Antisense composition and method for treating muscle atrophy
First Claim
1. A method of treating skeletal muscle mass deficiency in a human subject comprising(a) measuring blood or tissue levels of myostatin in the subject,(b) administering to the subject, a myostatin-expression-inhibiting amount of a substantially uncharged antisense 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, (ii) capable of uptake by target muscle cells in the subject, (iii) containing between 10-40 nucleotide bases, and (iv) having a base sequence that is complementary to at least 12 contiguous bases in a target region of preprocessed human myostatin RNA transcript, identified by SEQ ID NO;
13, wherein the antisense compound includes a base sequence as set forth in SEQ ID NO;
3 and is capable of effectively blocking production of a full-length processed myostatin transcript from a preprocessed myostatin transcript,(c) by said administering, forming within target muscle cells in the subject, a base-paired heteroduplex structure composed of human myostatin RNA transcript and the antisense compound and having a Tm of dissociation of at least 45°
C., thereby inhibiting expression of myostatin in said cells,(d) at a selected time following said administering, measuring a blood or tissue level of myostatin in the subject, and(e) repeating said administering, using the myostatin levels measured in (d) to adjust the dose or dosing schedule of the amount of antisense compound administered, if necessary, so as to reduce measured levels of myostatin over those initially measured and to maintain such levels of myostatin measured in step (d) within a range determined for normal, healthy individuals.
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Abstract
A method and compound for treating skeletal muscle mass deficiency in a human subject are disclosed. The composition is an oligomer of morpholino subunits and phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ exocyclic carbon of an adjacent subunit, contains between 10-40 nucleotide bases, has a base sequence effective to hybridize to an expression-sensitive region of processed or preprocessed human myostatin RNA transcript, identified, in its processed form, by SEQ ID NO:6, and is capable of uptake by target muscle cells in the subject. In practicing the method, the compound is administered in an amount and at a dosage schedule to produce an overall reduction in the level of serum myostatin measured in the patient, and preferably to bring the myostatin level within the a range determined for normal, healthy individuals.
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Citations
16 Claims
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1. A method of treating skeletal muscle mass deficiency in a human subject comprising
(a) measuring blood or tissue levels of myostatin in the subject, (b) administering to the subject, a myostatin-expression-inhibiting amount of a substantially uncharged antisense 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, (ii) capable of uptake by target muscle cells in the subject, (iii) containing between 10-40 nucleotide bases, and (iv) having a base sequence that is complementary to at least 12 contiguous bases in a target region of preprocessed human myostatin RNA transcript, identified by SEQ ID NO;
13, wherein the antisense compound includes a base sequence as set forth in SEQ ID NO;
3 and is capable of effectively blocking production of a full-length processed myostatin transcript from a preprocessed myostatin transcript,(c) by said administering, forming within target muscle cells in the subject, a base-paired heteroduplex structure composed of human myostatin RNA transcript and the antisense compound and having a Tm of dissociation of at least 45°
C., thereby inhibiting expression of myostatin in said cells,(d) at a selected time following said administering, measuring a blood or tissue level of myostatin in the subject, and (e) repeating said administering, using the myostatin levels measured in (d) to adjust the dose or dosing schedule of the amount of antisense compound administered, if necessary, so as to reduce measured levels of myostatin over those initially measured and to maintain such levels of myostatin measured in step (d) within a range determined for normal, healthy individuals. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)
- exocyclic carbon of an adjacent subunit, (ii) capable of uptake by target muscle cells in the subject, (iii) containing between 10-40 nucleotide bases, and (iv) having a base sequence that is complementary to at least 12 contiguous bases in a target region of preprocessed human myostatin RNA transcript, identified by SEQ ID NO;
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10. An antisense composition for use in increasing skeletal muscle mass in a human subject, comprising a substantially uncharged antisense 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,
(ii) capable of uptake by target muscle cells in the subject, (iii) containing between 10-40 nucleotide bases, and (iv) having a base sequence that is complementary to at least 12 contiguous bases in a target region of preprocessed human myostatin transcript identified by SEQ ID NO;
13,wherein the antisense compound includes a base sequence as set forth in SEQ ID NO;
3 and is capable of effectively blocking production of a full-length processed myostatin transcript from a preprocessed myostatin transcript. - View Dependent Claims (11, 12, 13, 14, 15, 16)
- exocyclic carbon of an adjacent subunit,
Specification