Polynucleotides encoding phenylalanine hydroxylase for the treatment of phenylketonuria

Abstract

This disclosure relates to mRNA therapy for the treatment of phenylketonuria. mRNAs for use in the invention, when administered in vivo, encode phenylalanine hydroxylase. mRNA therapies of the disclosure increase and / or restore deficient levels of phenylalanine hydroxylase expression and / or activity in subjects.

Description

[0001] Attorney Docket No.45817-0152WO1 / MTX975.20 POLYNUCLEOTIDES ENCODING PHENYLALANINE HYDROXYLASE FOR THE TREATMENT OF PHENYLKETONURIA CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority of U.S. Provisional Application No.63 / 538,395, filed on September 14, 2023, the contents of which is incorporated by reference in its entirety herein. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on September 10, 2024, is named 45817- 0152WO1_SL.xml and is 262,015 bytes in size. BACKGROUND Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism that results from a deficiency in the hepatic enzyme phenylalanine hydroxylase (PAH). This disease is found in all ethnic groups and its incidence varies widely around the world with the highest incidence being in Northern Europe. PKU is mainly caused by mutations in the PAH gene that results in decreased catalytic activity affecting the catabolic pathway of phenylalanine (Phe). The PAH enzyme requires the activity of the cofactor tetrahydrobiopterin (BH4) in order to convert Phe to tyrosine (Tyr). A deficiency in either PAH or its cofactor, results in the accumulation of excess phenylalanine. This can result in severe and irreversible intellectual disability if left untreated. Other clinical features associated with untreated PKU include autistic behaviors, motor deficits, eczematous rash, and seizures. Behavioral impairment as well as psychiatric disturbances generally become apparent with age. Currently, there is no cure for PKU. The prevailing treatment is mainly through dietary restriction of Phe to the minimum required for normal growth, supplemented with specifically designed medical foods. However, there are at least four major issues with current dietary treatment: (i) dietary compliance due to unpalatability of the diet; (ii) persisting neurological or psychosocial issues and poor Attorney Docket No.45817-0152WO1 / MTX975.20 quality of life despite early intervention; (iii) potential nutritional deficiencies resulting from restrictive diet; and (iv) financial burden due to the cost of special medical food and dietary supplements. For a subset of patients with hyperphenylalaninemia that have mutations in the cofactor BH4, a synthetic analogue of BH4 called sapropterin is typically used for treatment. One can distinguish between PKU caused by a defect in PAH versus a defect in BH4 by a BH4 loading test. While treatment with synthetic biopterin compounds or sapropterin are generally successful in BH4-responsive PKU patients, for about 90% of patients with classical PKU, who comprise about 50-80% of patients detected by newborn screening (PAHdb; pahdb.mcgill.ca), BH4therapy has no beneficial effects. SUMMARY The present disclosure provides messenger RNA (mRNA) therapeutics for the treatment of PKU. The mRNA therapeutics of the invention are particularly well- suited for the treatment of PKU as the technology provides for the intracellular delivery of mRNA encoding a phenylalanine hydroxylase polypeptide followed by de novo synthesis of functional phenylalanine hydroxylase polypeptide within target cells. In one aspect, the disclosure features a method of treating phenylketonuria in a human subject in need thereof, comprising administering to the human subject by intravenous infusion a lipid nanoparticle comprising a messenger RNA (mRNA) comprising an open reading frame (ORF) encoding the phenylalanine hydroxylase polypeptide of SEQ ID NO:1, wherein the mRNA is administered at a dose of about 0.4 mg / kg to about 1.7 mg / kg. In some embodiments, the ORF is at least 80% identical to the nucleotide sequence of SEQ ID NO:10. In some embodiments, the ORF is at least 95% identical to the nucleotide sequence of SEQ ID NO:10. In some embodiments, the ORF is at least 99% identical to the nucleotide sequence of SEQ ID NO:10. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the ORF is 100% identical to the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA comprises a 5' UTR comprising the nucleotide sequence of SEQ ID NO:56. In some embodiments, the mRNA comprises a 3' UTR comprising the nucleotide sequence of SEQ ID NO:108. In some embodiments, the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA comprises a 5′ terminal cap. In some embodiments, the 5' terminal cap comprises m7G-ppp-Gm. In some embodiments, the mRNA comprises a poly-A region. In some embodiments, the poly-A region comprises SEQ ID NO:195. In some embodiments, the poly-A region comprises A100-UCUAG-A20-inverted deoxy-thymidine (SEQ ID NO:211). In some embodiments, all of the uracils of the mRNA are N1- methylpseudouracils. In some embodiments, the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered at a dose of about 0.4 mg / kg. In some embodiments, the mRNA is administered at a dose of about 0.5 mg / kg. In some embodiments, the mRNA is administered at a dose of about 0.6 mg / kg. In some embodiments, the mRNA is administered at a dose of about 0.7 mg / kg. In some embodiments, the mRNA is administered at a dose of about 0.8 mg / kg. In some embodiments, the mRNA is administered at a dose of about 0.9 mg / kg. In some embodiments, the mRNA is administered at a dose of about 1.0 mg / kg. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the mRNA is administered at a dose of about 1.1 mg / kg. In some embodiments, the mRNA is administered at a dose of about 1.2 mg / kg. In some embodiments, the mRNA is administered at a dose of about 1.3 mg / kg. In some embodiments, the mRNA is administered at a dose of about 1.4 mg / kg. In some embodiments, the mRNA is administered at a dose of about 1.5 mg / kg. In some embodiments, the mRNA is administered at a dose of about 1.6 mg / kg. In some embodiments, the mRNA is administered at a dose of about 1.7 mg / kg. In some embodiments, the mRNA is administered at a dose of about 0.4 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered at a dose of about 0.5 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered at a dose of about 0.6 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered at a dose of about 0.7 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered at a dose of about 0.8 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered at a dose of about 0.9 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered at a dose of about 1.0 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered at a dose of about 1.1 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered at a dose of about 1.2 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the mRNA is administered at a dose of about 1.3 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered at a dose of about 1.4 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered at a dose of about 1.5 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered at a dose of about 1.6 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered at a dose of about 1.7 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered at a dose of about 0.4 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered at a dose of about 0.5 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered at a dose of about 0.6 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered at a dose of about 0.7 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered at a dose of about 0.8 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered at a dose of about 0.9 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered at a dose of about 1.0 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered at a dose of about 1.1 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered at a dose of about 1.2 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered at a dose of about 1.3 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered at a dose of about 1.4 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the mRNA is administered at a dose of about 1.5 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered at a dose of about 1.6 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered at a dose of about 1.7 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered at a dose of about 0.4 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered at a dose of about 0.5 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered at a dose of about 0.6 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered at a dose of about 0.7 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered at a dose of about 0.8 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered at a dose of about 0.9 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered at a dose of about 1.0 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered at a dose of about 1.1 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered at a dose of about 1.2 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered at a dose of about 1.3 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered at a dose of about 1.4 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered at a dose of about 1.5 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered at a dose of about 1.6 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the mRNA is administered at a dose of about 1.7 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the method comprises multiple administrations of the dose. In some embodiments, the dose is administered repeatedly at intervals of about once every 1 to 4 weeks. In some embodiments, the dose is administered repeatedly at intervals of about once every week. In some embodiments, the dose is administered repeatedly at intervals of about once every 2 weeks. In some embodiments, the dose is administered repeatedly at intervals of about once every 3 weeks. In some embodiments, the dose is administered repeatedly at intervals of about once every 4 weeks. In some embodiments, the mRNA is administered once every week at a dose of about 0.4 mg / kg. In some embodiments, the mRNA is administered once every week at a dose of about 0.5 mg / kg. In some embodiments, the mRNA is administered once every week at a dose of about 0.6 mg / kg. In some embodiments, the mRNA is administered once every week at a dose of about 0.7 mg / kg. In some embodiments, the mRNA is administered once every week at a dose of about 0.8 mg / kg. In some embodiments, the mRNA is administered once every week at a dose of about 0.9 mg / kg. In some embodiments, the mRNA is administered once every week at a dose of about 1.0 mg / kg. In some embodiments, the mRNA is administered once every week at a dose of about 1.1 mg / kg. In some embodiments, the mRNA is administered once every week at a dose of about 1.2 mg / kg. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the mRNA is administered once every week at a dose of about 1.3 mg / kg. In some embodiments, the mRNA is administered once every week at a dose of about 1.4 mg / kg. In some embodiments, the mRNA is administered once every week at a dose of about 1.5 mg / kg. In some embodiments, the mRNA is administered once every week at a dose of about 1.6 mg / kg. In some embodiments, the mRNA is administered once every week at a dose of about 1.7 mg / kg. In some embodiments, the mRNA is administered once every week at a dose of about 0.4 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every week at a dose of about 0.5 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every week at a dose of about 0.6 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every week at a dose of about 0.7 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every week at a dose of about 0.8 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every week at a dose of about 0.9 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every week at a dose of about 1.0 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the mRNA is administered once every week at a dose of about 1.1 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every week at a dose of about 1.2 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every week at a dose of about 1.3 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every week at a dose of about 1.4 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every week at a dose of about 1.5 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every week at a dose of about 1.6 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every week at a dose of about 1.7 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every week at a dose of about 0.4 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every week at a dose of about 0.5 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every week at a dose of about 0.6 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the mRNA is administered once every week at a dose of about 0.7 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every week at a dose of about 0.8 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every week at a dose of about 0.9 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every week at a dose of about 1.0 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every week at a dose of about 1.1 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every week at a dose of about 1.2 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every week at a dose of about 1.3 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every week at a dose of about 1.4 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every week at a dose of about 1.5 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every week at a dose of about 1.6 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the mRNA is administered once every week at a dose of about 1.7 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every week at a dose of about 0.4 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every week at a dose of about 0.5 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every week at a dose of about 0.6 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every week at a dose of about 0.7 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every week at a dose of about 0.8 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every week at a dose of about 0.9 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every week at a dose of about 1.0 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every week at a dose of about 1.1 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every week at a dose of about 1.2 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the mRNA is administered once every week at a dose of about 1.3 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every week at a dose of about 1.4 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every week at a dose of about 1.5 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every week at a dose of about 1.6 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every week at a dose of about 1.7 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.4 mg / kg. