Methods for treating chronic kidney disease
Inventors
Feinstein, Elena • Adamsky, Svetlana • Erlich, Shai • Molitoris, Bruce
Assignees
US Department of Veterans Affairs • Quark Pharmaceuticals Inc
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Publication Number
US-8637482-B2
Publication Date
2014-01-28
Expiration Date
2030-06-07
Abstract
The present invention relates to methods for treating chronic kidney disease (CKD) including methods for preventing or delaying onset of CKD and methods for preventing exacerbation and progression of CKD. In particular embodiments, the invention provides methods for treating a subject at risk of developing CKD comprising administering to the subject a composition comprising a) a therapeutically effective amount of at least one oligonucleotide compound which inhibits the expression of a human target gene associated with the kidney disease; and b) a pharmaceutically acceptable excipient or carrier, or mixtures thereof, thereby reducing the risk of CKD in the subject.
Core Innovation
The invention provides methods for treating chronic kidney disease (CKD) which include preventing or delaying the onset of CKD as well as preventing exacerbation and progression of CKD. Specifically, it involves administering to a subject at risk a therapeutically effective amount of an oligonucleotide compound that inhibits the expression of a human target gene associated with kidney disease. The therapeutic composition further includes a pharmaceutically acceptable excipient or carrier, thereby reducing the subject's risk of CKD.
The method particularly involves treatment of subjects at risk of CKD or CKD progression due to exposure to repeated renal insults such as ischemia/reperfusion injury, nephrotoxins, sepsis, surgery, radiocontrast agents, or acute kidney injury (AKI). The oligonucleotide compounds used inhibit expression of target genes upregulated following renal injury, including p53 and CASP2, among others listed in Table 1. Administration typically occurs within 24 hours, preferably within a time window around the insult, to attenuate kidney damage and CKD progression.
The problem being solved relates to the worldwide public health issue posed by CKD, which is characterized by progressive nephron loss leading to decreased glomerular filtration rate (GFR) and eventual end stage renal disease (ESRD). The kidney adapts to injury with hyperfiltration and hypertrophy, thought to contribute to progressive damage. Current treatments for CKD and its progression due to recurrent acute renal insults are inadequate. There is a need for effective methods to prevent and treat CKD and its progression, especially in high-risk subjects exposed to nephrotoxic agents or suffering from repeated AKI episodes.
Claims Coverage
The patent claims one independent method claim encompassing key inventive features related to the treatment of chronic kidney disease (CKD) by oligonucleotide compounds targeting specific genes involved in kidney injury.
Method of treating CKD by inhibiting gene expression of p53 or CASP2 genes
A method of treating a subject having chronic kidney disease (CKD) resulting from exposure to recurring renal insults by administering a therapeutically effective dose of an oligonucleotide compound that down-regulates expression of a target gene, wherein the target gene is either the p53 gene (SEQ ID Nos: 67-73) or the CASP2 gene (SEQ ID Nos: 12 or 13), thereby treating CKD.
Administration timing relative to renal insult
The oligonucleotide compound is administered in proximity to the renal insult, specifically within a time window from about 72 hours before to 8 hours after the renal insult, with preferred administration within about 4 hours, 0.5 hours, or 0 to 4 hours post-insult.
Renal insults associated with the method
The method covers renal insults including surgery (cardiovascular and cardiopulmonary surgery), exposure to myoglobinuria, ischemia/reperfusion injury, sepsis, urinary tract obstruction, and exposure to nephrotoxins such as radiocontrast imaging agents, antibiotics, chemotherapeutic agents, proteinuria, increased renal ammoniagenesis, hyperlipidemia, and hyperphosphatemia with calcium phosphate deposition.
Nature of the oligonucleotide compound
The oligonucleotide compound can be selected from unmodified or chemically modified siRNA, shRNA, aptamers, antisense molecules, miRNA, and ribozymes, with a preference for chemically modified siRNA compounds.
siRNA structural features
The siRNA compounds have a general double stranded structure comprising antisense and sense strands as described, including specific modifications as exemplified by the I5 siRNA compound targeting p53.
Treatment goal includes attenuating progression and severity of CKD
The method aims to attenuate progression of chronic kidney disease by reducing the severity of renal insults, thereby preventing exacerbation of CKD.
The independent claim focuses on using an oligonucleotide compound, particularly chemically modified siRNAs targeting p53 or CASP2 genes, administered in a defined time window around renal insults to treat CKD caused by recurring kidney injury. The claim also covers various types of renal insults and oligonucleotide forms, emphasizing therapeutic timing and structural features of the siRNA compounds.
Stated Advantages
The invention provides a therapeutic approach effective in preventing or delaying onset of chronic kidney disease and in attenuating progression and severity of CKD following renal insults.
Administration of the oligonucleotide compound improves kidney function as evidenced by preservation of glomerular filtration rate and reduction of proteinuria in animal models.
The compounds are chemically modified for enhanced activity, stability, reduced toxicity, off-target effects, and diminished innate immune response compared to unmodified molecules.
The delivery of the compounds is effective when administered in close temporal proximity to renal insults, facilitating clinical application in at-risk subjects.
Documented Applications
Treatment of chronic kidney disease (CKD) in subjects at risk due to recurring renal insults such as acute kidney injury (AKI), ischemia/reperfusion injury, nephrotoxins exposure, sepsis, and surgery.
Prevention or delay of onset of CKD in high-risk patients including those undergoing cardiovascular or cardiopulmonary surgery, radiocontrast imaging, or treatment with nephrotoxic drugs.
Attenuation of progression and severity of CKD following repeated episodes of acute kidney injury, including models involving ischemic injury and high salt diet induced CKD in animals.
Use in subjects experiencing or at risk of contrast-induced nephropathy (CIN) due to iodinated contrast media administration.
Treatment of kidney damage resulting from surgical interventions, exposure to myoglobinuria, urinary tract obstruction, proteinuria, hyperlipidemia, hyperphosphatemia, and other nephrotoxic insults.
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