Polynucleotides encoding propionyl-coa carboxylase alpha and beta subunits for the treatment of propionic acidemia

Patent metadata

Field	Value
Publication number	US-2022265856-A1
Application number	US-201816765632-A
Country	US
Kind code	A1
Filing date	Nov 21, 2018
Priority date	Nov 22, 2017
Publication date	Aug 25, 2022
Grant date	—

Abstract

This disclosure relates to mRNA therapy for the treatment of propionic acidemia (PA). mRNAs for use in the invention, when administered in vivo, encode human propionyl-CoA carboxylase alpha (PCCA) and/or human propionyl-CoA carboxylase beta (PCCB), and isoforms thereof, functional fragments thereof, and fusion proteins comprising PCCA and/or PCCB. mRNAs of the invention are preferably encapsulated in lipid nanoparticles (LNPs) to effect efficient delivery to cells and/or tissues in subjects, when administered thereto. mRNA therapies of the invention increase and/or restore deficient levels of propionyl-CoA carboxylase (PCC) expression and/or activity in subjects. mRNA therapies of the invention further decrease levels of disease-associated toxic metabolites associated with deficient PCCA or PCCB activity, in subjects.

First claim

1 . A pharmaceutical composition comprising a delivery agent comprising a lipid nanoparticle comprising a compound of Formula (I):

or an N-oxide, salt, or isomer thereof, wherein:
R 1 is selected from the group consisting of C 5-30 alkyl, C 5-20 alkenyl, —R*YR″, —YR″, and —R″M′R′;
R 2 and R 3 are independently selected from the group consisting of H, C 1-14 alkyl, C 2-14 alkenyl, —R*YR″, —YR″, and —R*OR″, or R 2 and R 3 , together with the atom to which they are attached, form a heterocycle or carbocycle;
R 4 is selected from the group consisting of hydrogen, a C 3-6 carbocycle, —(CH 2 ) n Q, —(CH 2 ) n CHQR, —CHQR, —CQ(R) 2 , and unsubstituted C 1-6 alkyl, where Q is selected from a carbocycle, heterocycle, —OR, —O(CH 2 ) n N(R) 2 , —C(O)OR, —OC(O)R, —CX 3 , —CX 2 H, —CXH 2 , —CN, —N(R) 2 , —C(O)N(R) 2 , —N(R)C(O)R, —N(R)S(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)C(S)N(R) 2 , —N(R)R 8 , —N(R)S(O) 2 R 8 , —O(CH 2 ) n OR, —N(R)C(═NR 9 )N(R) 2 , —N(R)C(═CHR 9 )N(R) 2 , —OC(O)N(R) 2 , —N(R)C(O)OR, —N(OR)C(O)R, —N(OR)S(O) 2 R, —N(OR)C(O)OR, —N(OR)C(O)N(R) 2 , —N(OR)C(S)N(R) 2 , —N(OR)C(═NR 9 )N(R) 2 , —N(OR)C(═CHR 9 )N(R) 2 , —C(═NR 9 )N(R) 2 , —C(═NR 9 )R, —C(O)N(R)OR, and —C(R)N(R) 2 C(O)OR, and each n is independently selected from 1, 2, 3, 4, and 5;
each R 5 is independently selected from the group consisting of C 1-3 alkyl, C 2-3 alkenyl, and H;
each R 6 is independently selected from the group consisting of C 1-3 alkyl, C 2-3 alkenyl, and H;
M and M′ are independently selected from —C(O)O—, —OC(O)—, —OC(O)-M″-C(O)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, in which M″ is a bond, C 1-13 alkyl or C 2-13 alkenyl;
R 7 is selected from the group consisting of C 1-3 alkyl, C 2-3 alkenyl, and H;
R 8 is selected from the group consisting of C 3-6 carbocycle and heterocycle;
R 9 is selected from the group consisting of H, CN, NO 2 , C 1-6 alkyl, —OR, —S(O) 2 R, —S(O) 2 N(R) 2 , C 2-6 alkenyl, C 3-6 carbocycle and heterocycle;
each R is independently selected from the group consisting of C 1-3 alkyl, C 2-3 alkenyl, and H;
each R′ is independently selected from the group consisting of C 1-18 alkyl, C 2-18 alkenyl, —R*YR″, —YR″, and H;
each R″ is independently selected from the group consisting of C 3-15 alkyl and C 3-15 alkenyl;
each R* is independently selected from the group consisting of C 1-12 alkyl and C 2-12 alkenyl;
each Y is independently a C 3-6 carbocycle;
each X is independently selected from the group consisting of F, Cl, Br, and I;
m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13; and
wherein when R 4 is —(CH 2 ) n Q, —(CH 2 ) n CHQR, —CHQR, or —CQ(R) 2 , then (i) Q is not —N(R) 2 when n is 1, 2, 3, 4 or 5, or (ii) Q is not 5, 6, or 7-membered heterocycloalkyl when n is 1 or 2,
wherein the pharmaceutical composition comprises an mRNA comprising an open reading frame (ORF) encoding a propionyl-CoA carboxylase alpha (PCCA) polypeptide, and wherein the pharmaceutical composition when administered as a single intravenous dose to a human subject in need thereof is sufficient to:
(i) increase the level of PCC activity in liver tissue to within at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% of normal PCC activity level for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks post-administration;
(ii) increase the level of PCC activity in liver tissue at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 20-fold, or at least 50-fold compared to the subject's baseline PCC activity level or a reference PCC activity level in a human subject having propionic academia (PA) for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks post-administration;
(iii) reduce plasma, serum, whole blood, and/or liver levels of propionic acid at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% compared to the subject's baseline plasma, serum, whole blood and/or liver propionic acid level or a reference plasma, serum, whole blood and/or liver propionic acid level in a human subject having propionic acidemia (PA) for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks post-administration;
(iv) reduce plasma, serum, whole blood, and/or urine levels of propionyl-L-carnitine (C3), 2-methylcitric acid (2-MC), 3-hydroxypropionic acid, (30HPA), and/or ammonia at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% compared to the subject's baseline plasma, serum, or urine level or a reference plasma, serum, or urine C3, 2-MC, 3OHPA, and/or ammonia level in a human subject having PA for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks post-administration;
(v) reduce plasma, serum, whole blood and/or liver levels of propionic acid at least 1.5-fold, at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, or at least 50-fold as compared to the subject's baseline plasma, serum, whole blood and/or liver propionic acid level or a reference plasma, serum, whole blood and/or liver propionic acid level in a patient with PA for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks post-administration; and/or
(vi) reduce plasma, serum, and/or urine level of C3, 2-MC, 30HPA, and/or ammonia at least 1.5-fold, at least 2-fold at least 5-fold, at least 10-fold, at least 20-fold or at least 50-fold as compared to the subject's baseline plasma, serum, and/or urine C3, 2-MC, 3OHPA, and/or ammonia level or a reference plasma, serum, and/or urine C3, 2-MC, 30HPA, and/or ammonia level in a patient with PA for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks post-administration.

2 . A pharmaceutical composition comprising a delivery agent comprising a lipid nanoparticle comprising a compound of Formula (I):

or an N-oxide, salt, or isomer thereof, wherein:
R 1 is selected from the group consisting of C 5-30 alkyl, C 5-20 alkenyl, —R*YR″, —YR″, and —R″M′R′;
R 2 and R 3 are independently selected from the group consisting of H, C 1-14 alkyl, C 2-14 alkenyl, —R*YR″, —YR″, and —R*OR″, or R 2 and R 3 , together with the atom to which they are attached, form a heterocycle or carbocycle;
R 4 is selected from the group consisting of hydrogen, a C 3-6 carbocycle, —(CH 2 ) n Q, —(CH 2 ) n CHQR, —CHQR, —CQ(R) 2 , and unsubstituted C 1-6 alkyl, where Q is selected from a carbocycle, heterocycle, —OR, —O(CH 2 ) n N(R) 2 , —C(O)OR, —OC(O)R, —CX 3 , —CX 2 H, —CXH 2 , —CN, —N(R) 2 , —C(O)N(R) 2 , —N(R)C(O)R, —N(R)S(O) 2 R,

Assignees

• Modernatx Inc

Inventors

• Jiang Lei
• Guey Lin Tung
• Martini Paolo G V
• Presnyak Vladimir

Classifications

• C12N2830/50

  regulating RNA stability, not being an intron, e.g. poly A signal · CPC title

• A61K38/53

  Ligases (6) · 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

• C12Y604/01003 Primary

  Propionyl-CoA carboxylase (6.4.1.3) · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title