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.5 mg / kg. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.6 mg / kg. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.7 mg / kg. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.8 mg / kg. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.9 mg / kg. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.0 mg / kg. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.1 mg / kg. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.2 mg / kg. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.3 mg / kg. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.4 mg / kg. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.5 mg / kg. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.6 mg / kg. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.7 mg / kg. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.4 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.5 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.6 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.7 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.8 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.9 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.0 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.1 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.2 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.3 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.4 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.5 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.6 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.7 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.4 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.5 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.6 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.7 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.8 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.9 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.0 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.1 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.2 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.3 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.4 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.5 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.6 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.7 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:11. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.4 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.5 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.6 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.7 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.8 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 0.9 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.0 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.1 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.2 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.3 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.4 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.5 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.6 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the mRNA is administered once every 2 weeks at a dose of about 1.7 mg / kg, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:12. In some embodiments, the human subject is at least 18 years of age. In some embodiments, phenylketonuria in the human subject is confirmed by a genetic test identifying a mutation in the phenylalanine hydroxylase gene. In some embodiments, the human subject does not have a BH4 deficiency or a DNAJC12 deficiency. In some embodiments, prior to treatment the human subject has blood phenylalanine levels of at least 360 μmol / L. In some embodiments, prior to treatment the human subject has blood phenylalanine levels of at least 600 μmol / L. In some embodiments, the treatment reduces blood phenylalanine levels from baseline. In some embodiments, the treatment increases blood tyrosine levels from baseline. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the human subject is administered at least one of an H2-receptor blocker, an H1-receptor blocker, or acetaminophen / paracetamol or ibuprofen prior to infusion of the lipid nanoparticle. In some embodiments, the human subject is administered an H2-receptor blocker, an H1-receptor blocker, and acetaminophen / paracetamol or ibuprofen prior to infusion of the lipid nanoparticle. In some embodiments, the lipid nanoparticle comprises a compound of Formula (I): ; wherein denotes a point of attachment; are each independently selected from the group consisting of H, C2-12alkyl, and C2-12alkenyl; R2and R3are each independently selected from the group consisting of C1-14 alkyl and C2-14 alkenyl; R4is selected from the group consisting of -(CH2)nOH, wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, , wherein denotes a point R10is N(R)2; each R is independently selected from the group consisting of C1-6alkyl, C2-3alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R5is independently selected from the group consisting of C1-3 alkyl, C2-3 alkenyl, and H; Attorney Docket No.45817-0152WO1 / MTX975.20 each R6is independently selected from the group consisting of C1-3 alkyl, C2-3alkenyl, and H; M and M’ are each independently selected from the group consisting of - C(O)O- and -OC(O)-; R’ is a C1-12alkyl or C2-12alkenyl; l is selected from the group consisting of 1, 2, 3, 4, and 5; and m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13. In some embodiments, the lipid nanoparticle further comprises a phospholipid, a structural lipid, and a PEG-lipid. In some embodiments, the compound of Formula (I) is Compound II. In some embodiments, the phospholipid is DSPC. In some embodiments, the structural lipid is cholesterol. In some embodiments, the PEG-lipid is Compound I. In some embodiments, the lipid nanoparticle comprises: (i) 40-50 mol% of the compound of Formula (I), 30-45 mol% of the structural lipid, 5-15 mol% of the phospholipid, and 1-5 mol% of the PEG-lipid; or (ii) 45-50 mol% of the compound of Formula (I), 35-45 mol% of the structural lipid, 8-12 mol% of the phospholipid, and 1.5 to 3.5 mol% of the PEG-lipid. In some embodiments, the lipid nanoparticle comprises: (i) Compound II, (ii) cholesterol, and (iii) PEG-DMG or Compound I; (i) Compound VI, (ii) cholesterol, and (iii) PEG-DMG or Compound I; (i) Compound II, (ii) DSPC or DOPE, (iii) cholesterol, and (iv) PEG-DMG or Compound I; (i) Compound VI, (ii) DSPC or DOPE, (iii) cholesterol, and (iv) PEG-DMG or Compound I; (i) Compound II, (ii) cholesterol, and (iii) Compound I; (i) Compound II, (ii) DSPC or DOPE, (iii) cholesterol, and (iv) Compound I; (i) Compound B, (ii) cholesterol, and (iii) PEG-DMG or Compound I; (i) Compound B, (ii) DSPC or DOPE, (iii) cholesterol, and (iv) PEG-DMG or Compound I; (i) Compound B, (ii) cholesterol, and (iii) Compound I; Attorney Docket No.45817-0152WO1 / MTX975.20 (i) Compound B, (ii) DSPC or DOPE, (iii) cholesterol, and (iv) Compound I; (i) Compound A, (ii) cholesterol, and (iii) PEG-DMG or Compound I; (i) Compound A, (ii) DSPC or DOPE, (iii) cholesterol, and (iv) PEG-DMG or Compound I; (i) Compound A, (ii) cholesterol, and (iii) Compound I; or (i) Compound A, (ii) DSPC or DOPE, (iii) cholesterol, and (iv) Compound I. In some embodiments, the lipid nanoparticle comprises Compound II and Compound I. In some embodiments, the lipid nanoparticle comprises Compound II, DSPC, cholesterol, and Compound I. BRIEF DESCRIPTION OF THE DRAWINGS Fig.1A is a graph depicting mean (± SD) serum concentrations of PAH- mRNA at baseline and 6, 24, 48, 72, 96, and 168 hours postdose in PAHenu2mice treated with a single intravenous dose of LNP1 (triangle – mRNA at 0.25 mg / kg; square - mRNA at 0.5 mg / kg; circle – mRNA at 1.0 mg / kg). Fig.1B is a graph depicting mean (± SD) liver concentrations of PAH-mRNA at baseline and 6, 24, 48, 72, 96, and 168 hours postdose in PAHenu2mice treated with a single intravenous dose of LNP1 (triangle – mRNA at 0.25 mg / kg; square - mRNA at 0.5 mg / kg; circle – mRNA at 1.0 mg / kg). Fig.1C is a graph depicting mean (± SD) liver concentrations of PAH-protein at baseline and 6, 24, 48, 72, 96, and 168 hours postdose in PAHenu2mice treated with a single intravenous dose of LNP1 (triangle – mRNA at 0.25 mg / kg; square - mRNA at 0.5 mg / kg; circle – mRNA at 1.0 mg / kg). Fig.1D is a graph depicting mean (± SD) blood Phe levels at baseline and 6, 24, 48, 72, 96, and 168 hours postdose in PAHenu2mice treated with a single intravenous dose of LNP1 (circle – saline control, with highest Phe levels at 6, 24, 48, 72, and 96 hours; triangle – mRNA at 0.25 mg / kg; square - mRNA at 0.5 mg / kg; circle, with lowest Phe levels at 6, 24, 48, 72, and 96 hours – mRNA at 1.0 mg / kg). Attorney Docket No.45817-0152WO1 / MTX975.20 Fig.2 is a graph depicting the predicted relationship between PAH-mRNA dose and blood Phe levels at steady state after weekly dosing. Solid lines represent the pre-dose levels at steady state (median). Shaded regions represent the 95% prediction interval. DETAILED DESCRIPTION Phenylalanine Hydroxylase (PAH) Phenylalanine hydroxylase (PAH, EC 1.14.16.1) catalyzes the conversion of L-phenylalanine (L-Phe) to L-tyrosine (L-Tyr) by para-hydroxylation of the aromatic side-chain. In mammals, this tetrahydrobiopterin (BH4)-dependent reaction is the initial and rate-limiting step in the degradation of excess L-Phe from dietary proteins, where L-Tyr is further degraded to products that feed into the citric acid cycle. PAH consumes about 75% of the phenylalanine input from the diet and protein catabolism under physiological conditions. PAH is primarily present in the liver, where removal of excess L-Phe prevents the neurotoxic effect of hyperphenylalaninemia (HPA). However, L-Phe is also an essential proteinogenic amino acid so it is important that it is not fully catabolized. To accomplish this dual role of preserving, yet removing excess L-Phe effectively, mammalian PAH has developed several regulatory mechanisms. Mammalian PAH is a homo-tetrameric enzyme of 50 kDa subunits. Each PAH subunit is composed of an N-terminal regulatory domain (residues 1–110), a central catalytic domain (residues 111–410), and a C-terminal oligomerization domain (residues 411–452). The N-terminal regulatory domain is flexibly attached to the catalytic domain via a hinge region (Arg111–Thr117). The regulatory domain is necessary for manifestation of the regulatory properties, such as activation by L-Phe, and there is an ongoing debate as to whether or not it includes an allosteric binding- site for L-Phe. The catalytic domain contains the binding sites for iron, cofactor, and substrate. At the active site iron binds to two histidines (His285 and His290 in hPAH) and a glutamate (Glu330 in hPAH). The oligomerization domain starts by an antiparallel-sheet (residues 411–414, 421–424), responsible for dimerization, Attorney Docket No.45817-0152WO1 / MTX975.20 followed by a 40 Å long-helix (428–452) that mediates tetramerization through domain swapping and antiparallel coiled-coil formation with the other monomers. In humans, mutations in the PAH gene lead to phenylketonuria (PKU), and most mutations are mainly associated with PAH misfolding and instability. There are more than 500 disease-causing mutations (pahdb.mcgill.ca and biopku.org). Dysfunctional PAH leads to increased concentration of L-Phe in the blood and the appearance in urine of metabolites that arise from the transamination of L-Phe to phenylpyruvate. This is the hallmark of the hyperphenylalaninemias (HPAs), of which classic phenylketonuria (PKU) is the most severe form with plasma L-Phe levels greater than 1,200 µM. The accumulation of L-Phe and the subsequent disturbance in brain neurotransmitters leads to neurological symptoms including mental retardation, purposeless movements, and depression. The dietary intake of L-Phe must therefore be strictly controlled in PKU patients. The amino acid sequence of a PAH polypeptide in which the methionine residue at position 180 of human PAH is substituted with threonine (i.e., M180T) is provided in SEQ ID NO:1. This PAH polypeptide (and nucleic acids encoding it) is described in WO 2021 / 247507, the contents of which are incorporated herein by reference in their entirety. In certain aspects, the disclosure provides a polynucleotide (e.g., a RNA, e.g., a mRNA) comprising a nucleotide sequence (e.g., an open reading frame) encoding a PAH polypeptide. In some embodiments, a polynucleotide disclosed herein comprises a sequence encoding the PAH polypeptide of SEQ ID NO:1. Polynucleotides and Open Reading Frames (ORFs) The instant invention features mRNAs for use in treating or preventing a hyperphenylalaninema such as PKU. The mRNAs featured for use in the invention are administered to subjects and encode a PAH protein in vivo. Accordingly, the invention relates to polynucleotides, e.g., mRNA, comprising an open reading frame of linked nucleosides encoding a PAH protein (e.g., SEQ ID NO:1). In some embodiments, the open reading frame is sequence-optimized. