Abstract: What is described is a method of synthesis of the compound of formula 1A, or a salt thereof, wherein R3 is a linear or branched alkene of 1, 2, 3, 4, 5 or 6 carbons; R4 and R5 are the same or different, each a hydrogen, or a linear or branched alkyl of 1, 2, 3, 4, 5 or 6 carbons; and L3 is a bond or an alkane of 1, 2, 3, 4, 5 or 6 carbons.

Abstract: This invention provides a range of translatable messenger UNA (mUNA) molecules. The mUNA molecules can be translated in vitro and in vivo to provide an active polypeptide or protein, or to provide an immunization agent or vaccine component. The mUNA molecules can be used as an active agent to express an active polypeptide or protein in cells or subjects. Among other things, the mUNA molecules are useful in methods for treating rare diseases.

Abstract: A method of producing a lipid-encapsulated RNA nanoparticle, comprising the steps a) flowing an aqueous solution comprising an RNA through a 1st tube having an inner diameter (ID) of between about 0.1? and 0.132?; b) flowing an ethanol solution comprising lipids through a 2nd tube having an ID of between about 0.005? and 0.02? at one third the flow rate of the aqueous solution through the 1st tube, wherein the lipids comprise a cationic lipid; and c) mixing the ethanol solution with the aqueous solution by flowing the ethanol solution and the aqueous solution into a mixing module consisting of the 2nd tube perpendicularly joined to the 1st tube; wherein the mixing produces an output solution flowing in the 1st tube comprising a turbulent flow of the RNA and the lipids in between about 10% to 75% ethanol v/v, and wherein the lipid-encapsulated RNA nanoparticles have a bilayer structure.

Abstract: Disclosed herein is a lipid composition comprising a compound having the formula IA, or a pharmaceutically acceptable salt thereof, wherein R3 is a linear or branched alkylene of 1-6 carbons; R4 and R5 are the same or different, each a hydrogen, or a linear or branched alkyl of 1-6 carbons; and L3 is a bond or an alkane of 1-6 carbons.

Abstract: This invention provides UNA oligomers for gene silencing with reduced off-target effects. The UNA oligomers can have a first strand and a second strand, each of the strands being 19-29 monomers in length, the monomers being UNA monomers and various nucleic acid monomers. Embodiments include pharmaceutical compositions and methods for treating or preventing TTR-related amyloidosis with reduced off-target effects by administering a UNA oligomer to a subject.

Abstract: The present disclosure provides a modified human OTC protein having improved properties for the treatment of OTC deficiency in a patient. Preferably, the protein of the disclosure is produced from a codon optimized mRNA suitable for administration to a patient suffering from OTC deficiency wherein upon administration of the mRNA to the patient, the protein of the disclosure is expressed in the patient in therapeutically effective amounts to treat OTC deficiency. The present disclosure also provides codon optimized mRNA sequences encoding wild type human OTC comprising a 5? UTR derived from a gene expressed by Arabidopsis thaliana for use in treating OTC deficiency in a patient.

Abstract: This invention provides a range of translatable polynucleotide and oligomer molecules for expressing a human amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase (AGL), or a fragment thereof having AGL activity. The polynucleotide and oligomer molecules are expressible to provide the human AGL or a fragment thereof having AGL activity. The molecules can be used as active agents to express an active polypeptide or protein in cells or subjects. The agents can be used in methods for ameliorating, preventing, delaying onset, or treating a disease or condition associated with reduced activity of amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase (AGL) in a subject.

Abstract: What is described is a method of synthesis of the compound of formula 1A, or a salt thereof, wherein R3 is a linear or branched alkene of 1, 2, 3, 4, 5 or 6 carbons; R4 and R5 are the same or different, each a hydrogen, or a linear or branched alkyl of 1, 2, 3, 4, 5 or 6 carbons; and L3 is a bond or an alkane of 1, 2, 3, 4, 5 or 6 carbons.

Abstract: This invention encompasses compounds and compositions useful in methods for medical therapy, in general, for inhibiting Hepatitis B virus in a subject. The compounds have a first strand and a second strand, each of the strands being 19-29 monomers in length, the monomers comprising UNA monomers and nucleic acid monomers, and the compounds are targeted to a sequence of an HBV genome.

Abstract: This invention provides a range of translatable polynucleotide and oligomer molecules for expressing a human phenylalanine hydroxylase (PAH), or a fragment thereof having PAH activity. The polynucleotide and oligomer molecules are expressible to provide the human PAH or a fragment thereof having PAH activity. The molecules can be used as active agents to express an active polypeptide or protein in cells or subjects. The agents can be used in methods for ameliorating, preventing, delaying onset, or treating a disease or condition associated with phenylketonuria, decreased metabolism of phenylalanine, or increased levels of phenylalanine in a subject.

