Compositions and methods for making therapies delivered by viral vectors reversible for safety and allele-specificity

Patent metadata

Field	Value
Publication number	US-9375440-B2
Application number	US-59281206-A
Country	US
Kind code	B2
Filing date	Nov 3, 2006
Priority date	Nov 3, 2006
Publication date	Jun 28, 2016
Grant date	Jun 28, 2016

Abstract

The present invention is directed to compositions methods and kits for regulation of gene therapies, including, without limitation, reversible gene therapies and allele-specific therapies.

First claim

The invention claimed is:

1. A system for delivering a deoxyribonucleic acid sequence to a human patient, comprising:
(a) a delivery device providing an access to a target area in the body of the patient; and
(b) a deliverable amount of a deoxyribonucleic acid sequence comprising:
(1) a first sequence, said first sequence having a 5′ end and a 3′ end; and
(2) a second sequence, said second sequence having a 5′ end and a 3′ end; and
(3) a first pair of flanking sequences, wherein a first member of the first pair is located upstream of the 5′ end of the first sequence and a second member of the first pair is located downstream of the 3′ end of the first sequence; and
(4) a second pair of flanking sequences, wherein a first member of the second pair is located downstream of the 3′ end of a second member of the first pair and upstream of the 5′ end of the second sequence; and a second member of the second pair is located downstream of the 3′ end of the second sequence; and
wherein the first sequence is excisable from the said deoxyribonucleic acid sequence upon exposure of said deoxyribonucleic acid sequence to a first sequence modifier, and
wherein the second sequence is excisable from the said deoxyribonucleic acid sequence upon exposure of said deoxyribonucleic acid sequence to a second sequence modifier.

2. A method of providing an at least partially reversible gene therapy to a human patient, comprising:
(a) accessing a target area in the central nervous system of the body of the patient with a delivery device;
(b) delivering intracranially at a first time a deliverable amount of a deoxyribonucleic acid sequence comprising:
(1) a first sequence, said first sequence having a 5′ end and a 3′ end; and
(2) a second sequence, said second sequence having a 5′ end and a 3′ end; and
(3) a first pair of flanking sequences, wherein a first member of the first pair is located upstream of the 5′ end of the first sequence and a second member of the first pair is located downstream of the 3′ end of the first sequence; and
(4) a second pair of flanking sequences, wherein a first member of the second pair is located downstream of the 3′ end of a second member of the first pair and upstream of the 5′ end of the second sequence; and a second member of the second pair is located downstream of the 3′ end of the second sequence; and
wherein the first sequence is excisable from the said deoxyribonucleic acid sequence upon exposure of said deoxyribonucleic acid sequence to a first sequence modifier, and
wherein the second sequence is excisable from the said deoxyribonucleic acid sequence upon exposure of said deoxyribonucleic acid sequence to a second sequence modifier; and

(c) delivering intracranially at a second time after the first time the first sequence modifier, the second sequence modifier, or a combination thereof.

3. A kit for providing a deoxyribonucleic acid sequence to a human patient, comprising:
(a) a deliverable amount of a deoxyribonucleic acid sequence comprising:
(1) a first sequence, said first sequence having a 5′ end and a 3′ end; and
(2) a second sequence, said second sequence having a 5′ end and a 3′ end; and
(3) a first pair of flanking sequences, wherein a first member of the first pair is located upstream of the 5′ end of the first sequence and a second member of the first pair is located downstream of the 3′ end of the first sequence; and
(4) a second pair of flanking sequences, wherein a first member of the second pair is located downstream of the 3′ end of a second member of the first pair and upstream of the 5′ end of the second sequence; and a second member of the second pair is located downstream of the 3′ end of the second sequence; and
wherein the first sequence is excisable from the said deoxyribonucleic acid sequence upon exposure of said deoxyribonucleic acid sequence to a first sequence modifier, and
wherein the second sequence is excisable from the said deoxyribonucleic acid sequence upon exposure of said deoxyribonucleic acid sequence to a second sequence modifier; and

(b) a set of instructions.