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) of the invention comprises a nucleotide sequence (e.g., an ORF) encoding a PAH polypeptide (e.g., SEQ ID NO:1), wherein the nucleotide sequence has at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:10. In some embodiments, the polynucleotide of the invention (e.g., a RNA, e.g., an mRNA) comprises a nucleotide sequence (e.g., an ORF, e.g., SEQ ID NO:10) encoding a PAH polypeptide further comprises a 5′-UTR (e.g., SEQ ID NO:56) and a 3′-UTR (e.g., SEQ ID NO:108). In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) of the invention comprises the sequence of SEQ ID NO:10. In a further embodiment, the polynucleotide (e.g., a RNA, e.g., an mRNA) comprises a 5′ terminal cap (e.g., m7G-ppp-Gm-AG, Cap0, Cap1, ARCA, inosine, N1-methyl- guanosine, 2′-fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino- guanosine, LNA-guanosine, 2-azidoguanosine, Cap2, Cap4, 5′ methylG cap, or an analog thereof) and a poly-A-tail region (e.g., about 100 nucleotides in length (SEQ ID NO:195)). In some embodiments, the mRNA comprises a polyA tail. In some instances, the poly A tail is 50-150 (SEQ ID NO:197), 75-150 (SEQ ID NO:198), 85- 150 (SEQ ID NO:199), 90-120 (SEQ ID NO:193), 90-130 (SEQ ID NO:194), or 90- 150 (SEQ ID NO:192) nucleotides in length. In some instances, the poly A tail is 100 nucleotides in length (SEQ ID NO:195). In some instances, the poly A tail is protected (e.g., with an inverted deoxy-thymidine). In some instances, the poly A tail comprises A100-UCUAG-A20-inverted deoxy-thymidine (SEQ ID NO:211). In some instances, the poly A tail is A100-UCUAG-A20-inverted deoxy-thymidine (SEQ ID NO:211). In some embodiments, the polynucleotide of the invention (e.g., a RNA, e.g., an mRNA) comprises a nucleotide sequence (e.g., an ORF) encoding a PAH polypeptide is single stranded or double stranded. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the polynucleotide of the invention comprising a nucleotide sequence (e.g., an ORF) encoding a PAH polypeptide is DNA or RNA. In some embodiments, the polynucleotide of the invention is RNA. In some embodiments, the polynucleotide of the invention is, or functions as, an mRNA. In some embodiments, the mRNA comprises a nucleotide sequence (e.g., an ORF) that encodes at least one PAH polypeptide, and is capable of being translated to produce the encoded PAH polypeptide in vitro, in vivo, in situ or ex vivo. In some embodiments, the polynucleotide of the invention (e.g., a RNA, e.g., an mRNA) comprises a sequence-optimized nucleotide sequence (e.g., an ORF) encoding a PAH polypeptide, wherein the polynucleotide comprises at least one chemically modified nucleobase, e.g., N1-methylpseudouracil or 5-methoxyuracil. In certain embodiments, all uracils in the polynucleotide are N1-methylpseudouracils. In other embodiments, all uracils in the polynucleotide are 5-methoxyuracils. In some embodiments, the polynucleotide further comprises a miRNA binding site, e.g., a miRNA binding site that binds to miR-142 and / or a miRNA binding site that binds to miR-126. In some embodiments, the polynucleotide (e.g., a RNA, e.g., a mRNA) disclosed herein is formulated with a delivery agent comprising, e.g., a compound having the Formula (I), e.g., Compound II or Compound A; a compound having the Formula (III), (IV), (V), or (VI), e.g., Compound VI or Compound I, or any combination thereof. In some embodiments, the delivery agent comprises an ionizable amino lipid (e.g., Compound II, VI, or A), a helper lipid (e.g., DSPC), a sterol (e.g., Cholesterol), and a PEG lipid (e.g., Compound I or PEG-DMG), e.g., with a mole ratio in the range of about (i) 40-50 mol% ionizable amino lipid (e.g., Compound II, VI, or A), optionally 45-50 mol% ionizable amino lipid, for example, 45-46 mol%, 46-47 mol%, 47-48 mol%, 48-49 mol%, or 49-50 mol% for example about 45 mol%, 45.5 mol%, 46 mol%, 46.5 mol%, 47 mol%, 47.5 mol%, 48 mol%, 48.5 mol%, 49 mol%, or 49.5 mol%; (ii) 30-45 mol% sterol (e.g., cholesterol), optionally 35-42 mol% sterol, for example, 30-31 mol%, 31-32 mol%, 32-33 mol%, 33-34 mol%, 35-35 mol%, 35-36 mol%, 36-37 mol%, 37-38 mol%, 38-39 mol%, or 39-40 mol%, or 40-42 mol% sterol; (iii) 5-15 mol% helper lipid (e.g., DSPC), optionally 10-15 mol% helper lipid, for example, 5-6 mol%, 6-7 mol%, 7-8 mol%, 8- Attorney Docket No.45817-0152WO1 / MTX975.20 9 mol%, 9-10 mol%, 10-11 mol%, 11-12 mol%, 12-13 mol%, 13-14 mol%, or 14-15 mol% helper lipid; and (iv) 1-5% PEG lipid (e.g., Compound I or PEG-DMG), optionally 1-5 mol% PEG lipid, for example 1.5 to 2.5 mol%, 1-2 mol%, 2-3 mol%, 3-4 mol%, or 4-5 mol% PEG lipid. In some embodiments, the polynucleotide of the disclosure is an mRNA that comprises a 5′-terminal cap (e.g., Cap1, e.g., m7Gp-ppGm-A), a 5′UTR (e.g., SEQ ID NO:56), an ORF sequence of SEQ ID NO:10, a 3′UTR (e.g., SEQ ID NO:108), and a poly A tail (e.g., about 100 nt in length, e.g., SEQ ID NO:195), wherein all uracils in the polynucleotide are N1-methylpseudouracils. In some embodiments, the polynucleotide of the disclosure is an mRNA that comprises a 5′-terminal cap (e.g., Cap1, e.g., m7Gp-ppGm-A), a 5′UTR (e.g., any one of SEQ ID NOs:50-79), an ORF sequence of SEQ ID NO:10, a 3′UTR (e.g., any one of SEQ ID NOs:100-136), and a poly A tail (e.g., about 100 nt in length, e.g., SEQ ID NO:195), wherein all uracils in the polynucleotide are N1-methylpseudouracils. In some embodiments, the delivery agent comprises Compound II as the ionizable amino lipid and PEG-DMG or Compound I as the PEG lipid. In some embodiments, the polynucleotide of the disclosure is an mRNA that comprises a 5′-terminal cap (e.g., Cap 1, e.g., m7Gp-ppGm-A), a 5′UTR (e.g., SEQ ID NO:56), an ORF sequence of SEQ ID NO:10, a 3′UTR (e.g., SEQ ID NO:108), and a poly A tail (e.g., about 100 nt in length (SEQ ID NO:195)), wherein all uracils in the polynucleotide are N1-methylpseudouracils. In some embodiments, the delivery agent comprises Compound II or Compound VI as the ionizable amino lipid and PEG-DMG or Compound I as the PEG lipid. In some embodiments, the delivery agent comprises Compound II as the ionizable amino lipid and Compound I as the PEG lipid. In some embodiments, the polynucleotide of the disclosure is an mRNA that comprises an ORF sequence of SEQ ID NO:10. In some embodiments, the polynucleotide of the disclosure is an mRNA that comprises an ORF sequence of SEQ ID NO:10, wherein all uracils in the polynucleotide are N1-methylpseudouracils. In some embodiments, the polynucleotide of the disclosure is an mRNA that comprises an ORF sequence of SEQ ID NO:10, wherein the mRNA is formulated with a delivery agent comprising Compound II as the ionizable amino lipid and Compound I as the PEG lipid. In some embodiments, the polynucleotide of the Attorney Docket No.45817-0152WO1 / MTX975.20 disclosure is an mRNA that comprises an ORF sequence of SEQ ID NO:10, wherein all uracils in the polynucleotide are N1-methylpseudouracils, wherein the mRNA is formulated with a delivery agent comprising Compound II as the ionizable amino lipid and Compound I as the PEG lipid. In some embodiments, the polynucleotide of the disclosure is an mRNA that comprises the sequence of SEQ ID NO:11. In some embodiments, the polynucleotide of the disclosure is an mRNA that comprises the sequence of SEQ ID NO:11, wherein all uracils in the polynucleotide are N1-methylpseudouracils. In some embodiments, the polynucleotide of the disclosure is an mRNA that comprises the sequence of SEQ ID NO:11, wherein the mRNA is formulated with a delivery agent comprising Compound II as the ionizable amino lipid and Compound I as the PEG lipid. In some embodiments, the polynucleotide of the disclosure is an mRNA that comprises the sequence of SEQ ID NO:11, wherein all uracils in the polynucleotide are N1-methylpseudouracils, wherein the mRNA is formulated with a delivery agent comprising Compound II as the ionizable amino lipid and Compound I as the PEG lipid. In some embodiments, the polynucleotide of the disclosure is an mRNA that comprises the sequence of SEQ ID NO:12. In some embodiments, the polynucleotide of the disclosure is an mRNA that comprises the sequence of SEQ ID NO:12, wherein the mRNA is formulated with a delivery agent comprising Compound II as the ionizable amino lipid and Compound I as the PEG lipid. Signal Sequences The polynucleotides (e.g., a RNA, e.g., an mRNA) of the invention can also comprise nucleotide sequences that encode additional features that facilitate trafficking of the encoded polypeptides to therapeutically relevant sites. One such feature that aids in protein trafficking is the signal sequence, or targeting sequence. The peptides encoded by these signal sequences are known by a variety of names, including targeting peptides, transit peptides, and signal peptides. In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) comprises a nucleotide sequence (e.g., an ORF) that encodes a signal peptide operably linked to a nucleotide sequence that encodes a PAH polypeptide described herein. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the "signal sequence" or "signal peptide" is a polynucleotide or polypeptide, respectively, which is from about 30-210, e.g., about 45-80 or 15-60 nucleotides (e.g., about 20, 30, 40, 50, 60, or 70 amino acids) in length that, optionally, is incorporated at the 5′ (or N-terminus) of the coding region or the polypeptide, respectively. Addition of these sequences results in trafficking the encoded polypeptide to a desired site, such as the endoplasmic reticulum or the mitochondria through one or more targeting pathways. Some signal peptides are cleaved from the protein, for example by a signal peptidase after the proteins are transported to the desired site. In some embodiments, the polynucleotide of the invention comprises a nucleotide sequence encoding a PAH polypeptide, wherein the nucleotide sequence further comprises a 5′ nucleic acid sequence encoding a heterologous signal peptide. Sequence-Optimized Nucleotide Sequences Encoding PAH polypeptides In some embodiments, the polynucleotide of the invention comprises a sequence-optimized nucleotide sequence encoding a PAH polypeptide disclosed herein. In some embodiments, the polynucleotide of the invention comprises an open reading frame (ORF) encoding a PAH polypeptide, wherein the ORF has been sequence optimized. An exemplary sequence-optimized nucleotide sequence encoding PAH is set forth as SEQ ID NO:10. A further exemplary sequence-optimized nucleotide sequence encoding PAH is set forth as SEQ ID NO:11. A further exemplary sequence-optimized nucleotide sequence encoding PAH is set forth as SEQ ID NO:12. In some embodiments, the sequence optimized PAH sequences, fragments, and variants thereof are used to practice the methods disclosed herein. In some embodiments, a polynucleotide of the present disclosure, for example a polynucleotide comprising an mRNA nucleotide sequence encoding a PAH polypeptide, comprises from 5′ to 3′ end: (i) a 5′ cap provided herein, for example, Cap1; (ii) a 5′ UTR, such as the sequences provided herein, for example, SEQ ID NO:56; (iii) an open reading frame encoding a PAH polypeptide, e.g., a sequence optimized nucleic acid sequence encoding PAH set forth as SEQ ID NO:10; Attorney Docket No.45817-0152WO1 / MTX975.20 (iv) at least one stop codon (if not present at 5′ terminus of 3′UTR); (v) a 3′ UTR, such as the sequences provided herein, for example, SEQ ID NO:108; and (vi) a poly-A tail provided above. In certain embodiments, all uracils in the polynucleotide are N1-methylpseudouracil. In certain embodiments, all uracils in the polynucleotide are 5-methoxyuracil. The sequence-optimized nucleotide sequences disclosed herein are distinct from the corresponding wild type nucleotide acid sequences and from other known sequence-optimized nucleotide sequences, e.g., these sequence-optimized nucleic acids have unique compositional characteristics. In some embodiments, the percentage of uracil or thymine nucleobases in a sequence-optimized nucleotide sequence (e.g., encoding a PAH polypeptide) is modified (e.g., reduced) with respect to the percentage of uracil or thymine nucleobases in the reference wild-type nucleotide sequence. Such a sequence is referred to as a uracil-modified or thymine-modified sequence. The percentage of uracil or thymine content in a nucleotide sequence can be determined by dividing the number of uracils or thymines in a sequence by the total number of nucleotides and multiplying by 100. In some embodiments, the sequence-optimized nucleotide sequence has a lower uracil or thymine content than the uracil or thymine content in the reference wild-type sequence. In some embodiments, the uracil or thymine content in a sequence-optimized nucleotide sequence of the invention is greater than the uracil or thymine content in the reference wild-type sequence and still maintain beneficial effects, e.g., increased expression and / or reduced Toll-Like Receptor (TLR) response when compared to the reference wild-type sequence. Methods for optimizing codon usage are known in the art. For example, an ORF of any one or more of the sequences provided herein may be codon optimized. Codon optimization, in some embodiments, may be used to match codon frequencies in target and host organisms to ensure proper folding; bias GC content to increase mRNA stability or reduce secondary structures; minimize tandem repeat codons or base runs that may impair gene construction or expression; customize transcriptional and translational control regions; insert or remove protein trafficking sequences; Attorney Docket No.45817-0152WO1 / MTX975.20 remove / add post translation modification sites in encoded protein (e.g., glycosylation sites); add, remove or shuffle protein domains; insert or delete restriction sites; modify ribosome binding sites and mRNA degradation sites; adjust translational rates to allow the various domains of the protein to fold properly; or reduce or eliminate problem secondary structures within the polynucleotide. Codon optimization tools, algorithms and services are known in the art - non-limiting examples include services from GeneArt (Life Technologies), DNA2.0 (Menlo Park CA) and / or proprietary methods. In some embodiments, the open reading frame (ORF) sequence is optimized using optimization algorithms. Identification and Ratio Determination (IDR) Sequences An Identification and Ratio Determination (IDR) sequence is a sequence of a biological molecule (e.g., nucleic acid or protein) that, when combined with the sequence of a target biological molecule, serves to identify the target biological molecule. Typically, an