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 iransfection 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.

The present invention provides, among other things, methods of treating ornithine transcarbamylase (OTC) deficiency, including administering to a subject in need of treatment a composition comprising an mRNA encoding an ornithine transcarbamylase (OTC) protein at an effective dose and an administration interval such that at least one symptom or feature of the OTC deficiency is reduced in intensity, severity, or frequency or has delayed onset. In some embodiments, the mRNA is encapsulated in a liposome comprising one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids.

The present disclosure provides, among other things, polynucleotide constructs, compositions, and methods of treating ornithine transcarbamylase deficiency, including administering to a subject in need thereof a composition comprising a polynucleotide construct comprising a 5′ UTR, a codon optimized mRNA encoding an ornithine transcarbamylase, and a 3′ UTR.

A microorganism is transformed to be capable of producing guanidinoacetic acid (GAA). A method can be used for the fermentative production of GAA using such a microorganism. A corresponding method can be used for the fermentative production of creatine.

The present disclosure relates to a novel polypeptide having an ability to export an ornithine-based product, and a method for producing an ornithine-based product using the same.

The present invention provides, among other things, methods of formulating nucleic acid-containing nanoparticles with an enzyme to afford efficient delivery of payload to a cell or tissue of interest via subcutaneous administration. In some embodiments, the present invention provides a process in which mRNA-loaded lipid nanoparticles are co-mixed with various amounts of hyaluronidase and administered via subcutaneous administration. The resulting payload can be efficiently delivered to the liver and other organs or tissues of a treated subject.

The present invention provides, in part, cyclic amino acid lipid compounds of formula (A′), and sub-formulas thereof or a pharmaceutically acceptable salt thereof. The compounds provided herein can be useful for delivery and expression of mRNA and encoded protein, e.g., as a component of liposomal delivery vehicle, and accordingly can be useful for treating various diseases, disorders and conditions, such as those associated with deficiency of one or more proteins.

##STR00001##

The present disclosure is directed to compositions and methods for the treatment of Metabolic Liver Disorders. The compositions and methods can comprise an adeno-associated virus (AAV) piggyBac polynucleotide comprising a transgene. The transgene may comprise ornithine transcarbamylase (OTC) or methylmalonyl-CoA mutase (MUT1).

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.

Compositions for modulating the expression of a protein in a target cell comprising at least one RNA molecule which comprises at least one modification 5 conferring stability to the RNA, as well as related methods, are disclosed.