Abstract: Disclosed herein is a compound of Formula I, wherein R1 is a branched chain alkyl consisting of 10 to 31 carbons; R2 is a linear alkyl, alkenyl, or alkynyl consisting of 2 to 20 carbons, or a branched chain alkyl consisting of 10 to 31 carbons; L1 and L2 are the same or different, each a linear alkane of 1 to 20 carbons or a linear alkene of 2 to 20 carbons; X1 is S or O; R3 is a linear or branched alkylene consisting of 1 to 6 carbons; and R4 and R5 are the same or different, each a hydrogen or a linear or branched alkyl consisting of 1 to 6 carbons; or a pharmaceutically acceptable salt or solvate thereof.

Abstract: This invention provides pharmaceutical compositions containing a UNA oligomer targeted to TTR and a pharmaceutically acceptable carrier. The compositions can be used in methods for treating or preventing TTR-related amyloidosis in a primate. The compositions, upon administering a single dose to the primate, can reduce TTR protein in the primate for a period of days to weeks.

Abstract: A nucleic acid vaccine composition comprising one or more of a plasmid-based nucleic acid vaccine and immunotherapy, as well as a lipid formulation, is provided. In addition, the present invention provides a method of enhancing the potency of plasmid-based DNA vaccines and immunotherapies, by formulating a vaccine and/or immunotherapy in a lipid formulation, which is stable when refrigerated or stored frozen, is then delivered to a vaccinee by either needle/syringe, jet injection, or microneedles. The lipid formulation of the present invention comprises one or more lipid excipients selected from 1,2-Distearoyl-sn-glycero-3-phosphocholine, Cholest-5-en-3?-ol, 1,2-Dimyristoyl-rac-glycero-3-methylpolyoxyethlene, and or more symmetric ionizable cationic lipids. The present invention increases vaccine potency dramatically.

Abstract: What is described is a compound of formula III or IV wherein R1 is a branched alkyl with 12 to 20 carbons; R2 is a linear alkyl with 5 to 10 carbons or a branched alkyl with 12 to 20 carbons; L1 and L2 are each a bond or a linear alkylene having 1 to 3 carbon atoms, when L3 is a bond; L1 and L2 are each a linear alkylene or alkenylene 5 to 18 carbon atoms, when L3 is an alkylene of 5 to 18 carbons; X is S or O; R3 is of a lower alkyl; and R4 and R5 are the same or different, each a lower alkyl; or a pharmaceutically acceptable salt thereof.

Abstract: What is described is a trinucleotide cap analog comprising m7G(5?)p3-N1pN2 for increased efficiency of in vitro transcription of m7G(5?)p3-RNA, wherein m7G is N7-methylguanosine or analog, (5?)p3 is a 5?,5?-triphosphate bridge, and N1 or N2 or both ribonucleotide analogs linked to each other by a phosphate, p, and wherein the trinucleotide cap analog increases the efficiency of in vitro transcription.

Abstract: What is described is a compound of formula I consisting of a compound in which R1 is a branched chain alkyl consisting of 10 to 31 carbons; R2 is a linear alkyl, alkenyl, or alkynyl consisting of 2 to 20 carbons, or a branched chain alkyl consisting of 10 to 31 carbons; L1 and L2 are the same or different, each a linear alkane of 1 to 20 carbons or a linear alkene of 2 to 20 carbons; X1 is S or O; R3 is a linear or branched alkylene consisting of 1 to 6 carbons; and R4 and R5 are the same or different, each a hydrogen or a linear or branched alkyl consisting of 1 to 6 carbons; or a pharmaceutically acceptable salt thereof.

Abstract: This invention provides UNA oligomers for regulating the expression of a target gene. The UNA oligomers contain UNA monomer linkers, and may contain one or more nucleotides modified with a 2?-O-methyl group, one or more nucleotides modified with a 2?-deoxy-2?-fluoro group, and one or more phosphorothioate or chiral phosphorothioate intermonomer linkages. UNA oligomers can be used as active agents for preventing or treating disease.

Abstract: What is described is a compound of formula I consisting of a compound in which R1 is a branched chain alkyl consisting of 10 to 31 carbons; R2 is a linear alkyl, alkenyl, or alkynyl consisting of 2 to 20 carbons; L1 and L2 are the same or different, each a linear alkylene or alkenylene consisting of 2 to 20 carbons; X1 is S or O; R3 is a linear or branched alkylene consisting of 1 to 6 carbons; and R4 and R5 are the same or different, each a hydrogen or a linear or branched alkyl consisting of 1 to 6 carbons; or a pharmaceutically acceptable salt thereof.

Abstract: What is described is a trinucleotide cap analog comprising m7G(5?)p3-N1pN2 for increased efficiency of in vitro transcription of m7G(5?)p3-RNA, wherein m7G is N7-methylguanosine or analog, (5?)p3 is a 5?,5?-triphosphate bridge, and N1 or N2 or both ribonucleotide analogs linked to each other by a phosphate, p, and wherein the trinucleotide cap analog increases the efficiency of in vitro transcription.

Abstract: This invention encompasses compounds and compositions useful in methods for medical therapy, in general, for inhibiting expression of a TTR gene in a subject. The compounds have a first strand and a second strand, the monomers comprising UNA monomers and nucleic acid monomers, and the compounds are targeted to a sequence of a TTR gene.