IONIZABLE CATIONIC LIPIDS

• US 20170240501A1
• Filed: 12/02/2016
• Published: 08/24/2017
• Est. Priority Date: 03/29/2012
• Status: Active Grant

• Current Assignee: Translate Bio, Inc. (Sanofi )
• Original Assignee: Shire Human Genetic Therapies, Inc. (Shire plc)
• Inventors: DeRosa, Frank, Guild, Braydon Charles, Heartlein, Michael
• Granted Patent: US 10,065,919 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 38/1816 Erythropoietin [EPO]
• CPC Class Codes: A61K 38/47 acting on glycosyl compounds (3.2), e.g. cellulases, lactases
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 211/21 Monoamines
• CPC Class Codes: C12N 15/85 for animal cells
• CPC Class Codes: C12Y 302/01023 Beta-galactosidase (3.2.1.23), i.e. exo-(1-->4)-beta-D-galactanase

Abstract

Disclosed herein are novel compounds, pharmaceutical compositions comprising such compounds and related methods of their use. The compounds described herein are useful, e.g., as liposomal delivery vehicles to facilitate the delivery of encapsulated polynucleotides to target cells and subsequent transfection of said target cells, and in certain embodiments are characterized as having one or more properties that afford such compounds advantages relative to other similarly classified lipids.

Claims

1-89. -89. (canceled)

90. A lipid nanoparticle comprising a lipid compound having the structure:

91. The lipid nanoparticle of claim 90, comprising one or more polynucleotides.

92. The lipid nanoparticle of claim 91, comprising encapsulated DNA or RNA.

93. The lipid nanoparticle of claim 92, wherein said RNA is mRNA.

94. The lipid nanoparticle of claim 93, wherein said mRNA encodes a protein or an enzyme selected from the group consisting of human growth hormone, erythropoietin, α

1-antitrypsin, acid alpha glucosidase, arylsulfatase A, carboxypeptidase N, α

-galactosidase A, alpha-L-iduronidase, iduronate-2-sulfatase, iduronate sulfatase, N-acetylglucosamine-1-phosphate transferase, N-acetylglucosaminidase, alpha-glucosaminide acetyltransferase, N-acetylglucosamine 6-sulfatase, N-acetylgalactosamine-4-sulfatase, beta-glucosidase, galactose-6-sulfate sulfatase, beta-galactosidase, beta-glucuronidase, glucocerebrosidase, heparan sulfamidase, heparin-N-sulfatase, lysosomal acid lipase, hyaluronidase, galactocerebrosidase, ornithine transcarbamylase (OTC), carbamoyl-phosphate synthetase 1 (CPS1), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), arginase 1 (ARG1), cystic fibrosis transmembrane conductance regulator (CFTR), survival motor neuron (SMN), Factor VIII, Factor IX and low density lipoprotein receptors (LDLR).

95. The lipid nanoparticle of claim 90, further comprising one or more lipids selected from the group consisting of a cationic lipid, a neutral lipid, a PEG-modified lipid, a non-cationic lipid and a helper lipid.

96. The lipid nanoparticle of claim 90, wherein L₁ and L₂ are each an optionally substituted polyunsaturated C₁₈ alkenyl.

97. The lipid nanoparticle of claim 91, wherein said lipid compound is:

98. A lipid nanoparticle comprising a lipid compound having the structure:

99. The lipid nanoparticle of claim 98, comprising one or more polynucleotides.

100. The lipid nanoparticle of claim 99, comprising encapsulated DNA or RNA.

101. The lipid nanoparticle of claim 100, wherein said RNA is mRNA.

102. The lipid nanoparticle of claim 101, wherein said mRNA encodes a protein or an enzyme selected from the group consisting of human growth hormone, erythropoietin, α

1-antitrypsin, acid alpha glucosidase, arylsulfatase A, carboxypeptidase N, α

-galactosidase A, alpha-L-iduronidase, iduronate-2-sulfatase, iduronate sulfatase, N-acetylglucosamine-1-phosphate transferase, N-acetylglucosaminidase, alpha-glucosaminide acetyltransferase, N-acetylglucosamine 6-sulfatase, N-acetylgalactosamine-4-sulfatase, beta-glucosidase, galactose-6-sulfate sulfatase, beta-galactosidase, beta-glucuronidase, glucocerebrosidase, heparan sulfamidase, heparin-N-sulfatase, lysosomal acid lipase, hyaluronidase, galactocerebrosidase, ornithine transcarbamylase (OTC), carbamoyl-phosphate synthetase 1 (CPS1), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), arginase 1 (ARG1), cystic fibrosis transmembrane conductance regulator (CFTR), survival motor neuron (SMN), Factor VIII, Factor IX and low density lipoprotein receptors (LDLR).

103. The lipid nanoparticle of claim 98, further comprising one or more lipids selected from the group consisting of a cationic lipid, a neutral lipid, a PEG-modified lipid, a non-cationic lipid and a helper lipid.

104. The lipid nanoparticle of claim 98, wherein L₁ and L₂ are each an optionally substituted polyunsaturated C₁₈ alkenyl.

105. The lipid nanoparticle of claim 99, wherein said lipid compound is:

106. A lipid nanoparticle comprising:

a lipid compound having the structure;

107. The lipid nanoparticle of claim 106, comprising encapsulated DNA or RNA.

108. The lipid nanoparticle of claim 107, wherein said RNA is mRNA.

109. The lipid nanoparticle of claim 108, wherein said mRNA encodes a protein or an enzyme selected from the group consisting of human growth hormone, erythropoietin, α

1-antitrypsin, acid alpha glucosidase, arylsulfatase A, carboxypeptidase N, α

-galactosidase A, alpha-L-iduronidase, iduronate-2-sulfatase, iduronate sulfatase, N-acetylglucosamine-1-phosphate transferase, N-acetylglucosaminidase, alpha-glucosaminide acetyltransferase, N-acetylglucosamine 6-sulfatase, N-acetylgalactosamine-4-sulfatase, beta-glucosidase, galactose-6-sulfate sulfatase, beta-galactosidase, beta-glucuronidase, glucocerebrosidase, heparan sulfamidase, heparin-N-sulfatase, lysosomal acid lipase, hyaluronidase, galactocerebrosidase, ornithine transcarbamylase (OTC), carbamoyl-phosphate synthetase 1 (CPS1), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), arginase 1 (ARG1), cystic fibrosis transmembrane conductance regulator (CFTR), survival motor neuron (SMN), Factor VIII, Factor IX and low density lipoprotein receptors (LDLR).

110. The lipid nanoparticle of claim 106, further comprising one or more lipids selected from the group consisting of a cationic lipid, a neutral lipid, a PEG-modified lipid, a non-cationic lipid and a helper lipid.

111. The lipid nanoparticle of claim 106, wherein x is a C_6-10 alkenyl or a C_6-10 alkyl.

112. The lipid nanoparticle of claim 106, wherein said lipid compound is: