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Publication Number
US-7842674-B2
Publication Date
2010-11-30
Expiration Date
Abstract
The invention relates to a double-stranded compound, preferably an oligoribonucleotide, which down-regulates the expression of a human p53 gene. The invention also relates to a pharmaceutical composition comprising the compound, or a vector capable of expressing the oligoribonucleotide compound, and a pharmaceutically acceptable carrier. The present invention also contemplates a method of treating a patient suffering from alopecia or acute renal failure or other diseases comprising administering to the patient the pharmaceutical composition in a therapeutically effective dose so as to thereby treat the patient. The alopecia may be induced by chemotherapy or radiotherapy, and the patient may be suffering from cancer, in particular breast cancer.
Core Innovation
The disclosed invention provides a method of treating a patient in whom p53 is elevated as a result of a stress. The method uses a siRNA compound to down-regulate p53 in the patient and thereby treat the patient.
The siRNA compound is a double-stranded oligoribonucleotide with an antisense strand and a sense strand given by specific sequences. Each consecutive ribonucleotide is joined by a covalent bond, and the ribonucleotides are unmodified or 2′—O-Me sugar-modified ribonucleotides.
In the specified compound, alternating ribonucleotides in both the antisense and sense strands are modified in their sugar residues such that a 2′—O-Me group is present, with modified sugar residues at the 5′ and 3′ termini of the antisense strand and unmodified sugar residues at the 5′ and 3′ termini of the sense strand. The described therapy is directed to temporary p53 inhibition using double-stranded p53-targeting siRNA and pharmaceutical compositions.
The document further describes conditions associated with p53 elevation, including alopecia and acute renal failure, including ischemia-reperfusion and sepsis-associated acute renal failure. Reported results in the document include reduced serum creatinine, reduced tubular necrosis, and reduced Puma expression when p53 siRNA is used.
Claims Coverage
The independent claim covers a method of treating a surgery patient with elevated p53 caused by stress by administering a specified double-stranded siRNA compound in an amount effective to down-regulate p53 and thereby treat the patient. The claim set is further refined in dependent claims primarily by stress type and by narrowing the therapeutic endpoint to specific surgical and renal contexts, including ischemia-reperfusion injury and graft tissue survival after transplantation.
Specified 2′—O-Me modified double-stranded p53-targeting siRNA compound
Administering a siRNA compound having the antisense strand sequence (SEQ ID NO: 48) and sense strand sequence (SEQ ID NO: 25), wherein each ribonucleotide is unmodified or 2′—O-Me sugar-modified, each consecutive ribonucleotide is joined by a covalent bond, and alternating ribonucleotides in both strands have 2′—O-Me sugar residues with termini-specific unmodified/modified sugar residues as specified.
Down-regulation of p53 in a surgery patient with stress-elevated p53
Administering the specified siRNA compound in an amount effective to down-regulate p53 in the surgery patient in whom p53 is elevated as a result of a stress, thereby treating the patient.
Stress type selection for surgery patients
Treating the surgery patient by selecting the stress from burn, hyperthermia, hypoxia, stroke, and ischemia.
Reduction of acute renal injury/acute renal failure associated with elevated p53
Reducing acute renal injury or acute renal failure by administering a compound in an amount effective to down-regulate p53 and thereby reduce acute renal failure.
Reduction of ischemia-reperfusion injury linked to elevated p53
Reducing ischemia-reperfusion injury in a surgical patient linked to elevated p53 by administering a compound effective to down-regulate p53.
Reduction of deterioration of renal function
Reducing deterioration of renal function in a surgery patient associated with elevated p53 by administering a compound effective to down-regulate p53 and thereby reduce the deterioration.
Improvement of graft tissue survival in organ transplant patients
Treating an organ transplant patient to improve graft tissue survival after transplantation by administering a compound in an effective amount to down-regulate p53.
Overall, the claim coverage centers on administering a specified double-stranded p53-targeting siRNA with alternating 2′—O-Me sugar modifications and termini-specific sugar patterns to down-regulate p53 in surgery patients whose p53 is elevated due to stress. Dependent claims further refine stress selection and narrow therapeutic endpoints to acute renal injury/acute renal failure, ischemia-reperfusion injury reduction, deterioration of renal function reduction, and improved graft tissue survival after organ transplantation.
Stated Advantages
Down-regulation of p53 in the patient.
Treatment of the patient in whom p53 is elevated as a result of a stress.
Reduction of acute renal injury and/or acute renal failure.
Reduction of ischemia-reperfusion injury linked to elevated p53.
Reduction of deterioration of renal function.
Improvement of graft tissue survival after transplantation.
Documented Applications
Treatment of conditions including alopecia (including chemotherapy-induced alopecia and radiation-induced alopecia) using double-stranded p53-targeting siRNA.
Treatment of acute renal failure, including ischemia-reperfusion and sepsis-associated acute renal failure, using p53 siRNA.
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