Compositions and methods for modulating angiogenesis
AssigneesThe Johns Hopkins University, The Trustees of the University of Pennsylvania
InventorsJoshua T. Mendell, Erik A. Wentzel, Andrei Thomas-Tikhonenko, Michael Dews, Asal Homayouni
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Abstract
The invention generally features compositions and methods that are useful for modulating angiogenesis.
Claims32
1-17. (canceled)
A method for increasing the expression of a TSR protein in a cell, the method comprising contacting the cell with an effective amount of an inhibitory nucleic acid molecule complementary to at least a portion of a microRNA nucleic acid molecule of the mir-17-92 cluster, thereby increasing the expression of a TSR protein.
A method of treating an apoptosis resistant neoplasm or chemo-resistant neoplasm in a subject, the method comprising:
- (a) identifying a subject as having an apoptosis resistant neoplasm;
- and
- (b) administering to the subject an effective amount of an inhibitory nucleic acid molecule complementary to at least a portion of a microRNA of the mir-17-92 cluster.
A method of treating or preventing a neoplasm in a subject in need thereof, the method comprising:
- (a) identifying a neoplasm having an increase in the expression of a TSR protein;
- and
- (b) administering to the subject an effective amount of an inhibitory nucleic acid molecule complementary to at least a portion of a microRNA of the mir-17-92 cluster.
A method of treating an ocular disease characterized by increased angiogenesis in a subject, the method comprising administering to the subject an effective amount of an inhibitory nucleic acid molecule complementary to at least a portion of a microRNA of the mir-17-92 cluster.
29-40. (canceled)
42-43. (canceled)
A method of selecting a treatment for a subject having a neoplasm, the method comprising
- (a) detecting an increase the expression of a microRNA encoded by a mir-17-92 cluster or a TSR protein;
- and
- (b) identifying the patient as having a neoplasm amenable to treatment with an inhibitory nucleic acid molecule that reduces the expression of a microRNA of the miR-17-92 cluster.
A method of monitoring the treatment of a subject having a neoplasia, the method comprising:
- (a) assaying the expression of a TSR protein in a cell of the subject;
- and
- (b) detecting an increase or a decrease in the expression of a TSR protein relative to a reference.
(canceled)
An isolated nucleic acid molecule having at least 85% nucleic acid sequence identity to a microRNA encoded by the miR-17-92 cluster, wherein expression of the nucleic acid molecule in a cell enhances angiogenesis.
49-51. (canceled)
53-54. (canceled)
56-60. (canceled)
A method of identifying an agent that reduces angiogenesis, the method comprising
- (a) contacting a cell that expresses a TSR selected from the group consisting of:
- Connective tissue growth factor (CTGF), thrombospondin, type I domain containing 3 isoform 3 (THSD3), A disintegrin and metalloproteinase with Tsp motifs 18 (ADAMTS18), A disintegrin and metalloproteinase with Tsp motifs 12 (ADAMTS12), Thrombospondin 1 (THBS1), Thrombospondin, type 1 domain containing 1 (THSD1), A disintegrin and metalloproteinase with Tsp motifs 1 (ADAMTS1), A disintegrin and metalloproteinase with Tsp motifs 6 (ADAMTS6), WNT1 inducible signaling pathway protein 2 (WISP2), and Brain-specific angiogenesis inhibitor 3 (BAD) and a microRNA of the mir-17-92 cluster with a test agent;
- and
- (b) detecting an increase in the level of TSR expression in the cell contacted by the agent with the level present in a control cell, wherein the increase in TSR expression identifying the agent as reducing angiogenesis.
A method of identifying an agent that treats or prevents an apoptosis resistant neoplasm, the method comprising
- (a) contacting a cell that expresses a microRNA of the mir-17-92 cluster with an agent, and
- (b) detecting a reduction in the level of microRNA expression in the cell contacted by the agent with the level of expression in a control cell, wherein an agent that decreases microRNA expression thereby treats or prevents a neoplasm.
63-64. (canceled)
A method for diagnosing a subject as having or having a propensity to develop an apoptosis resistant neoplasia, the method comprising
- (a) measuring the level of a TSR protein selected from the group consisting of:
- Connective tissue growth factor (CTGF), thrombospondin, type I domain containing 3 isoform 3 (THSD3), A disintegrin and metalloproteinase with Tsp motifs 18 (ADAMTS18), A disintegrin and metalloproteinase with Tsp motifs 12 (ADAMTS12), Thrombospondin 1 (THBS1), Thrombospondin, type 1 domain containing 1 (THSD1), A disintegrin and metalloproteinase with Tsp motifs 1 (ADAMTS1), A disintegrin and metalloproteinase with Tsp motifs 6 (ADAMTS6), WNT1 inducible signaling pathway protein 2 (WISP2), and Brain-specific angiogenesis inhibitor 3 (BAI3) in a biological sample from the subject;
- and
- (b) comparing the level of the TSR protein in the subject to the level present in a control subject, wherein a reduced level of TSR protein indicates the subject has or has a propensity to develop an apoptosis resistant neoplasia.
A method for diagnosing a subject as having or having a propensity to develop an apoptosis resistant neoplasia, the method comprising
- (a) measuring the level of a mir17-92 encoded microRNA in a biological sample derived from a subject;
- and
- (b) detecting an increased level of the microRNA relative to the level present in a control sample, wherein a, wherein an increase in the level of the mir-17-92 encoded microRNA indicates the subject has or has a propensity to develop a an apoptosis resistant neoplasia.
67-68. (canceled)
A pharmaceutical composition for treating an apoptosis resistant neoplasm in a subject comprising an effective amount of an inhibitory nucleic acid molecule that is complementary to at least a fragment of mir-17-92 in a pharmaceutically acceptable excipient.
Dependencies are inferred from the claim text.