[미국특허]
Devices, systems and methods for improving memory and/or cognitive function through brain delivery of siRNA
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C12N-015/11
C07H-021/02
A01N-063/00
A61K-009/127
A61M-031/00
출원번호
US-0243458
(2011-09-23)
등록번호
US-8415319
(2013-04-09)
발명자
/ 주소
Kaemmerer, William F.
출원인 / 주소
Medtronic, Inc.
대리인 / 주소
Bauman, Mary P.
인용정보
피인용 횟수 :
0인용 특허 :
63
초록▼
The present invention relates to devices, systems, and methods for improving memory and/or cognitive function by brain delivery of compositions of small interfering RNA or vectors containing the DNA encoding for small interfering RNA. Such compositions can be administered using devices, systems and
The present invention relates to devices, systems, and methods for improving memory and/or cognitive function by brain delivery of compositions of small interfering RNA or vectors containing the DNA encoding for small interfering RNA. Such compositions can be administered using devices, systems and methods for direct delivery of the compositions to the brain, or using devices, systems, methods of delivery, and compositions that deliver small interfering RNA or vectors containing the DNA encoding the small interfering RNA across the blood-brain barrier. The present invention also provides valuable small interfering RNA vectors, and methods for reduction of BACE1 levels in the hippocampus, cerebral cortex, or other regions of the brain that have beneficial effects on improving memory and/or cognitive function in a subject.
대표청구항▼
1. A method for improving memory or cognitive function in a subject diagnosed as having a disorder in which a diminished declarative memory is a symptom, comprising intracranially administering to the subject a therapeutically effective dose of a composition that decreases the expression of a beta a
1. A method for improving memory or cognitive function in a subject diagnosed as having a disorder in which a diminished declarative memory is a symptom, comprising intracranially administering to the subject a therapeutically effective dose of a composition that decreases the expression of a beta amyloid cleaving enzyme type 1, or BACE1, in a cell of the nervous system of the subject, wherein the composition comprises a shRNA or a siRNA or a vector encoding said siRNA or said shRNA, wherein further said shRNA or said siRNA comprises a double-stranded portion 21 to 30 nucleotides long and wherein one strand of said double-stranded portion comprises 21 contiguous nucleotides encoded by SEQ ID NO: 26, 30, or 28, and wherein at least one attribute of said memory or cognitive function is improved. 2. The method of claim 1 wherein the composition is delivered to the subject by intracranial delivery through an intracranial access device. 3. The method of claim 2, further comprising the step of: implanting a pump outside the brain, the pump coupled to the proximal end of an intracranial catheter. 4. The method of claim 3 comprising operating the pump to deliver a predetermined dosage of the said shRNA or said siRNA or said vector encoding said siRNA or said shRNA from the pump through a discharge portion of the said intracranial catheter. 5. The method of claim 3 further comprising the step of periodically refreshing the pump with said composition. 6. The method of claim 3 wherein the pump is an infusion pump. 7. The method of claim 6 wherein the infusion pump is an electromechanical pump. 8. The method of claim 6 wherein the infusion pump is an osmotic pump. 9. The method of claim 1, wherein said composition is delivered to the nucleus basalis of Meynert or the cerebral cortex or the hippocampus. 10. The method of claim 1, wherein the composition comprises the vector encoding said siRNA or said shRNA. 11. The method of claim 10, wherein the vector is selected from the group consisting of adeno-associated virus, adenovirus, herpes simplex virus, lentivirus and a DNA plasmid. 12. A method of delivering a small interfering RNA across a blood-brain barrier for expression in the brain of a subject diagnosed as having or being at risk of developing disorders in which diminished declarative memory is a symptom comprising administering to a blood vessel directly supplying blood to the brain of the subject a composition comprising a liposome having an exterior surface and an internal compartment containing an artificial adeno-associated virus (AAV) encoding a shRNA comprising a double-stranded portion between 21 and 30 nucleotides long, wherein one strand of said double-stranded portion is encoded by SEQ ID NO: 26, 30, or 28. 13. The method of claim 12, wherein the artificial AAV vector is for delivery of a single stranded DNA encoding the shRNA, the artificial AAV vector comprising the single stranded DNA having AAV-ITRs at the 5-prime and 3-prime ends. 14. The method of claim 12, wherein the artificial AAV vector is for delivery of a single stranded DNA encoding the shRNA, the artificial AAV vector comprising, in 5-prime to 3-prime order: a 5-prime AAV-ITR; the single stranded DNA; an internal AAV-ITR; a reverse complement of the single stranded DNA; and a 3-prime AAV-ITR. 15. The method of claim 12, wherein the artificial AAV vector is for delivery of a linear, double stranded DNA encoding said shRNA, the artificial AAV vector comprising the linear, double stranded DNA having AAV-ITRs at the 5-prime and 3-prime ends of each strand, or wherein the artificial AAV vector is for delivery of a single stranded DNA encoding said shRNA, the artificial AAV vector comprising, in 5-prime to 3-prime order: a 5-prime AAV-ITR; DNA encoding one strand of said shRNA; an internal AAV-ITR; DNA encoding the other strand of said shRNA; and a 3-prime AAV-ITR. 16. The method of claim 12, wherein the composition is administered intra-arterially. 17. The method of claim 12, wherein the liposome comprises an exterior surface defining a sphere having a diameter of at most 200 nanometers. 18. The method of claim 12, wherein the liposome comprises one or more blood-brain barrier and brain cell membrane targeting agents and wherein at least 5 and at most 1000 blood-brain barrier or brain cell membrane targeting agents are conjugated to an exterior surface of the liposome. 19. The method of claim 18, wherein at least 25 and at most 40 blood-brain barrier or brain cell membrane targeting agents are conjugated to the surface of the liposome. 20. The method of claim 12, wherein the exterior surface of the liposome further comprises one or more conjugation agents selected from the group consisting of polyethylene glycol, sphingomyelin, biotin, streptavidin, organic polymers, and combinations thereof. 21. The method of claim 20, wherein the molecular weight of the conjugation agent is at least 1000 Daltons and at most 50,000 Daltons. 22. The method of claim 12, wherein the artificial AAV vector has been thermally treated in at least one heating and cooling cycle. 23. A medical system for delivering a small interfering RNA into a pre-determined location in a brain of a patient comprising: an intracranial access device selected from the group consisting of an intracranial catheter and an intracranial access port; a deliverable amount of a siRNA or a shRNA or a vector encoding said siRNA or said shRNA wherein said siRNA or said shRNA comprises a double-stranded portion between 21 and 30 nucleotides long, wherein one strand comprises 21 contiguous nucleotides encoded by SEQ ID NO: 26, 30, or 28; and a delivery means for delivering said small interfering RNA or vector encoding said small interfering RNA to said location of the brain from said intracranial access device. 24. The medical system of claim 23, wherein said delivery means is selected from the group consisting of an infusion pump, an electromechanical pump, and an osmotic pump. 25. The medical system of claim 23, wherein the predetermined location is the nucleus basalis of Meynert or the cerebral cortex or the hippocampus. 26. The medical system of claim 23, wherein the delivery means is injection from an external syringe into an intracranial access port.
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