This present disclosure provides recombinant adeno-associated virus (rAAV) and methods of their use in gene therapy for treating propionic acidemia (PA). Also provided are pharmaceutical compositions comprising a rAAV of the invention and a pharmaceutically acceptable carrier or excipient. These pharmaceutical compositions may be useful in gene therapy for the treatment of PA caused by a mutation in propionyl-CoA carboxylase α-subunit (PCCA) or a mutation in propionyl-CoA carboxylase β-subunit (PCCB).

Synthetic polynucleotides encoding human propionyl-CoA carboxylase beta (synPCCB) and exhibiting augmented expression in cell culture and/or in a subject are described herein. An adeno-associated viral (AAV) gene therapy vector encoding synPCCB successfully rescued the neonatal lethal phenotype displayed by propionyl-CoA carboxylase beta (Pccb.sup.−/−) deficient mice, lowered circulating methylcitrate levels in the treated animals, and resulted in prolonged hepatic expression of the product of the synPCCB transgene in vivo.

A coryneform bacteria cell with an increased provision of Malonyl-CoA compared to its archetype, wherein the regulation and/or expression of one or more of genes fasB, gltA, accBC and accD1, and/or the functionality of the enzyme encoded by each gene is modified in a targeted manner. The cell may have one or more targeted modifications, including reduced or eliminated functionality of the fatty acid synthase FasB, mutation or partial or complete deletion of the fatty acid synthase encoding gene fasB, and/or reduced functionality of the promoter operatively linked to the citrate synthase gene gtIA, among other targeted modifications.

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.

Sedoheptulose, which is a saccharide falling within the categories of ketoses and heptuloses, is one of a small number of heptuloses occurring in nature. A method for producing sedoheptulose may use a bacterium, and/or may improve the productivity of sedoheptulose by the bacterium, and the bacterium. To solve this problem, provided are a method for producing sedoheptulose using a bacterium owing to the deletion or attenuation of a specific enzymatic function, a method for improving the productivity of sedoheptulose by the bacterium, and the bacterium.

Synthetic polynucleotides encoding human propionyl-CoA carboxylase alpha (synPCCA) and exhibiting augmented expression in cell culture and/or in a subject are described herein. Adeno-associated viral (AAV) gene therapy vectors encoding synPCCA successfully rescued the neonatal lethal phenotype displayed by propionyl-CoA carboxylase alpha (Pcca.sup.−/−) deficient mice, lowered circulating methylcitrate levels in the treated animals, and resulted in prolonged hepatic expression of the product of the synPCCA transgene in vivo.

Provided herein, inter alia, is a modular-functional technology for the expression of a functional heterologous polyketide synthases (PKS) system in a photosynthetic cyanobacteria.

This present disclosure provides adeno-associated viral vectors, recombinant adeno-associated virus (rAAV), and methods of their use in gene therapy for treating propionic acidemia (PA). Also provided are pharmaceutical compositions comprising a recombinant adeno-associated virus of the invention and a pharmaceutically acceptable carrier or excipient. These pharmaceutical (compositions may be useful in gene therapy for the treatment of PA caused by mutations in propionyl-CoA carboxylase α-subunit (PCCA) or mutations in propionyl-CoA carboxylase β-subunit (PCCB).

Sedoheptulose, which is a saccharide falling within the categories of ketoses and heptuloses, is one of a small number of heptuloses occurring in nature. A method for producing sedoheptulose may use a bacterium, and/or may improve the productivity of sedoheptulose by the bacterium, and the bacterium. To solve this problem, provided are a method for producing sedoheptulose using a bacterium owing to the deletion or attenuation of a specific enzymatic function, a method for improving the productivity of sedoheptulose by the bacterium, and the bacterium.

Sedoheptulose, which is a saccharide falling within the categories of ketoses and heptuloses, is one of a small number of heptuloses occurring in nature. Provided are a method for producing sedoheptulose using a bacterium owing to the deletion or attenuation of a specific enzymatic function, a method for improving the productivity of sedoheptulose by the bacterium, and the bacterium.