4. A system for delivering a deoxyribonucleic acid sequence to a human patient, comprising:
(a) a delivery device providing an access to a target area within the patient's body; and
(b) a deliverable amount of a deoxyribonucleic acid sequence comprising:
(1) a first sequence, wherein said first sequence encodes a first bioactive molecule having a 5′ end and a 3′ end; and
(2) a second sequence, wherein said second sequence encodes a second bioactive molecule having a 5′ end and a 3′ end; and
(3) a first pair of flanking sequences, wherein a first member of the first pair is located upstream of the 5′ end of the first sequence and a second member of the first pair is located downstream of the 3′ end of the second sequence; and
(4) a second pair of flanking sequences, wherein a first member of the second pair is located downstream of the 3′ end of a first member of the first pair and upstream of the 5′ end of the first sequence; and a second member of the second pair is located downstream of the 3′ end of the first sequence and upstream of the 5′ end of the second sequence; and
wherein both the first and second sequences are excisable together from the said deoxyribonucleic acid sequence upon exposure of said deoxyribonucleic acid sequence to a first sequence modifier, and
wherein the first sequence is excisable from the said deoxyribonucleic acid sequence, but said second sequence is not excised, upon exposure of said deoxyribonucleic acid sequence to a second sequence modifier.

5. The system of claim 4 , wherein the first bioactive molecule and the second bioactive molecule are independently selected from the group consisting of miRNA, shRNA, and protein.

6. The system of claim 5 , wherein the first sequence encodes a first bioactive molecule which reduces the amount of expression of a target gene, and the second sequence encodes a second bioactive molecule which reduces the amount of expression of said target gene by a lesser amount, wherein further the target gene is selected from the group consisting of SOD1, APP, TorsinA, IT15/HD, DRPLA, SCA1, SCA2, SCA3/MJD, SCA7, BACE1, and SNCA/alpha-synuclein.

7. The system of claim 4 , wherein the first sequence modifier or the second sequence modifier or both the first sequence modifier and the second sequence modifier is operably linked to a cell penetrating peptide moiety that enhances cellular uptake of the sequence modifier.

8. The system of claim 4 , wherein the first sequence modifier is selected from the group consisting of Cre recombinase, FLP recombinase, and phiC31 recombinase and the second sequence modifier is selected from the group consisting of Cre recombinase, FLP recombinase, and phiC31 recombinase.

9. The system of claim 4 , wherein the deoxyribonucleic acid sequence is contained within a viral vector.

10. The system of claim 4 , wherein the first and second bioactive molecules have different therapeutic potencies.

11. The system of claim 4 , wherein the access device comprises an implantable catheter.

12. A method for delivering an at least partially reversible gene therapy to a human patient, comprising:
(a) providing an access to a target area within the central nervous system of the patient's body with a delivery device; and
(b) delivering intracranially a deliverable amount of a deoxyribonucleic acid sequence comprising:
(1) a first sequence, wherein said first sequence encodes a first bioactive molecule said first sequence having a 5′ end and a 3′ end; and
(2) a second sequence, wherein said second sequence encodes a second bioactive molecule said second seq

Assignees

• Kaemmerer William F
• Burright Eric
• Heisel Jennifer
• Thakker Deepak
• Medtronic Inc

Inventors

• Kaemmerer William F
• Burright Eric
• Heisel Jennifer
• Thakker Deepak

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K48/0066

  Manipulation of the nucleic acid to modify its expression pattern, e.g. enhance its duration of expression, achieved by the presence of particular introns in the delivered nucleic acid · CPC title

• A61K48/005

  characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered · CPC title

• A61K31/70 Primary

  Carbohydrates; Sugars; Derivatives thereof (sorbitol A61K31/047) · CPC title