Nucleic Acid-Based Therapy of Muscular Dystrophies

A pharmaceutical composition comprising a lipid nanoparticle, wherein

• the lipid nanoparticle comprises a compound having Formula (I):
• or a salt or isomer thereof, wherein:
• R1 is selected from the group consisting of C5-30 alkyl, C5-20 alkenyl, —R*YR″, —YR″, and —R″M′R′;
• R2 and R3 are independently selected from the group consisting of H, C1-14 alkyl, C2-14 alkenyl, —R*YR″, —YR″, and —R*OR″, or R2 and R3, together with the atom to which they are attached, form a heterocycle or carbocycle;
• R4 is selected from the group consisting of a C3-6 carbocycle, —(CH2)nQ, —(CH2)nCHQR, —CHQR, —CQ(R)2, and unsubstituted C1-6 alkyl, where Q is selected from a carbocycle, heterocycle, —OR, —O(CH2)nN(R)2, —C(O)OR, —OC(O)R, —CX3, —CX2H, —CXH2, —CN, —N(R)2, —C(O)N(R)2, —N(R)C(O)R, —N(R)S(O)2R, —N(R)C(O)N(R)2, —N(R)C(S)N(R)2, —N(R)R8, —O(CH2)nOR, —N(R)C(═NR9)N(R)2, —N(R)C(═CHR9)N(R)2, —OC(O)N(R)2, —N(R)C(O)OR, —N(OR)C(O)R, —N(OR)S(O)2R, —N(OR)C(O)OR, —N(OR)C(O)N(R)2, —N(OR)C(S)N(R)2, —N(OR)C(═NR9)N(R)2, —N(OR)C(═CHR9)N(R)2, —C(═NR9)N(R)2, —C(═NR9)R, —C(O)N(R)OR, and —C(R)N(R)2C(O)OR, and each n is independently selected from 1, 2, 3, 4, and 5;
• each R5 is independently selected from the group consisting of C1-3 alkyl, C2-3 alkenyl, and H;
• each R6 is independently selected from the group consisting of C1-3 alkyl, C2-3 alkenyl, and H;
• M and M′ are independently selected from —C(O)O—, —OC(O)—, —C(O)N(R′)—, —N(R′)C(O)—, —C(O)—, —C(S)—, —C(S)S—, —SC(S)—, —CH(OH)—, —P(O)(OR′)O—, —S(O)2—, —S—S—, an aryl group, and a heteroaryl group;
• R7 is selected from the group consisting of C1-3 alkyl, C2-3 alkenyl, and H;
• R8 is selected from the group consisting of C3-6 carbocycle and heterocycle;
• R9 is selected from the group consisting of H, CN, NO2, C1-6 alkyl, —OR, —S(O)2R, —S(O)2N(R)2, C2-6 alkenyl, C3-6 carbocycle and heterocycle;
• each R is independently selected from the group consisting of C1-3 alkyl, C2-3 alkenyl, and H;
• each R′ is independently selected from the group consisting of C1-18 alkyl, C2-18 alkenyl, —R*YR″, —YR″, and H;
• each R″ is independently selected from the group consisting of C3-14 alkyl and C3-14 alkenyl;
• each R* is independently selected from the group consisting of C1-12 alkyl and C2-12 alkenyl;
• each Y is independently a C3-6 carbocycle;
• each X is independently selected from the group consisting of F, Cl, Br, and I;
• and
• m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13,
• wherein the lipid nanoparticle comprises an mRNA that comprises an open reading frame (ORF) encoding a JAG1 polypeptide, wherein the composition is suitable for administration to a human subject in need of treatment for Duchenne muscular dystrophy.