IDR sequence is a heterologous sequence that is incorporated within or appended to a sequence of a target biological molecule and can be used as a reference to identify the target molecule. Thus, in some embodiments, a nucleic acid (e.g., mRNA) comprises (i) a target sequence of interest (e.g., a coding sequence encoding a therapeutic and / or antigenic peptide or protein); and (ii) a unique IDR sequence. An RNA species (e.g., RNA having a given coding sequence) may comprise an IDR sequence that differs from the IDR sequence of other RNA species (e.g., RNA(s) having different coding sequence(s)). Each IDR sequence thus identifies a particular RNA species, and so the abundance of IDR sequences may be measured to determine the abundance of each RNA species in a composition. Use of distinct IDR sequences to identify RNA species allows for analysis of multivalent RNA compositions (e.g., containing multiple RNA species) containing RNA species with similar coding sequences and / or lengths, which could otherwise be difficult to distinguish using PCR- or chromatography-based analysis of full-length RNAs. Each RNA species in a multivalent RNA composition may comprise an IDR sequence that is not a sequence isomer of an IDR sequence of another RNA species in Attorney Docket No.45817-0152WO1 / MTX975.20 a multivalent RNA composition (e.g., the IDR sequence does not have the same number of adenosine nucleotides, the same number of cytosine nucleotides, the same number of guanine nucleotides, and the same number of uracil nucleotides, as another IDR sequence in the composition, even if those sequences have different sequences). Having identical nucleotide compositions causes sequence isomers to have the same mass, presenting a challenge to distinguishing sequence isomers using mass-based identification methods (e.g., mass spectrometry). Each RNA species in a multivalent RNA composition may comprise an IDR sequence having a mass that differs from the mass of IDR sequences of each other RNA species in a multivalent RNA composition. For example, the mass of each IDR sequence may differ from the mass of other IDR sequences by at least 9 Da, at least 25 Da, at least 25 Da, or at least 50 Da. Use of IDR sequences with distinct masses allows RNA fragments comprising different IDR sequences to be distinguished using mass-based analysis methods (e.g., mass spectrometry), which do not require reverse transcription, amplification, or sequencing of RNAs. Each RNA species in an RNA composition may comprises an IDR sequence with a different length. For example, each IDR sequence may have a length independently selected from 0 to 25 nucleotides. The length of a nucleic acid influences the rate at which the nucleic acid traverses a chromatography column, and so the use of IDR sequences of different lengths on different RNA species allows RNA fragments having different IDR sequences to be distinguished using chromatography-based methods (e.g., LC-UV). IDR sequences may be chosen such that no IDR sequence comprises a start codon, ‘AUG’. Lack of a start codon in an IDR sequence prevents undesired translation of nucleotide sequences within and / or downstream from the IDR sequence. IDR sequences may be chosen such that no IDR sequence comprises a recognition site for a restriction enzyme. In one example, no IDR sequence comprises a recognition site for XbaI, ‘UCUAG’. Lack of a recognition site for a restriction enzyme (e.g., XbaI recognition site ‘UCUAG’) allows the restriction enzyme to be used in generating and modifying a DNA template for in vitro transcription, without affecting the IDR sequence or sequence of the transcribed RNA. Attorney Docket No.45817-0152WO1 / MTX975.20 Modified Nucleotide Sequences Encoding PAH polypeptides In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) of the invention comprises a chemically modified nucleobase, for example, a chemically modified uracil, e.g., pseudouracil, N1-methylpseudouracil, 5-methoxyuracil, or the like. In some embodiments, the mRNA is a uracil-modified sequence comprising an ORF encoding a PAH polypeptide, wherein the mRNA comprises a chemically modified nucleobase, for example, a chemically modified uracil, e.g., pseudouracil, N1-methylpseudouracil, or 5-methoxyuracil. In certain aspects of the invention, when the modified uracil base is connected to a ribose sugar, as it is in polynucleotides, the resulting modified nucleoside or nucleotide is referred to as modified uridine. In some embodiments, uracil in the polynucleotide is at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least 90%, at least 95%, at least 99%, or about 100% modified uracil. In one embodiment, uracil in the polynucleotide is at least 95% modified uracil. In another embodiment, uracil in the polynucleotide is 100% modified uracil. In embodiments where uracil in the polynucleotide is at least 95% modified uracil overall uracil content can be adjusted such that an mRNA provides suitable protein expression levels while inducing little to no immune response. In some embodiments, the uracil content of the ORF is between about 100% and about 150%, between about 100% and about 110%, between about 105% and about 115%, between about 110% and about 120%, between about 115% and about 125%, between about 120% and about 130%, between about 125% and about 135%, between about 130% and about 140%, between about 135% and about 145%, between about 140% and about 150% of the theoretical minimum uracil content in the corresponding wild-type ORF (%UTM). In other embodiments, the uracil content of the ORF is between about 121% and about 136% or between 123% and 134% of the %UTM. In some embodiments, the uracil content of the ORF encoding a PAH polypeptide is about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, or about 150% of the %UTM. In this context, the term "uracil" can refer to modified uracil and / or naturally occurring uracil. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the uracil content in the ORF of the mRNA encoding a PAH polypeptide of the invention is less than about 30%, about 25%, about 20%, about 15%, or about 10% of the total nucleobase content in the ORF. In some embodiments, the uracil content in the ORF is between about 10% and about 20% of the total nucleobase content in the ORF. In other embodiments, the uracil content in the ORF is between about 10% and about 25% of the total nucleobase content in the ORF. In one embodiment, the uracil content in the ORF of the mRNA encoding a PAH polypeptide is less than about 20% of the total nucleobase content in the open reading frame. In this context, the term "uracil" can refer to modified uracil and / or naturally occurring uracil. In further embodiments, the ORF of the mRNA encoding a PAH polypeptide having modified uracil and adjusted uracil content has increased Cytosine (C), Guanine (G), or Guanine / Cytosine (G / C) content (absolute or relative). In some embodiments, the overall increase in C, G, or G / C content (absolute or relative) of the ORF is at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 10%, at least about 15%, at least about 20%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 100% relative to the G / C content (absolute or relative) of the wild-type ORF. In some embodiments, the G, the C, or the G / C content in the ORF is less than about 100%, less than about 90%, less than about 85%, or less than about 80% of the theoretical maximum G, C, or G / C content of the corresponding wild type nucleotide sequence encoding the PAH polypeptide (%GTMX; %CTMX, or %G / CTMX). In some embodiments, the increases in G and / or C content (absolute or relative) described herein can be conducted by replacing synonymous codons with low G, C, or G / C content with synonymous codons having higher G, C, or G / C content. In other embodiments, the increase in G and / or C content (absolute or relative) is conducted by replacing a codon ending with U with a synonymous codon ending with G or C. In further embodiments, the ORF of the mRNA encoding a PAH polypeptide of the invention comprises modified uracil and has an adjusted uracil content containing less uracil pairs (UU) and / or uracil triplets (UUU) and / or uracil quadruplets (UUUU) than the corresponding wild-type nucleotide sequence encoding Attorney Docket No.45817-0152WO1 / MTX975.20 the PAH polypeptide. In some embodiments, the ORF of the mRNA encoding a PAH polypeptide of the invention contains no uracil pairs and / or uracil triplets and / or uracil quadruplets. In some embodiments, uracil pairs and / or uracil triplets and / or uracil quadruplets are reduced below a certain threshold, e.g., no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 occurrences in the ORF of the mRNA encoding the PAH polypeptide. In a particular embodiment, the ORF of the mRNA encoding the PAH polypeptide of the invention contains less than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 non-phenylalanine uracil pairs and / or triplets. In another embodiment, the ORF of the mRNA encoding the PAH polypeptide contains no non-phenylalanine uracil pairs and / or triplets. In further embodiments, the ORF of the mRNA encoding a PAH polypeptide of the invention comprises modified uracil and has an adjusted uracil content containing less uracil-rich clusters than the corresponding wild-type nucleotide sequence encoding the PAH polypeptide. In some embodiments, the ORF of the mRNA encoding the PAH polypeptide of the invention contains uracil-rich clusters that are shorter in length than corresponding uracil-rich clusters in the corresponding wild-type nucleotide sequence encoding the PAH polypeptide. In further embodiments, alternative lower frequency codons are employed. At least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% of the codons in the PAH polypeptide–encoding ORF of the modified uracil-comprising mRNA are substituted with alternative codons, each alternative codon having a codon frequency lower than the codon frequency of the substituted codon in the synonymous codon set. The ORF also has adjusted uracil content, as described above. In some embodiments, at least one codon in the ORF of the mRNA encoding the PAH polypeptide is substituted with an alternative codon having a codon frequency lower than the codon frequency of the substituted codon in the synonymous codon set. In some embodiments, the adjusted uracil content, PAH polypeptide-encoding ORF of the modified uracil-comprising mRNA exhibits expression levels of PAH Attorney Docket No.45817-0152WO1 / MTX975.20 when administered to a mammalian cell that are higher than expression levels of PAH from the corresponding wild-type mRNA. In some embodiments, the mammalian cell is a mouse cell, a rat cell, or a rabbit cell. In other embodiments, the mammalian cell is a monkey cell or a human cell. In some embodiments, the human cell is a HeLa cell, a BJ fibroblast cell, or a peripheral blood mononuclear cell (PBMC). In some embodiments, PAH is expressed at a level higher than expression levels of PAH from the corresponding wild-type mRNA when the mRNA is administered to a mammalian cell in vivo. In some embodiments, the mRNA is administered to mice, rabbits, rats, monkeys, or humans. In one embodiment, mice are null mice. In some embodiments, the mRNA is administered intravenously or intramuscularly. In other embodiments, the PAH polypeptide is expressed when the mRNA is administered to a mammalian cell in vitro. In some embodiments, the expression is increased by at least about 2- fold, at least about 5-fold, at least about 10-fold, at least about 50-fold, at least about 500-fold, at least about 1500-fold, or at least about 3000-fold. In other embodiments, the expression is increased by at least about 10%, about 20%, about 30%, about 40%, about 50%, 60%, about 70%, about 80%, about 90%, or about 100%. In some embodiments, adjusted uracil content, PAH polypeptide-encoding ORF of the modified uracil-comprising mRNA exhibits increased stability. In some embodiments, the mRNA exhibits increased stability in a cell relative to the stability of a corresponding wild-type mRNA under the same conditions. In some embodiments, the mRNA exhibits increased stability including resistance to nucleases, thermal stability, and / or increased stabilization of secondary structure. In some embodiments, increased stability exhibited by the mRNA is measured by determining the half-life of the mRNA (e.g., in a plasma, serum, cell, or tissue sample) and / or determining the area under the curve (AUC) of the protein expression by the mRNA over time (e.g., in vitro or in vivo). An mRNA is identified as having increased stability if the half-life and / or the AUC is greater than the half-life and / or the AUC of a corresponding wild-type mRNA under the same conditions. In some embodiments, the mRNA of the present invention induces a detectably lower immune response (e.g., innate or acquired) relative to the immune response induced by a corresponding wild-type mRNA under the same conditions. In other embodiments, the mRNA of the present disclosure induces a detectably lower Attorney Docket No.45817-0152WO1 / MTX975.20 immune response (e.g., innate or acquired) relative to the immune response induced by an mRNA that encodes for a PAH polypeptide but does not comprise modified uracil under the same conditions, or relative to the immune response induced by an mRNA that encodes for a PAH polypeptide and that comprises modified uracil but that does not have adjusted uracil content under the same conditions. The innate immune response can be manifested by increased expression of pro-inflammatory cytokines, activation of intracellular PRRs (RIG-I, MDA5, etc.), cell death, and / or termination or reduction in protein translation. In some embodiments, a reduction in the innate immune response can be measured by expression or activity level of Type 1 interferons (e.g., IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ) or the expression of interferon-regulated genes such as the toll-like receptors (e.g., TLR7 and TLR8), and / or by decreased cell death following one or more administrations of the mRNA of the invention into a cell. In some embodiments, the expression of Type-1 interferons by a mammalian cell in response to the mRNA of the present disclosure is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.9%, or greater than 99.9% relative to a corresponding