ANTISENSE COMPOUND FOR INDUCING IMMUNOLOGICAL TOLERANCE
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Abstract
A method and conjugate for selectively killing antigen-activated T cells are disclosed. The conjugate is composed of a substantially uncharged antisense compound targeted against the human cFLIP protein, and a reverse TAT (rTAT) polypeptide coupled covalently to the antisense compound. The rTAT polypeptide is effective to produce selective uptake of the conjugate into antigen-activated T cells, relative to the uptake of the conjugate into non-activated T cells. The cFLIP antisense compound causes activation induced cell death (AICD) of activated lymphocytes. The method is useful in treating transplantation rejection and autoimmune conditions.
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Citations
7 Claims
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1. (canceled)
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2. An antisense conjugate for use in inducing immunologic tolerance in a subject, comprising
(a) a substantially uncharged antisense oligonucleotide compound (i) composed of morpholino subunits and phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ - exocyclic carbon of an adjacent subunit, and containing 12-40 subunits,
(ii) having a base sequence that is complementary to at least 12 contiguous bases in a region extending from −
30 to +30 bases with respect to the AUG start site in a processed human cFLIP transcript, corresponding to base positions 452 to 512 in SEQ ID 16, and(iii) effective, when hybridized to the processed human cFLIP transcript, to block expression of cFLIP in lymphocytes, and (b) covalently coupled to the antisense oligonucleotide compound, an arginine-rich peptide effective to enhance the uptake of the antisense compound into lymphocytes. - View Dependent Claims (3, 4, 5, 6, 7)
- exocyclic carbon of an adjacent subunit, and containing 12-40 subunits,
Specification