGF antibody were administered PBS (i.p. 5 ml/kg). Blood samples were obtained from the tail vein. Blood clinical chemistry, performed by Quality Clinical Labs, Inc.
  • Glomerular filtration rate is the most widely measurement of kidney function.
  • Inulin clearance is a measurement of glomerular filtration rate.
  • glomerular filtration rate e.g., kidney function
  • Urine was collected via a cannulated ureter and blood was collected from the femoral artery. Urine volume was estimated gravimetrically.
  • Inulin concentration was determined using the Anthrone method.
  • Inulin clearance, indicative of GFR, was determined using the formula: (U cone ⁇ U vol )/S cone .
  • kidneys were removed for biochemical and histopathological evaluation.
  • Microalbuminuria characteristic of early stage diabetic nephropathy progresses to macroalbuminuria and late stage proteinuria.
  • significant increases in 24-hour total urinary protein i.e., late stage proteinuria
  • total urine protein in non-diabetic animals was approximately 100 mg/24-hours.
  • Diabetic animals with renal IR had total urine protein levels exceeding 350 mg/24-hours.
  • BUN levels are indicative of impaired kidney function associated with late stage diabetic nephropathy. Significant increases in BUN levels were observed in these diabetic animals. BUN levels in control non-diabetic animals (sham+PBS; IR+PBS) were below 20 mg/dL at 0, 4, and 10 weeks of the study. In diabetic animals with renal IR, BUN levels increased from approximately 22 mg/dL at week zero, to greater than 40 mg/dL at 4 weeks. (See FIG.
  • Glomerular filtration rate was determined for individual kidneys for each of the various experimental conditions described above.
  • GFR was greater than 0.3 mL/min/kidney/100 g.
  • Non-diabetic animals with renal IR had a GFR of approximately 0.28 mL/min/kidney/100 g.
  • Diabetic animals without renal IR had a GFR of approximately 0.17 mL/min/kidney/100 g. (Data not shown.)
  • Glomerular filtration rate was drastically reduced in the ischemic kidney of animals with diabetes mellitus at 10 weeks, to approximately 0.01 mL/min/kidney/100 g. (See FIG. 9 .)
  • Administration of anti-CTGF antibody significantly improved glomerular filtration rate in individual kidneys in diabetic animals affected by renal IR, to a level greater than 0.035 mL/min/kidney/100 g.
  • This data showed that administration of an antibody to CTGF increased glomerular filtration rate in diabetic animals in late-stage renal disease.

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US20070238788A1 (en) * 2005-12-22 2007-10-11 Wendy Hauck Treatment of renal disorders, diabetic nephropathy and dyslipidemias
US20080262088A1 (en) * 2006-12-22 2008-10-23 Wendy Hauck Methods, compounds, and compositions for treating metabolic disorders and diabetes
US20090054473A1 (en) * 2007-08-22 2009-02-26 Gilead Colorado, Inc. Therapy for complications of diabetes
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PL2670411T3 (pl) 2011-02-02 2019-09-30 Excaliard Pharmaceuticals, Inc. Związki antysensowne ukierunkowane na czynnik wzrostu tkanki łącznej (ctgf) do leczenia bliznowców lub blizn przerostowych
EP3074038B1 (en) * 2013-11-28 2019-01-02 CSL Limited Method of treating diabetic nephropathy
CN112512532A (zh) * 2018-07-31 2021-03-16 雷莫内克斯生物制药有限公司 用于抑制ctgf表达的组合物
CN109402127B (zh) * 2018-09-29 2021-12-10 复旦大学附属眼耳鼻喉科医院 一组与结缔组织生长因子特异性结合的高亲和力核酸适配体及其应用
CN109453191A (zh) * 2018-12-06 2019-03-12 郑州大学第附属医院 GSK-3β抑制剂及在糖尿病肾病干预新靶点的应用
CA3142092A1 (en) * 2019-06-04 2020-12-10 Jiangsu Hengrui Medicine Co., Ltd. Anti-connective tissue growth factor antibody and application thereof

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US20050136502A1 (en) * 1998-09-08 2005-06-23 Riser Bruce L. Treatment of disorders associated with elevated blood glucose or blood pressure
US20070238788A1 (en) * 2005-12-22 2007-10-11 Wendy Hauck Treatment of renal disorders, diabetic nephropathy and dyslipidemias
US8372886B2 (en) 2005-12-22 2013-02-12 Kiacta Sarl Treatment of renal disorders, diabetic nephropathy and dyslipidemias
US20080262088A1 (en) * 2006-12-22 2008-10-23 Wendy Hauck Methods, compounds, and compositions for treating metabolic disorders and diabetes
US20090054473A1 (en) * 2007-08-22 2009-02-26 Gilead Colorado, Inc. Therapy for complications of diabetes
US8623819B2 (en) * 2007-08-22 2014-01-07 AbbVie Deutschland GmbH & Co. KG Therapy for complications of diabetes
US8865650B2 (en) 2007-08-22 2014-10-21 AbbVie Deutschland GmbH & Co. KG Therapy for complications of diabetes
US9592231B2 (en) 2007-08-22 2017-03-14 AbbVie Deutschland GmbH & Co. KG Therapy for complications of diabetes
US11026625B2 (en) 2017-08-08 2021-06-08 Fresenius Medical Care Holdings, Inc. Systems and methods for treating and estimating progression of chronic kidney disease

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