wild-type mRNA, to an mRNA that encodes a PAH polypeptide but does not comprise modified uracil, or to an mRNA that encodes a PAH polypeptide and that comprises modified uracil but that does not have adjusted uracil content. In some embodiments, the interferon is IFN-β. In some embodiments, cell death frequency caused by administration of mRNA of the present disclosure to a mammalian cell is 10%, 25%, 50%, 75%, 85%, 90%, 95%, or over 95% less than the cell death frequency observed with a corresponding wild-type mRNA, an mRNA that encodes for a PAH polypeptide but does not comprise modified uracil, or an mRNA that encodes for a PAH polypeptide and that comprises modified uracil but that does not have adjusted uracil content. In some embodiments, the mammalian cell is a BJ fibroblast cell. In other embodiments, the mammalian cell is a splenocyte. In some embodiments, the mammalian cell is that of a mouse or a rat. In other embodiments, the mammalian cell is that of a human. In one embodiment, the mRNA of the present disclosure does not substantially induce an innate immune response of a mammalian cell into which the mRNA is introduced. Attorney Docket No.45817-0152WO1 / MTX975.20 Methods for Modifying Polynucleotides The disclosure includes modified polynucleotides comprising a polynucleotide described herein (e.g., a polynucleotide, e.g. mRNA, comprising a nucleotide sequence encoding a PAH polypeptide). The modified polynucleotides can be chemically modified and / or structurally modified. When the polynucleotides of the present invention are chemically and / or structurally modified the polynucleotides can be referred to as "modified polynucleotides." The present disclosure provides for modified nucleosides and nucleotides of a polynucleotide (e.g., RNA polynucleotides, such as mRNA polynucleotides) encoding a PAH polypeptide. A "nucleoside" refers to a compound containing a sugar molecule (e.g., a pentose or ribose) or a derivative thereof in combination with an organic base (e.g., a purine or pyrimidine) or a derivative thereof (also referred to herein as "nucleobase"). A “nucleotide" refers to a nucleoside including a phosphate group. Modified nucleotides can be synthesized by any useful method, such as, for example, chemically, enzymatically, or recombinantly, to include one or more modified or non- natural nucleosides. Polynucleotides can comprise a region or regions of linked nucleosides. Such regions can have variable backbone linkages. The linkages can be standard phosphodiester linkages, in which case the polynucleotides would comprise regions of nucleotides. The modified polynucleotides disclosed herein can comprise various distinct modifications. In some embodiments, the modified polynucleotides contain one, two, or more (optionally different) nucleoside or nucleotide modifications. In some embodiments, a modified polynucleotide, introduced to a cell can exhibit one or more desirable properties, e.g., improved protein expression, reduced immunogenicity, or reduced degradation in the cell, as compared to an unmodified polynucleotide. In some embodiments, a polynucleotide of the present invention (e.g., a polynucleotide comprising a nucleotide sequence encoding a PAH polypeptide) is structurally modified. As used herein, a "structural" modification is one in which two or more linked nucleosides are inserted, deleted, duplicated, inverted or randomized in a polynucleotide without significant chemical modification to the nucleotides themselves. Because chemical bonds will necessarily be broken and reformed to Attorney Docket No.45817-0152WO1 / MTX975.20 effect a structural modification, structural modifications are of a chemical nature and hence are chemical modifications. However, structural modifications will result in a different sequence of nucleotides. For example, the polynucleotide "ATCG" can be chemically modified to "AT-5meC-G". The same polynucleotide can be structurally modified from "ATCG" to "ATCCCG". Here, the dinucleotide "CC" has been inserted, resulting in a structural modification to the polynucleotide. Therapeutic compositions of the present disclosure comprise, in some embodiments, at least one nucleic acid (e.g., RNA) having an open reading frame encoding PAH (e.g., SEQ ID NO:10), wherein the nucleic acid comprises nucleotides and / or nucleosides that can be standard (unmodified) or modified as is known in the art. In some embodiments, nucleotides and nucleosides of the present disclosure comprise modified nucleotides or nucleosides. Such modified nucleotides and nucleosides can be naturally-occurring modified nucleotides and nucleosides or non- naturally occurring modified nucleotides and nucleosides. Such modifications can include those at the sugar, backbone, or nucleobase portion of the nucleotide and / or nucleoside as are recognized in the art. In some embodiments, a naturally-occurring modified nucleotide or nucleotide of the disclosure is one as is generally known or recognized in the art. Non-limiting examples of such naturally occurring modified nucleotides and nucleotides can be found, inter alia, in the widely recognized MODOMICS database. In some embodiments, a non-naturally occurring modified nucleotide or nucleoside of the disclosure is one as is generally known or recognized in the art. Non-limiting examples of such non-naturally occurring modified nucleotides and nucleosides can be found, inter alia, in published US application Nos. PCT / US2012 / 058519; PCT / US2013 / 075177; PCT / US2014 / 058897; PCT / US2014 / 058891; PCT / US2014 / 070413; PCT / US2015 / 36773; PCT / US2015 / 36759; PCT / US2015 / 36771; or PCT / IB2017 / 051367 all of which are incorporated by reference herein. In some embodiments, at least one RNA (e.g., mRNA) of the present disclosure is not chemically modified and comprises the standard ribonucleotides consisting of adenosine, guanosine, cytosine and uridine. In some embodiments, nucleotides and nucleosides of the present disclosure comprise standard nucleoside Attorney Docket No.45817-0152WO1 / MTX975.20 residues such as those present in transcribed RNA (e.g. A, G, C, or U). In some embodiments, nucleotides and nucleosides of the present disclosure comprise standard deoxyribonucleosides such as those present in DNA (e.g. dA, dG, dC, or dT). Hence, nucleic acids of the disclosure (e.g., DNA nucleic acids and RNA nucleic acids, such as mRNA nucleic acids) can comprise standard nucleotides and nucleosides, naturally-occurring nucleotides and nucleosides, non-naturally-occurring nucleotides and nucleosides, or any combination thereof. Nucleic acids of the disclosure (e.g., DNA nucleic acids and RNA nucleic acids, such as mRNA nucleic acids), in some embodiments, comprise various (more than one) different types of standard and / or modified nucleotides and nucleosides. In some embodiments, a particular region of a nucleic acid contains one, two or more (optionally different) types of standard and / or modified nucleotides and nucleosides. In some embodiments, a modified RNA nucleic acid (e.g., a modified mRNA nucleic acid), introduced to a cell or organism, exhibits reduced degradation in the cell or organism, respectively, relative to an unmodified nucleic acid comprising standard nucleotides and nucleosides. In some embodiments, a modified RNA nucleic acid (e.g., a modified mRNA nucleic acid), introduced into a cell or organism, may exhibit reduced immunogenicity in the cell or organism, respectively (e.g., a reduced innate response) relative to an unmodified nucleic acid comprising standard nucleotides and nucleosides. Nucleic acids (e.g., RNA nucleic acids, such as mRNA nucleic acids), in some embodiments, comprise non-natural modified nucleotides that are introduced during synthesis or post-synthesis of the nucleic acids to achieve desired functions or properties. The modifications may be present on internucleotide linkages, purine or pyrimidine bases, or sugars. The modification may be introduced with chemical synthesis or with a polymerase enzyme at the terminal of a chain or anywhere else in the chain. Any of the regions of a nucleic acid may be chemically modified. The present disclosure provides for modified nucleosides and nucleotides of a nucleic acid (e.g., RNA nucleic acids, such as mRNA nucleic acids). A “nucleoside” refers to a compound containing a sugar molecule (e.g., a pentose or ribose) or a derivative thereof in combination with an organic base (e.g., a purine or pyrimidine) Attorney Docket No.45817-0152WO1 / MTX975.20 or a derivative thereof (also referred to herein as “nucleobase”). A “nucleotide” refers to a nucleoside, including a phosphate group. Modified nucleotides may by synthesized by any useful method, such as, for example, chemically, enzymatically, or recombinantly, to include one or more modified or non-natural nucleosides. Nucleic acids can comprise a region or regions of linked nucleosides. Such regions may have variable backbone linkages. The linkages can be standard phosphodiester linkages, in which case the nucleic acids would comprise regions of nucleotides. Modified nucleotide base pairing encompasses not only the standard adenosine-thymine, adenosine-uracil, or guanosine-cytosine base pairs, but also base pairs formed between nucleotides and / or modified nucleotides comprising non- standard or modified bases, wherein the arrangement of hydrogen bond donors and hydrogen bond acceptors permits hydrogen bonding between a non-standard base and a standard base or between two complementary non-standard base structures, such as, for example, in those nucleic acids having at least one chemical modification. One example of such non-standard base pairing is the base pairing between the modified nucleotide inosine and adenine, cytosine or uracil. Any combination of base / sugar or linker may be incorporated into nucleic acids of the present disclosure. In some embodiments, modified nucleobases in nucleic acids (e.g., RNA nucleic acids, such as mRNA nucleic acids) comprise N1-methyl-pseudouridine (m1ψ), 1-ethyl-pseudouridine (e1ψ), 5-methoxy-uridine (mo5U), 5-methyl-cytidine (m5C), and / or pseudouridine (ψ). In some embodiments, modified nucleobases in nucleic acids (e.g., RNA nucleic acids, such as mRNA nucleic acids) comprise 5- methoxymethyl uridine, 5-methylthio uridine, 1-methoxymethyl pseudouridine, 5- methyl cytidine, and / or 5-methoxy cytidine. In some embodiments, the polyribonucleotide includes a combination of at least two (e.g., 2, 3, 4 or more) of any of the aforementioned modified nucleobases, including but not limited to chemical modifications. In some embodiments, a RNA nucleic acid of the disclosure comprises N1- methyl-pseudouridine (m1ψ) substitutions at one or more or all uridine positions of the nucleic acid. In some embodiments, a RNA nucleic acid of the disclosure comprises N1- methyl-pseudouridine (m1ψ) substitutions at one or more or all uridine positions of Attorney Docket No.45817-0152WO1 / MTX975.20 the nucleic acid and 5-methyl cytidine substitutions at one or more or all cytidine positions of the nucleic acid. In some embodiments, a RNA nucleic acid of the disclosure comprises pseudouridine (ψ) substitutions at one or more or all uridine positions of the nucleic acid. In some embodiments, a RNA nucleic acid of the disclosure comprises pseudouridine (ψ) substitutions at one or more or all uridine positions of the nucleic acid and 5-methyl cytidine substitutions at one or more or all cytidine positions of the nucleic acid. In some embodiments, a RNA nucleic acid of the disclosure comprises uridine at one or more or all uridine positions of the nucleic acid. In some embodiments, nucleic acids (e.g., RNA nucleic acids, such as mRNA nucleic acids) are uniformly modified (e.g., fully modified, modified throughout the entire sequence) for a particular modification. For example, a nucleic acid can be uniformly modified with N1-methyl-pseudouridine, meaning that all uridine residues in the mRNA sequence are replaced with N1-methyl-pseudouridine. Similarly, a nucleic acid can be uniformly modified for any type of nucleoside residue present in the sequence by replacement with a modified residue such as those set forth above. The nucleic acids of the present disclosure may be partially or fully modified along the entire length of the molecule. For example, one or more or all or a given type of nucleotide (e.g., purine or pyrimidine, or any one or more or all of A, G, U, C) may be uniformly modified in a nucleic acid of the disclosure, or in a predetermined sequence region thereof (e.g., in the mRNA including or excluding the polyA tail). In some embodiments, all nucleotides X in a nucleic acid of the present disclosure (or in a sequence region thereof) are modified nucleotides, wherein X may be any one of nucleotides A, G, U, C, or any one of the combinations A+G, A+U, A+C, G+U, G+C, U+C, A+G+U, A+G+C, G+U+C or A+G+C. The nucleic acid may contain from about 1% to about 100% modified nucleotides (either in relation to overall nucleotide content, or in relation to one or more types of nucleotide, i.e., any one or more of A, G, U or C) or any intervening percentage (e.g., from 1% to 20%, from 1% to 25%, from 1% to 50%, from 1% to 60%, from 1% to 70%, from 1% to 80%, from 1% to 90%, from 1% to 95%, from Attorney Docket No.45817-0152WO1 / MTX975.20 10% to 20%, from 10% to 25%, from 10% to 50%, from 10% to 60%, from 10% to 70%, from 10% to 80%, from 10% to 90%, from 10% to 95%, from 10% to 100%, from 20% to 25%, from 20% to 50%, from 20% to 60%, from 20% to 70%, from 20% to 80%, from 20% to 90%, from 20% to 95%, from 20% to 100%, from 50% to 60%, from 50% to 70%, from 50% to 80%, from 50% to 90%, from 50% to 95%, from 50% to 100%, from 70% to 80%, from 70% to 90%, from 70% to 95%, from 70% to 100%, from 80% to 90%, from 80% to 95%, from 80% to 100%, from 90% to 95%, from 90% to 100%, and from 95% to 100%). It will be understood that any remaining percentage is accounted for by the presence of unmodified A, G, U, or C. The nucleic acids may contain at a minimum 1% and at maximum 100% modified nucleotides, or any intervening percentage, such as at least 5% modified nucleotides, at least 10% modified nucleotides, at least 25% modified nucleotides, at least 50% modified nucleotides, at least 80% modified nucleotides, or at least 90% modified nucleotides. For example, the nucleic acids may contain a