Antisense restenosis composition and method
First Claim
1. A method of reducing the risk of restenosis in a region of a patient'"'"'s coronary vessel which has been treated by coronary angioplasty using a catheter with a distal-end expandable balloon, or which is at a junction formed in a coronary bypass operation, said method comprising administering to the patient, by local administration directly to the vessel site of injury, a morpholino antisense compound having from 8 to 40 morpholino subunits (a) including a targeting base sequence that is complementary to a target sequence of at least 12 contiguous bases within the AUG start site region of human c-myc mRNA defined by SEQ ID NO:
- 2, and (b) that are linked by uncharged phosphorodiamidate linkages interspersed with at least two and up to half positively charged phosphorodiamidate linkages, in an amount effective to reduce the risk of restenosis in the patient, where said administering is carried out by a mode of administration selected from the group consisting of (a) contacting the region of the vessel with a reservoir containing the antisense compound, and introducing the compound from the reservoir into the vessel by iontophoresis or electroporation;
(b) injecting the compound from the catheter directly into the region of the vessel, under pressure, through injectors contained on the surface of the catheter balloon, where said injectors are capable of penetrating the tunica media in the vessel;
(c) injecting into or contacting the region of the vessel, microparticles containing the antisense compound in entrapped form;
(d) contacting the region of the vessel with a hydrogel coating contained on the surface of the catheter balloon, and containing the antisense compound is diffusable form; and
(e) contacting the region of the vessel with a stent having an outer surface layer containing the antisense compound in diffusable form.
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Accused Products
Abstract
The present invention provides an improved method for reducing the risk or severity of restenosis following cardiac angioplasty. The method includes administering to a target vessel region, a morpholino antisense compound having a phosphorus-containing backbone linkages, and spanning the start codon of a human c-myc mRNA. Also disclosed are novel antisense compounds and compositions, and a method for assaying the effectiveness of antisense delivery and uptake to a target vessel region.
61 Citations
23 Claims
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1. A method of reducing the risk of restenosis in a region of a patient'"'"'s coronary vessel which has been treated by coronary angioplasty using a catheter with a distal-end expandable balloon, or which is at a junction formed in a coronary bypass operation, said method comprising
administering to the patient, by local administration directly to the vessel site of injury, a morpholino antisense compound having from 8 to 40 morpholino subunits (a) including a targeting base sequence that is complementary to a target sequence of at least 12 contiguous bases within the AUG start site region of human c-myc mRNA defined by SEQ ID NO: - 2, and (b) that are linked by uncharged phosphorodiamidate linkages interspersed with at least two and up to half positively charged phosphorodiamidate linkages, in an amount effective to reduce the risk of restenosis in the patient, where said administering is carried out by a mode of administration selected from the group consisting of
(a) contacting the region of the vessel with a reservoir containing the antisense compound, and introducing the compound from the reservoir into the vessel by iontophoresis or electroporation;
(b) injecting the compound from the catheter directly into the region of the vessel, under pressure, through injectors contained on the surface of the catheter balloon, where said injectors are capable of penetrating the tunica media in the vessel;
(c) injecting into or contacting the region of the vessel, microparticles containing the antisense compound in entrapped form;
(d) contacting the region of the vessel with a hydrogel coating contained on the surface of the catheter balloon, and containing the antisense compound is diffusable form; and
(e) contacting the region of the vessel with a stent having an outer surface layer containing the antisense compound in diffusable form. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)
- 2, and (b) that are linked by uncharged phosphorodiamidate linkages interspersed with at least two and up to half positively charged phosphorodiamidate linkages, in an amount effective to reduce the risk of restenosis in the patient, where said administering is carried out by a mode of administration selected from the group consisting of
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14. A method of treating the risk of restenosis in a region of a patient'"'"'s coronary vessel, comprising
administering to the patient, by local delivery directly into the region of injury, a morpholino antisense compound having (i) the base sequence identified as SEQ ID NO: - 1, and (ii) composed of uncharged phosphorodiamidate linkages interspersed with at least two and up to half positively charged phosphorodiamidate linkages, where the phosphorodiamidate linkages have the structure;
where Y1=O, Z=O, Pj is a purine or pyrimidine base-pairing moiety effective to bind, by base-specific hydrogen bonding, to a base in a polynucleotide (where base-pairing moieties on different subunits may be the same or different), and X is alkyl, alkoxy, thioalkoxy, or alkyl amino of the form NR2, where each R is independently hydrogen or methyl, for the uncharged linkages, and the positively charged linkages are represented by the same structure, but where X is 1-piperazino. - View Dependent Claims (15)
- 1, and (ii) composed of uncharged phosphorodiamidate linkages interspersed with at least two and up to half positively charged phosphorodiamidate linkages, where the phosphorodiamidate linkages have the structure;
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16. A morpholino antisense compound having from 8 to 40 morpholino subunits (a) including a targeting base sequence that is complementary to a target sequence of at least 12 contiguous bases within the AUG start site region of human c-myc mRNA defined by SEQ ID NO:
- 2, and (b) that are linked by uncharged phosphorodiamidate linkages interspersed with at least two and up to half positively charged phosphorodiamidate linkages.
- View Dependent Claims (17, 20, 21, 22, 23)
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18. (canceled)
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19. (canceled)
Specification