Delivery platform and method of use for skeletal muscle

Abstract

The present disclosure relates to delivery vehicles that specifically and efficiently target a payload to skeletal muscle cells in a subject's body. The delivery vehicles disclosed herein include a targeting ligand (e.g., a compound with affinity for an integrin, including alpha-v-beta-6) and a pharmacokinetic / pharmacodynamic (PK / PD) modulator to facilitate delivery of the payload to cells, including skeletal muscle cells. Payloads suitable for use in the delivery vehicles disclosed herein include RNAi agents, which can be linked or conjugated to the delivery vehicle and, upon delivery in vivo, inhibit gene expression in skeletal muscle cells. Pharmaceutical compositions containing the delivery vehicles for skeletal muscle cells are also described, as well as methods for using them to treat various diseases and disorders in which delivery of a therapeutic payload to skeletal muscle cells is desirable.

Claims

1. A delivery vehicle for inhibiting the expression of genes expressed in skeletal muscle cells, (a) (i) Antisense strands containing 17 to 49 nucleotides, of which at least 15 nucleotides are complementary to the mRNA sequence of a gene expressed in skeletal muscle cells. (ii) A sense strand having a length of 16 to 49 nucleotides and being at least partially complementary to the antisense strand. RNAi agents containing; (b) Targeting ligands that have affinity for receptors present on the surface of skeletal muscle cells; and (c) Including PK / PD modulators; The aforementioned (b) targeting ligand is of the formula: 【Chemistry 1-1】 【Chemistry 1-2】 [Chemistry 1-3] [Chemistry 1-4] [Chemistry 1-5] [Chemistry 1-6] [Chemistry 1-7] This indicates a connection point to the remainder of the delivery vehicle, and The (c) PK / PD modulator is the PK / PD modulator of formula (I): [Chemistry 1-8] or a pharmaceutically acceptable salt thereof, in the formula, L A is a binding or bivalent portion that connects Z to the RNAi agent; Z is CH, phenyl, or N; L1 and L2 are linkers that independently contain at least approximately 5 PEGs; X and Y are each independently lipids containing 10 to 50 carbon atoms; and [Chemistry 1-9] This indicates the connection point to the RNAi agent, The RNAi agent is bound to the targeting ligand and the PK / PD modulator. Delivery vehicle.

2. The delivery vehicle according to claim 1, wherein the RNAi agent is linked to the targeting ligand and the PK / PD modulator via a linker.

3. The delivery vehicle according to claim 1, wherein the sense chain further comprises an inverted debasic deoxyribose residue at its 5' and / or 3' ends.

4. The aforementioned targeting ligand is of the formula: 【Chemistry 1】 or has a medicinally acceptable salt thereof (in the formula, 【Chemistry 2】 The delivery vehicle according to claim 1, (wherein indicates a connection point to the remainder of the delivery vehicle).

5. The aforementioned targeting ligand is of the formula: 【Transformation 3】 or has a medicinally acceptable salt thereof (in the formula, 【Chemistry 4】 The delivery vehicle according to claim 1, (wherein indicates a connection point to the remainder of the delivery vehicle).

6. The aforementioned PK / PD modulator Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 or a pharmaceutically acceptable salt of any of these PK / PD modulators (In the formula, 【Transformation 5】 (This indicates the connection point to the RNAi agent), and The aforementioned connection point includes a linker, The delivery vehicle according to claim 1.

7. At least one of X and Y is Table 3-1 Table 3-2 Selected from the group consisting of (in the formula, 【Transformation 8】 is L １ or L ２ The delivery vehicle according to claim 1, (showing a connection point to [a specific location]).

8. Both X and Y are independent of each other. Table 4-1 Table 4-2 Selected from the group consisting of (in the formula, 【Chemistry 9】 is L １ or L ２ The delivery vehicle according to claim 1, (showing a connection point to [a specific location]).

9. L Ａ but Table 5-1 Table 5-2 Selected from the group consisting of (wherein m, n, o, and a are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, and each 【Chemistry 10】 The delivery vehicle according to claim 1, (where Z indicates a connection point to the RNAi agent).

10. The PK / PD modulator, Table 6-1 Table 6-2 Table 6-3 Table 6-4 Table 6-5 Table 6-6 Table 6-7 Table 6-8 Table 6-9 Or selected from the group consisting of pharmaceutically acceptable salts of any of these PK / PD modulators (wherein each 【Chemistry 11】 (This indicates the connection point to the RNAi agent), and The aforementioned connection point includes a linker, The delivery vehicle according to claim 1.

11. The delivery vehicle according to any one of claims 1 to 10, wherein the RNAi agent inhibits the expression of mRNA of a single human gene in skeletal muscle cells.

12. The delivery vehicle according to any one of claims 1 to 11, wherein the pharmaceutically acceptable salt is a sodium salt.

13. The delivery vehicle according to any one of claims 1 to 11, wherein the pharmaceutically acceptable salt is a potassium salt.

14. A composition comprising a delivery vehicle according to any one of claims 1 to 13.

15. A pharmaceutical composition comprising the composition described in claim 14 and a pharmaceutical excipient.

16. The pharmaceutical composition according to claim 15, wherein the pharmaceutical excipient is selected from water for injection and physiological saline solution.

17. The pharmaceutical composition according to claim 16, wherein the pharmaceutical excipient is a physiological saline solution.

18. A delivery vehicle according to any one of claims 1 to 13, a composition according to claim 14, or a pharmaceutical composition according to any one of claims 15 to 17, for use in the treatment of muscular dystrophy.

19. The delivery vehicle, composition, or pharmaceutical composition according to claim 18, wherein the muscular dystrophy is selected from the group consisting of Duchenne muscular dystrophy, myotonic muscular dystrophy, Becker muscular dystrophy, limb-body muscular dystrophy, facioscapulohumeral muscular dystrophy, congenital muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, and Emery-Dreyfus muscular dystrophy.

20. A method for producing a delivery vehicle according to any one of claims 1 to 13, (i) Synthesize the sense chains; (ii) Synthesize the antisense chain; (iii) Anneal the sense chain and the antisense chain; (iv) before or after annealing of the sense strand and the antisense strand, the targeting ligand is attached to the sense strand or the antisense strand; and (v) A method comprising joining the PK / PD modulator to the sense strand or the antisense strand before or after annealing of the sense strand and the antisense strand, and before or after joining the targeting ligand to the sense strand or the antisense strand.

Images