modified pyrimidine such as a modified uracil or cytosine. In some embodiments, at least 5%, at least 10%, at least 25%, at least 50%, at least 80%, at least 90% or 100% of the uracil in the nucleic acid is replaced with a modified uracil (e.g., a 5-substituted uracil). The modified uracil can be replaced by a compound having a single unique structure, or can be replaced by a plurality of compounds having different structures (e.g., 2, 3, 4 or more unique structures). In some embodiments, at least 5%, at least 10%, at least 25%, at least 50%, at least 80%, at least 90% or 100% of the cytosine in the nucleic acid is replaced with a modified cytosine (e.g., a 5-substituted cytosine). The modified cytosine can be replaced by a compound having a single unique structure, or can be replaced by a plurality of compounds having different structures (e.g., 2, 3, 4 or more unique structures). Untranslated Regions (UTRs) Untranslated regions (UTRs) are nucleic acid sections of a polynucleotide before a start codon (5′ UTR) and after a stop codon (3′ UTR) that are not translated. In some embodiments, a polynucleotide (e.g., a ribonucleic acid (RNA), e.g., a messenger RNA (mRNA)) of the invention comprising an open reading frame (ORF) Attorney Docket No.45817-0152WO1 / MTX975.20 encoding a PAH polypeptide further comprises UTR (e.g., a 5′ UTR or functional fragment thereof, a 3′ UTR or functional fragment thereof, or a combination thereof). A UTR (e.g., 5′ UTR or 3′ UTR) can be homologous or heterologous to the coding region in a polynucleotide. In some embodiments, the UTR is homologous to the ORF encoding the PAH polypeptide. In some embodiments, the UTR is heterologous to the ORF encoding the PAH polypeptide. In some embodiments, the polynucleotide comprises two or more 5′ UTRs or functional fragments thereof, each of which has the same or different nucleotide sequences. In some embodiments, the polynucleotide comprises two or more 3′ UTRs or functional fragments thereof, each of which has the same or different nucleotide sequences. In some embodiments, the 5′ UTR or functional fragment thereof, 3′ UTR or functional fragment thereof, or any combination thereof is sequence optimized. In some embodiments, the 5′UTR or functional fragment thereof, 3′ UTR or functional fragment thereof, or any combination thereof comprises at least one chemically modified nucleobase, e.g., N1-methylpseudouracil or 5-methoxyuracil. UTRs can have features that provide a regulatory role, e.g., increased or decreased stability, localization and / or translation efficiency. A polynucleotide comprising a UTR can be administered to a cell, tissue, or organism, and one or more regulatory features can be measured using routine methods. In some embodiments, a functional fragment of a 5′ UTR or 3′ UTR comprises one or more regulatory features of a full length 5′ or 3′ UTR, respectively. Natural 5′ UTRs bear features that play roles in translation initiation. They harbor signatures like Kozak sequences that are commonly known to be involved in the process by which the ribosome initiates translation of many genes. Kozak sequences have the consensus CCR(A / G)CCAUGG, where R is a purine (adenine or guanine) three bases upstream of the start codon (AUG), which is followed by another ‘G’.5′ UTRs also have been known to form secondary structures that are involved in elongation factor binding. By engineering the features typically found in abundantly expressed genes of specific target organs, one can enhance the stability and protein production of a polynucleotide. For example, introduction of 5′ UTR of liver-expressed mRNA, such Attorney Docket No.45817-0152WO1 / MTX975.20 as albumin, serum amyloid A, Apolipoprotein A / B / E, transferrin, alpha fetoprotein, erythropoietin, or Factor VIII, can enhance expression of polynucleotides in hepatic cell lines or liver. Likewise, use of 5′UTR from other tissue-specific mRNA to improve expression in that tissue is possible for muscle (e.g., MyoD, Myosin, Myoglobin, Myogenin, Herculin), for endothelial cells (e.g., Tie-1, CD36), for myeloid cells (e.g., C / EBP, AML1, G-CSF, GM-CSF, CD11b, MSR, Fr-1, i-NOS), for leukocytes (e.g., CD45, CD18), for adipose tissue (e.g., CD36, GLUT4, ACRP30, adiponectin) and for lung epithelial cells (e.g., SP-A / B / C / D). In some embodiments, UTRs are selected from a family of transcripts whose proteins share a common function, structure, feature or property. For example, an encoded polypeptide can belong to a family of proteins (i.e., that share at least one function, structure, feature, localization, origin, or expression pattern), which are expressed in a particular cell, tissue or at some time during development. The UTRs from any of the genes or mRNA can be swapped for any other UTR of the same or different family of proteins to create a new polynucleotide. In some embodiments, the 5′ UTR and the 3′ UTR can be heterologous. In some embodiments, the 5′ UTR can be derived from a different species than the 3′ UTR. In some embodiments, the 3′ UTR can be derived from a different species than the 5′ UTR. Co-owned International Patent Application No. PCT / US2014 / 021522 (Publ. No. WO / 2014 / 164253, incorporated herein by reference in its entirety) provides a listing of exemplary UTRs that can be utilized in the polynucleotide of the present invention as flanking regions to an ORF. Additional exemplary UTRs of the application include, but are not limited to, one or more 5′UTR and / or 3′UTR derived from the nucleic acid sequence of: a globin, such as an α- or β-globin (e.g., a Xenopus, mouse, rabbit, or human globin); a strong Kozak translational initiation signal; a CYBA (e.g., human cytochrome b-245 α polypeptide); an albumin (e.g., human albumin7); a HSD17B4 (hydroxysteroid (17-β) dehydrogenase); a virus (e.g., a tobacco etch virus (TEV), a Venezuelan equine encephalitis virus (VEEV), a Dengue virus, a cytomegalovirus (CMV) (e.g., CMV immediate early 1 (IE1)), a hepatitis virus (e.g., hepatitis B virus), a sindbis virus, or a PAV barley yellow dwarf virus); a heat shock protein (e.g., hsp70); a translation Attorney Docket No.45817-0152WO1 / MTX975.20 initiation factor (e.g., elF4G); a glucose transporter (e.g., hGLUT1 (human glucose transporter 1)); an actin (e.g., human α or β actin); a GAPDH; a tubulin; a histone; a citric acid cycle enzyme; a topoisomerase (e.g., a 5′UTR of a TOP gene lacking the 5′ TOP motif (the oligopyrimidine tract)); a ribosomal protein Large 32 (L32); a ribosomal protein (e.g., human or mouse ribosomal protein, such as, for example, rps9); an ATP synthase (e.g., ATP5A1 or the β subunit of mitochondrial H+-ATP synthase); a growth hormone e (e.g., bovine (bGH) or human (hGH)); an elongation factor (e.g., elongation factor 1 α1 (EEF1A1)); a manganese superoxide dismutase (MnSOD); a myocyte enhancer factor 2A (MEF2A); a β-F1-ATPase, a creatine kinase, a myoglobin, a granulocyte-colony stimulating factor (G-CSF); a collagen (e.g., collagen type I, alpha 2 (Col1A2), collagen type I, alpha 1 (Col1A1), collagen type VI, alpha 2 (Col6A2), collagen type VI, alpha 1 (Col6A1)); a ribophorin (e.g., ribophorin I (RPNI)); a low density lipoprotein receptor-related protein (e.g., LRP1); a cardiotrophin-like cytokine factor (e.g., Nnt1); calreticulin (Calr); a procollagen- lysine, 2-oxoglutarate 5-dioxygenase 1 (Plod1); and a nucleobindin (e.g., Nucb1). In some embodiments, the 5′ UTR is selected from the group consisting of a β-globin 5′ UTR; a 5′UTR containing a strong Kozak translational initiation signal; a cytochrome b-245 α polypeptide (CYBA) 5′ UTR; a hydroxysteroid (17-β) dehydrogenase (HSD17B4) 5′ UTR; a Tobacco etch virus (TEV) 5′ UTR; a Venezuelen equine encephalitis virus (TEEV) 5′ UTR; a 5′ proximal open reading frame of rubella virus (RV) RNA encoding nonstructural proteins; a Dengue virus (DEN) 5′ UTR; a heat shock protein 70 (Hsp70) 5′ UTR; a eIF4G 5′ UTR; a GLUT1 5′ UTR; functional fragments thereof and any combination thereof. In some embodiments, the 3′ UTR is selected from the group consisting of a β-globin 3′ UTR; a CYBA 3′ UTR; an albumin 3′ UTR; a growth hormone (GH) 3′ UTR; a VEEV 3′ UTR; a hepatitis B virus (HBV) 3′ UTR; α-globin 3′UTR; a DEN 3′ UTR; a PAV barley yellow dwarf virus (BYDV-PAV) 3′ UTR; an elongation factor 1 α1 (EEF1A1) 3′ UTR; a manganese superoxide dismutase (MnSOD) 3′ UTR; a β subunit of mitochondrial H(+)-ATP synthase (β-mRNA) 3′ UTR; a GLUT13′ UTR; a MEF2A 3′ UTR; a β-F1-ATPase 3′ UTR; functional fragments thereof and combinations thereof. Attorney Docket No.45817-0152WO1 / MTX975.20 Wild-type UTRs derived from any gene or mRNA can be incorporated into the polynucleotides of the invention. In some embodiments, a UTR can be altered relative to a wild type or native UTR to produce a variant UTR, e.g., by changing the orientation or location of the UTR relative to the ORF; or by inclusion of additional nucleotides, deletion of nucleotides, swapping or transposition of nucleotides. In some embodiments, variants of 5′ or 3′ UTRs can be utilized, for example, mutants of wild type UTRs, or variants wherein one or more nucleotides are added to or removed from a terminus of the UTR. Additionally, one or more synthetic UTRs can be used in combination with one or more non-synthetic UTRs. See, e.g., Mandal and Rossi, Nat. Protoc.2013 8(3):568-82, the contents of which are incorporated herein by reference in their entirety. UTRs or portions thereof can be placed in the same orientation as in the transcript from which they were selected or can be altered in orientation or location. Hence, a 5′ and / or 3′ UTR can be inverted, shortened, lengthened, or combined with one or more other 5′ UTRs or 3′ UTRs. In some embodiments, the polynucleotide comprises multiple UTRs, e.g., a double, a triple or a quadruple 5′ UTR or 3′ UTR. For example, a double UTR comprises two copies of the same UTR either in series or substantially in series. For example, a double beta-globin 3′UTR can be used (see US2010 / 0129877, the contents of which are incorporated herein by reference in its entirety). The polynucleotides of the invention can comprise combinations of features. For example, the ORF can be flanked by a 5′UTR that comprises a strong Kozak translational initiation signal and / or a 3′UTR comprising an oligo(dT) sequence for templated addition of a poly-A tail. A 5′UTR can comprise a first polynucleotide fragment and a second polynucleotide fragment from the same and / or different UTRs (see, e.g., US2010 / 0293625, herein incorporated by reference in its entirety). Other non-UTR sequences can be used as regions or subregions within the polynucleotides of the invention. For example, introns or portions of intron sequences can be incorporated into the polynucleotides of the invention. Incorporation of intronic sequences can increase protein production as well as polynucleotide expression levels. In some embodiments, the polynucleotide of the invention Attorney Docket No.45817-0152WO1 / MTX975.20 comprises an internal ribosome entry site (IRES) instead of or in addition to a UTR (see, e.g., Yakubov et al., Biochem. Biophys. Res. Commun.2010394(1):189-193, the contents of which are incorporated herein by reference in their entirety). In some embodiments, the polynucleotide comprises an IRES instead of a 5′ UTR sequence. In some embodiments, the polynucleotide comprises an ORF and a viral capsid sequence. In some embodiments, the polynucleotide comprises a synthetic 5′ UTR in combination with a non-synthetic 3′ UTR. In some embodiments, the UTR can also include at least one translation enhancer polynucleotide, translation enhancer element, or translational enhancer elements (collectively, "TEE," which refers to nucleic acid sequences that increase the amount of polypeptide or protein produced from a polynucleotide. As a non-limiting example, the TEE can be located between the transcription promoter and the start codon. In some embodiments, the 5′ UTR comprises a TEE. In one aspect, a TEE is a conserved element in a UTR that can promote translational activity of a nucleic acid such as, but not limited to, cap-dependent or cap-independent translation. a.5′ UTR sequences 5′ UTR sequences are important for ribosome recruitment to the mRNA and have been reported to play a role in translation (Hinnebusch A, et al., (2016) Science, 352:6292: 1413-6). Disclosed herein, inter alia, is a polynucleotide, e.g., mRNA, comprising an open reading frame encoding a PAH polypeptide (e.g., SEQ ID NO:1), which polynucleotide has a 5′ UTR that confers an increased half-life, increased expression and / or increased activity of the polypeptide encoded by said polynucleotide, or of the polynucleotide itself. In an embodiment, a polynucleotide disclosed herein comprises: (a) a 5′-UTR (e.g., as provided in Table 1 or a variant or fragment thereof); (b) a coding region comprising a stop element (e.g., as described herein); and (c) a 3′-UTR (e.g., as described herein), and LNP compositions comprising the same. In an embodiment, the polynucleotide comprises a 5′-UTR comprising a sequence provided Attorney Docket No.45817-0152WO1 / MTX975.20 in Table 1 or a variant or fragment thereof (e.g., a functional variant or fragment thereof). In an embodiment, the polynucleotide having a 5′ UTR sequence provided in Table 1 or a variant or fragment thereof, has an increase in the half-life of the polynucleotide, e.g., about 1.5-20-fold increase in half-life of the polynucleotide. In an embodiment, the increase in half-life is about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20-fold, or more. In an embodiment, the increase in half life is about 1.5-fold or more. In an embodiment, the increase in half life is about 2- fold or more. In an embodiment, the increase in half life is about 3-fold or more. In an embodiment, the increase in half life is about 4-fold or more. In an embodiment, the increase in half life is about 5-fold or more. In an embodiment, the polynucleotide having a 5′ UTR sequence provided in Table 1 or a variant or fragment thereof, results in an increased level and / or activity, e.g., output, of the polypeptide encoded by the polynucleotide. In an embodiment, the 5′UTR results in about 1.5-20-fold increase in level and / or activity, e.g., output, of the polypeptide encoded by the polynucleotide. In an embodiment, the increase in level and / or activity is about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20-fold, or more. In an embodiment, the increase in level and / or activity is about 1.5-fold or more. In an embodiment, the increase in level and / or activity is about 2- fold or more. In an embodiment, the increase in level and / or activity is about 3-fold or more. In an embodiment, the increase in level and / or activity is about 4-fold or more. In an embodiment, the increase in level and / or activity is about 5-fold or more. In an embodiment, the increase is compared to an otherwise similar polynucleotide which does not have a 5′ UTR, has a different 5′ UTR, or does not have a 5′ UTR described in Table 1 or a variant or fragment thereof. In an embodiment, the increase in half-life of the polynucleotide is measured according to an assay that measures the half-life of a polynucleotide. In an embodiment, the increase in level and / or activity, e.g., output, of the polypeptide encoded by the polynucleotide is measured according to an assay that measures the level and / or activity of a polypeptide. In an embodiment, the 5′ UTR comprises a sequence provided in Table 1 or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity Attorney Docket No.45817-0152WO1 / MTX975.20 to a 5′ UTR sequence provided in Table 1, or a variant or a fragment thereof. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, or SEQ ID NO: 78. In an embodiment, the 5′ UTR comprises the sequence of SEQ ID NO:56. In an embodiment, the 5′ UTR consists of the sequence of SEQ ID NO:56. In an embodiment, a 5′ UTR sequence provided in Table 1 has a first nucleotide which is an A. In an embodiment, a 5′ UTR sequence provided in Table 1 has a first nucleotide which is a G. Table 1: 5′ UTR sequences SEQ ID Sequence Sequence NO AAU U A C AGC UA Attorney Docket No.45817-0152WO1 / MTX975.20 SEQ ID Sequence Sequence NO: name A A C A C n in GGG Attorney Docket No.45817-0152WO1 / MTX975.20 SEQ ID Sequence Sequence NO: name GUGCCGUAAGAAGAA Attorney Docket No.45817-0152WO1 / MTX975.20 SEQ ID Sequence Sequence NO: name AA , embodiment, the variant of SEQ ID NO:50 comprises a nucleic acid sequence of Formula A: G G A A A U C G C A A A A (N2)X(N3)XC U (N4)X(N5)XC G C G U U A G A U U U (N5)x is a uracil and x is an integer from 0 to 5, e.g., wherein x =2 or 3; N6 is a uracil or cytosine; N7is a uracil or guanine; N8 is adenine or guanine and x is an integer from 0 to 1. In an embodiment (N2)xis a uracil and x is 0. In an embodiment (N2)xis a uracil and x is 1. In an embodiment (N2)x is a uracil and x is 2. In an embodiment (N2)xis a uracil and x is 3. In an embodiment, (N2)xis a uracil and x is 4. In an embodiment (N2)x is a uracil and x is 5. In an embodiment, (N3)xis a guanine and x is 0. In an embodiment, (N3)xis a guanine and x is 1. In an embodiment, (N4)xis a cytosine and x is 0. In an embodiment, (N4)xis a cytosine and x is 1. Attorney Docket No.45817-0152WO1 / MTX975.20 In an embodiment (N5)x is a uracil and x is 0. In an embodiment (N5)x is a uracil and x is 1. In an embodiment (N5)xis a uracil and x is 2. In an embodiment (N5)x is a uracil and x is 3. In an embodiment, (N5)x is a uracil and x is 4. In an embodiment (N5)xis a uracil and x is 5. In an embodiment, N6 is a uracil. In an embodiment, N6 is a cytosine. In an embodiment, N7 is a uracil. In an embodiment, N7 is a guanine. In an embodiment, N8 is an adenine and x is 0. In an embodiment, N8 is an adenine and x is 1. In an embodiment, N8 is a guanine and x is 0. In an embodiment, N8 is a guanine and x is 1. In an embodiment, the 5′ UTR comprises a variant of SEQ ID NO:56. In an embodiment, the variant of SEQ ID NO:56 comprises a sequence with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:56. In an embodiment, the variant of SEQ ID NO:56 comprises a sequence with at least 50% identity to SEQ ID NO:56. In an embodiment, the variant of SEQ ID NO:56 comprises a sequence with at least 60% identity to SEQ ID NO:56. In an embodiment, the variant of SEQ ID NO:56 comprises a sequence with at least 70% identity to SEQ ID NO:56. In an embodiment, the variant of SEQ ID NO:56 comprises a sequence with at least 80% identity to SEQ ID NO:56. In an embodiment, the variant of SEQ ID NO:56 comprises a sequence with at least 90% identity to SEQ ID NO:56. In an embodiment, the variant of SEQ ID NO:56 comprises a sequence with at least 95% identity to SEQ ID NO:56. In an embodiment, the variant of SEQ ID NO:56 comprises a sequence with at least 96% identity to SEQ ID NO:56. In an embodiment, the variant of SEQ ID NO:56 comprises a sequence with at least 97% identity to SEQ ID NO:56. In an embodiment, the variant of SEQ ID NO:56 comprises a sequence with at least 98% identity to SEQ ID NO:56. In an embodiment, the variant of SEQ ID NO:56 comprises a sequence with at least 99% identity to SEQ ID NO:56. In an embodiment, the variant of SEQ ID NO:56 comprises a uridine content of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%. In an embodiment, the variant of SEQ ID NO:56 comprises a uridine content of at least 5%. In an embodiment, the variant of SEQ ID NO:56 comprises a uridine content of at least Attorney Docket No.45817-0152WO1 / MTX975.20 10%. In an embodiment, the variant of SEQ ID NO:56 comprises a uridine content of at least 20%. In an embodiment, the variant of SEQ ID NO:56 comprises a uridine content of at least 30%. In an embodiment, the variant of SEQ ID NO:56 comprises a uridine content of at least 40%. In an embodiment, the variant of SEQ ID NO:56 comprises a uridine content of at least 50%. In an embodiment, the variant of SEQ ID NO:56 comprises a uridine content of at least 60%. In an embodiment, the variant of SEQ ID NO:56 comprises a uridine content of at least 70%. In an embodiment, the variant of SEQ ID NO:56 comprises a uridine content of at least 80%. In an embodiment, the variant of SEQ ID NO:56 comprises at least 2, 3, 4, 5, 6 or 7 consecutive uridines (e.g., a polyuridine tract). In an embodiment, the polyuridine tract in the variant of SEQ ID NO:56 comprises at least 1-7, 2-7, 3-7, 4-7, 5-7, 6-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-6, or 3-5 consecutive uridines. In an embodiment, the polyuridine tract in the variant of SEQ ID NO:56 comprises 4 consecutive uridines. In an embodiment, the polyuridine tract in the variant of SEQ ID NO:56 comprises 5 consecutive uridines. In an embodiment, the variant of SEQ ID NO:56 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 polyuridine tracts. In an embodiment, the variant of SEQ ID NO:56 comprises 3 polyuridine tracts. In an embodiment, the variant of SEQ ID NO:56 comprises 4 polyuridine tracts. In an embodiment, the variant of SEQ ID NO:56 comprises 5 polyuridine tracts. In an embodiment, one or more of the polyuridine tracts are adjacent to a different polyuridine tract. In an embodiment, each of, e.g., all, the polyuridine tracts are adjacent to each other, e.g., all of the polyuridine tracts are contiguous. In an embodiment, one or more of the polyuridine tracts are separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 2, 13, 14, 15, 16, 17, 18.19, 20, 30, 40, 50 or 60 nucleotides. In an embodiment, each of, e.g., all of, the polyuridine tracts are separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 2, 13, 14, 15, 16, 17, 18.19, 20, 30, 40, 50 or 60 nucleotides. In an embodiment, a first polyuridine tract and a second polyuridine tract are adjacent to each other. In an embodiment, a subsequent, e.g., third, fourth, fifth, sixth or seventh, eighth, ninth, or tenth, polyuridine tract is separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, Attorney Docket No.45817-0152WO1 / MTX975.20 2, 13, 14, 15, 16, 17, 18.19, 20, 30, 40, 50 or 60 nucleotides from the first polyuridine tract, the second polyuridine tract, or any one of the subsequent polyuridine tracts. In an embodiment, a first polyuridine tract is separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 2, 13, 14, 15, 16, 17, 18.19, 20, 30, 40, 50 or 60 nucleotides from a subsequent polyuridine tract, e.g., a second, third, fourth, fifth, sixth or seventh, eighth, ninth, or tenth polyuridine tract. In an embodiment, one or more of the subsequent polyuridine tracts are adjacent to a different polyuridine tract. In an embodiment, the 5′ UTR comprises a Kozak sequence, e.g., a GCCRCC nucleotide sequence wherein R is an adenine or guanine. In an embodiment, the Kozak sequence is disposed at the 3′ end of the 5′UTR sequence. In an aspect, the polynucleotide (e.g., mRNA) comprising an open reading frame encoding a PAH polypeptide (e.g., SEQ ID NO:1) and comprising a 5′ UTR sequence disclosed herein is formulated as an LNP. In an embodiment, the LNP composition comprises: (i) an ionizable lipid, e.g., an amino lipid; (ii) a sterol or other structural lipid; (iii) a non-cationic helper lipid or phospholipid; and (iv) a PEG-lipid. In another aspect, the LNP compositions of the disclosure are used in a method of treating PKU in a subject. In an aspect, an LNP composition comprising a polynucleotide disclosed herein encoding a PAH polypeptide, e.g., as described herein, can be administered with an additional agent, e.g., as described herein. b.3′ UTR sequences 3′UTR sequences have been shown to influence translation, half-life, and subcellular localization of mRNAs (Mayr C., Cold Spring Harb Persp Biol 2019 Oct 1;11(10):a034728). Disclosed herein, inter alia, is a polynucleotide, e.g., mRNA, comprising an open reading frame encoding a PAH polypeptide (e.g., SEQ ID NO:1), which polynucleotide has a 3′ UTR that confers an increased half-life, increased expression and / or increased activity of the polypeptide encoded by said polynucleotide, or of the polynucleotide itself. In an embodiment, a polynucleotide disclosed herein comprises: (a) a 5′-UTR (e.g., as described herein); (b) a coding region comprising a stop element (e.g., as described herein); and (c) a 3′-UTR (e.g., as provided in Table 2 or a variant Attorney Docket No.45817-0152WO1 / MTX975.20 or fragment thereof), and LNP compositions comprising the same. In an embodiment, the polynucleotide comprises a 3′-UTR comprising a sequence provided in Table 2 or a variant or fragment thereof. In an embodiment, the polynucleotide having a 3′ UTR sequence provided in Table 2 or a variant or fragment thereof, results in an increased half-life of the polynucleotide, e.g., about 1.5-10-fold increase in half-life of the polynucleotide. In an embodiment, the increase in half-life is about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold, or more. In an embodiment, the increase in half-life is about 1.5-fold or more. In an embodiment, the increase in half-life is about 2-fold or more. In an embodiment, the increase in half-life is about 3-fold or more. In an embodiment, the increase in half- life is about 4-fold or more. In an embodiment, the increase in half-life is about 5-fold or more. In an embodiment, the increase in half-life is about 6-fold or more. In an embodiment, the increase in half-life is about 7-fold or more. In an embodiment, the increase in half-life is about 8-fold. In an embodiment, the increase in half-life is about 9-fold or more. In an embodiment, the increase in half-life is about 10-fold or more. In an embodiment, the polynucleotide having a 3′ UTR sequence provided in Table 2 or a variant or fragment thereof, results in a polynucleotide with a mean half- life score of greater than 10. In an embodiment, the polynucleotide having a 3′ UTR sequence provided in Table 2 or a variant or fragment thereof, results in an increased level and / or activity, e.g., output, of the polypeptide encoded by the polynucleotide. In an embodiment, the increase is compared to an otherwise similar polynucleotide which does not have a 3′ UTR, has a different 3′ UTR, or does not have a 3′ UTR of Table 2 or a variant or fragment thereof. In an embodiment, the polynucleotide comprises a 3′ UTR sequence provided in Table 2 or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to a 3′ UTR sequence provided in Table 2, or a fragment thereof. In an embodiment, the 3′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ Attorney Docket No.45817-0152WO1 / MTX975.20 ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114, or SEQ ID NO:115. In an embodiment, the 3′ UTR comprises the sequence of SEQ ID NO:108, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO:108. Table 2: 3′ UTR sequences SEQ Sequence Sequence ID information C U G U G G U A G G C G G A G A A Attorney Docket No.45817-0152WO1 / MTX975.20 SEQ Sequence Sequence ID information G G C G C C G C C G C C U C C U C C C C C Attorney Docket No.45817-0152WO1 / MTX975.20 SEQ Sequence Sequence ID information U G C U G G A U C GUA G U C U G U C C U Attorney Docket No.45817-0152WO1 / MTX975.20 SEQ Sequence Sequence ID information C C U U U C C U U U U U U U U G U G G A A G C A Attorney Docket No.45817-0152WO1 / MTX975.20 SEQ Sequence Sequence ID information C G C U C C U G n an em o ment, t e compr ses a m cro (m ) n ng s te, e.g., as described herein, which binds to a miR present in a human cell. In an embodiment, the 3′ UTR comprises a miRNA binding site of SEQ ID NO:212, SEQ ID NO:174, SEQ ID NO:152 or a combination thereof. In an embodiment, the 3′ UTR comprises a plurality of miRNA binding sites, e.g., 2, 3, 4, 5, 6, 7 or 8 miRNA binding sites. In an embodiment, the plurality of miRNA binding sites comprises the same or different miRNA binding sites. miR122 bs = CAAACACCAUUGUCACACUCCA (SEQ ID NO: 212) miR-142-3p bs = UCCAUAAAGUAGGAAACACUACA (SEQ ID NO: 174) miR-126 bs = CGCAUUAUUACUCACGGUACGA (SEQ ID NO: 152) Regions having a 5′ Cap The disclosure also includes a polynucleotide that comprises both a 5′ Cap and a polynucleotide of the present invention (e.g., a polynucleotide comprising a nucleotide sequence encoding a PAH polypeptide to be expressed). Attorney Docket No.45817-0152WO1 / MTX975.20 The 5′ cap structure of a natural mRNA is involved in nuclear export, increasing mRNA stability and binds the mRNA Cap Binding Protein (CBP), which is responsible for mRNA stability in the cell and translation competency through the association of CBP with poly(A) binding protein to form the mature cyclic mRNA species. The cap further assists the removal of 5′ proximal introns during mRNA splicing. Endogenous mRNA molecules can be 5′-end capped generating a 5′-ppp-5′- triphosphate linkage between a terminal guanosine cap residue and the 5′-terminal transcribed sense nucleotide of the mRNA molecule. This 5′-guanylate cap can then be methylated to generate an N7-methyl-guanylate residue. The ribose sugars of the terminal and / or anteterminal transcribed nucleotides of the 5′ end of the mRNA can optionally also be 2′-O-methylated.5′-decapping through hydrolysis and cleavage of the guanylate cap structure can target a nucleic acid molecule, such as an mRNA molecule, for degradation. In some embodiments, the polynucleotides of the present invention (e.g., a polynucleotide comprising a nucleotide sequence encoding a PAH polypeptide) incorporate a cap moiety. In some embodiments, polynucleotides of the present invention comprise a non-hydrolyzable cap structure preventing decapping and thus increasing mRNA half- life. Because cap structure hydrolysis requires cleavage of 5′-ppp-5′ phosphorodiester linkages, modified nucleotides can be used during the capping reaction. For example, a Vaccinia Capping Enzyme from New England Biolabs (Ipswich, MA) can be used with α-thio-guanosine nucleotides according to the manufacturer's instructions to create a phosphorothioate linkage in the 5′-ppp-5′ cap. Additional modified guanosine nucleotides can be used such as α-methyl-phosphonate and seleno-phosphate nucleotides. Additional modifications include, but are not limited to, 2′-O-methylation of the ribose sugars of 5′-terminal and / or 5′-anteterminal nucleotides of the polynucleotide (as mentioned above) on the 2′-hydroxyl group of the sugar ring. Multiple distinct 5′-cap structures can be used to generate the 5′-cap of a nucleic acid molecule, such as a polynucleotide that functions as an mRNA molecule. Cap analogs, which herein are also referred to as synthetic cap analogs, chemical caps, Attorney Docket No.45817-0152WO1 / MTX975.20 chemical cap analogs, or structural or functional cap analogs, differ from natural (i.e., endogenous, wild-type or physiological) 5′-caps in their chemical structure, while retaining cap function. Cap analogs can be chemically (i.e., non-enzymatically) or enzymatically synthesized and / or linked to the polynucleotides of the invention. For example, the Anti-Reverse Cap Analog (ARCA) cap contains two guanines linked by a 5′-5′-triphosphate group, wherein one guanine contains an N7 methyl group as well as a 3′-O-methyl group (i.e., N7,3′-O-dimethyl-guanosine-5′- triphosphate-5′-guanosine (m7G-3′mppp-G; which can equivalently be designated 3′ O-Me-m7G(5′)ppp(5′)G). The 3′-O atom of the other, unmodified, guanine becomes linked to the 5′-terminal nucleotide of the capped polynucleotide. The N7- and 3′-O- methlyated guanine provides the terminal moiety of the capped polynucleotide. Another exemplary cap is mCAP, which is similar to ARCA but has a 2′-O- methyl group on guanosine (i.e., N7,2′-O-dimethyl-guanosine-5′-triphosphate-5′- guanosine, m7Gm-ppp-G). Another exemplary cap is m7G-ppp-Gm-A (i.e., N7,guanosine-5′-triphosphate- 2′-O-dimethyl-guanosine-adenosine). In some embodiments, the cap is a dinucleotide cap analog. As a non-limiting example, the dinucleotide cap analog can be modified at different phosphate positions with a boranophosphate group or a phosphoroselenoate group such as the dinucleotide cap analogs described in U.S. Patent No. US 8,519,110, the contents of which are herein incorporated by reference in its entirety. In another embodiment, the cap is a cap analog is a N7-(4- chlorophenoxyethyl) substituted dinucleotide form of a cap analog known in the art and / or described herein. Non-limiting examples of a N7-(4-chlorophenoxyethyl) substituted dinucleotide form of a cap analog include a N7-(4-chlorophenoxyethyl)- G(5′)ppp(5′)G and a N7-(4-chlorophenoxyethyl)-m3′-OG(5′)ppp(5′)G cap analog (See, e.g., the various cap analogs and the methods of synthesizing cap analogs described in Kore et al. Bioorganic & Medicinal Chemistry 201321:4570-4574; the contents of which are herein incorporated by reference in its entirety). In another embodiment, a cap analog of the present invention is a 4-chloro / bromophenoxyethyl analog. Polynucleotides of the invention can also be capped post-manufacture (whether IVT or chemical synthesis), using enzymes, in order to generate more Attorney Docket No.45817-0152WO1 / MTX975.20 authentic 5′-cap structures. As used herein, the phrase "more authentic" refers to a feature that closely mirrors or mimics, either structurally or functionally, an endogenous or wild type feature. That is, a "more authentic" feature is better representative of an endogenous, wild-type, natural or physiological cellular function and / or structure as compared to synthetic features or analogs, etc., of the prior art, or which outperforms the corresponding endogenous, wild-type, natural or physiological feature in one or more respects. Non-limiting examples of more authentic 5′cap structures of the present invention are those that, among other things, have enhanced binding of cap binding proteins, increased half-life, reduced susceptibility to 5′ endonucleases and / or reduced 5′decapping, as compared to synthetic 5′cap structures known in the art (or to a wild-type, natural or physiological 5′cap structure). For example, recombinant Vaccinia Virus Capping Enzyme and recombinant 2′-O- methyltransferase enzyme can create a canonical 5′-5′-triphosphate linkage between the 5′-terminal nucleotide of a polynucleotide and a guanine cap nucleotide wherein the cap guanine contains an N7 methylation and the 5′-terminal nucleotide of the mRNA contains a 2′-O-methyl. Such a structure is termed the Cap1 structure. This cap results in a higher translational-competency and cellular stability and a reduced activation of cellular pro-inflammatory cytokines, as compared, e.g., to other 5′cap analog structures known in the art. Cap structures include, but are not limited to, 7mG(5′)ppp(5′)N1pN2p (cap 0), 7mG(5′)ppp(5′)N1mpNp (cap 1), and 7mG(5′)- ppp(5′)N1mpN2mp (cap 2). As a non-limiting example, capping chimeric polynucleotides post- manufacture can be more efficient as nearly 100% of the chimeric polynucleotides can be capped. This is in contrast to ~80% when a cap analog is linked to a chimeric polynucleotide in the course of an in vitro transcription reaction. According to the present invention, 5′ terminal caps can include endogenous caps or cap analogs. According to the present invention, a 5′ terminal cap can comprise a guanine analog. Useful guanine analogs include, but are not limited to, inosine, N1-methyl-guanosine, 2′fluoro-guanosine, 7-deaza-guanosine, 8-oxo- guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine. Also provided herein are exemplary caps including those that can be used in co-transcriptional capping methods for ribonucleic acid (RNA) synthesis, using RNA Attorney Docket No.45817-0152WO1 / MTX975.20 polymerase, e.g., wild type RNA polymerase or variants thereof, e.g., such as those variants described herein. In one embodiment, caps can be added when RNA is produced in a “one-pot” reaction, without the need for a separate capping reaction. Thus, the methods, in some embodiments, comprise reacting a polynucleotide template with an RNA polymerase variant, nucleoside triphosphates, and a cap analog under in vitro transcription reaction conditions to produce RNA transcript. As used here the term “cap” includes the inverted G nucleotide and can comprise one or more additional nucleotides 3’ of the inverted G nucleotide, e.g., 1, 2, 3, or more nucleotides 3’ of the inverted G nucleotide and 5’ to the 5’ UTR, e.g., a 5’ UTR described herein. Exemplary caps comprise a sequence of GG, GA, or GGA, wherein the underlined, italicized G is an in inverted G nucleotide followed by a 5’-5’- triphosphate group. In one embodiment, a cap comprises a compound of formula (I) a ; ring B1 is a modified or unmodified Guanine; Attorney Docket No.45817-0152WO1 / MTX975.20 ring B2 and ring B3 each independently is a nucleobase or a modified nucleobase; X2 is O, S(O)p, NR24 or CR25R26 in which p is 0, 1, or 2; Y0is O or CR6R7; Y1 is O, S(O)n, CR6R7, or NR8, in which n is 0, 1 , or 2; each --- is a single bond or absent, wherein when each --- is a single bond, Yi is O, S(O)n, CR6R7, or NR8; and when each --- is absent, Y1 is void; Y2is (OP(O)R4)min which m is 0, 1, or 2, or -O-(CR40R41)u-Q0-(CR42R43)v-, in which Q0 is a bond, O, S(O)r, NR44, or CR45R46, r is 0, 1 , or 2, and each of u and v independently is 1, 2, 3 or 4; each R2 and R2' independently is halo, LNA, or OR3; each R3independently is H, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl and R3, when being C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, is optionally substituted with one or more of halo, OH and C1-C6alkoxyl that is optionally substituted with one or more OH or OC(O)-C1-C6 alkyl; each R4 and R4' independently is H, halo, C1-C6 alkyl, OH, SH, SeH, or BH3-; each of R6, R7, and R8, independently, is -Q1-T1, in which Q1is a bond or C1- C3 alkyl linker optionally substituted with one or more of halo, cyano, OH and C1-C6 alkoxy, and T1is H, halo, OH, COOH, cyano, or Rs1, in which Rs1is C1-C3alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1- C6 alkoxyl, C(O)O-C1-C6 alkyl, C3-C8 cycloalkyl, C6- C10aryl, NR31R32, (NR31R32R33)+, 4 to 12- membered heterocycloalkyl, or 5- or 6- membered heteroaryl, and Rs1 is optionally substituted with one or more substituents selected from the group consisting of halo, OH, oxo, C1-C6alkyl, COOH, C(O)O-C1- C6 alkyl, cyano, C1-C6 alkoxyl, NR31R32, (NR31R32R33)+, C3-C8 cycloalkyl, C6- C10aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; each of R10, R11, R12, R13 R14, and R15, independently, is -Q2-T2, in which Q2 is a bond or C1-C3alkyl linker optionally substituted with one or more of halo, cyano, OH and C1-C6 alkoxy, and T2 is H, halo, OH, NH2, cyano, NO2, N3, Rs2, or ORs2, in which Rs2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C6-C10aryl, NHC(O)-C1-C6 alkyl, NR31R32, (NR31R32R33)+, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and Rs2is optionally substituted with one or more substituents selected from the group consisting of halo, OH, oxo, C1-C6 alkyl, COOH, Attorney Docket No.45817-0152WO1 / MTX975.20 C(O)O-C1-C6 alkyl, cyano, C1 - C6 alkoxyl, NR31R32, (NR31R32R33)+, C3- C8cycloalkyl, C6-C10aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6- membered heteroaryl; or alternatively R12 together with R14 is oxo, or R13 together with R15is oxo, each of R20, R21, R22, and R23 independently is -Q3-T3, in which Q3 is a bond or C1-C3alkyl linker optionally substituted with one or more of halo, cyano, OH and C1-C6 alkoxy, and T3 is H, halo, OH, NH2, cyano, NO2, N3, RS3, or ORS3, in which RS3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C6-C10aryl, NHC(O)-C1-C6 alkyl, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, 4 to 12- membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and Rs3is optionally substituted with one or more substituents selected from the group consisting of halo, OH, oxo, C1-C6alkyl, COOH, C(O)O-C1-C6alkyl, cyano, C1-C6alkoxyl, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12- membered heterocycloalkyl, and 5- or 6-membered heteroaryl; each of R24, R25, and R26 independently is H or C1-C6 alkyl; each of R27 and R28 independently is H or OR29; or R27 and R28 together form O-R30-O; each R29independently is H, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl and R29, when being C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, is optionally substituted with one or more of halo, OH and C1-C6alkoxyl that is optionally substituted with one or more OH or OC(O)-C1-C6 alkyl; R30is C1-C6alkylene optionally substituted with one or more of halo, OH and C1-C6 alkoxyl; each of R31, R32, and R33, independently is H, C1-C6alkyl, C3-C8cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl; each of R40, R41, R42, and R43independently is H, halo, OH, cyano, N3, OP(O)R47R48, or C1-C6 alkyl optionally substituted with one or more OP(O)R47R48, or one R41and one R43, together with the carbon atoms to which they are attached and Q0, form C4-C10 cycloalkyl, 4- to 14-membered heterocycloalkyl, C6-C10 aryl, or 5- to 14-membered heteroaryl, and each of the cycloalkyl, heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with one or more of OH, halo, cyano, N3, oxo, OP(O)R47R48, C1-C6alkyl, C1-C6haloalkyl, COOH, C(O)O-C1-C6 Attorney Docket No.45817-0152WO1 / MTX975.20 alkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, amino, mono-C1-C6 alkylamino, and di-C1- C6alkylamino; R44 is H, C1-C6 alkyl, or an amine protecting group; each of R45and R46independently is H, OP(O)R47R48, or C1-C6alkyl optionally substituted with one or more OP(O)R47R48, and each of R47and R48, independently is H, halo, C1-C6alkyl, OH, SH, SeH, or BH3. It should be understood that a cap analog, as provided herein, may include any of the cap analogs described in international publication WO 2017 / 066797, published on 20 April 2017, incorporated by reference herein in its entirety. In some embodiments, the B2 middle position can be a non-ribose molecule, such as arabinose. In some embodiments R2 is ethyl-based. Thus, in some embodiments, a cap comprises the following structure:

[0002] Attorney Docket No.45817-0152WO1 / MTX975.20 a cap structure:

[0003] Attorney Docket No.45817-0152WO1 / MTX975.20 R is a methyl group (e.g., C1 alkyl). In some embodiments, R is an ethyl group (e.g., C2alkyl). In some embodiments, a cap comprises a sequence selected from the following sequences: GAA, GAC, GAG, GAU, GCA, GCC, GCG, GCU, GGA , GGC, GGG, GGU, GUA, GUC, GUG, and GUU. In some embodiments, a cap comprises GAA. In some embodiments, a cap comprises GAC. In some embodiments, a cap comprises GAG. In some embodiments, a cap comprises GAU. In some embodiments, a cap comprises GCA. In some embodiments, a cap comprises GCC. In some embodiments, a cap comprises GCG. In some embodiments, a cap comprises GCU. In some embodiments, a cap comprises GGA. In some embodiments, a cap comprises GGC. In some embodiments, a cap comprises GGG. In some embodiments, a cap comprises GGU. In some embodiments, a cap comprises GUA. In some embodiments, a cap comprises GUC. In some embodiments, a cap comprises GUG. In some embodiments, a cap comprises GUU. In some embodiments, a cap comprises a sequence selected from the following sequences: m7GpppApA, m7GpppApC, m7GpppApG, m7GpppApU, m7GpppCpA, m7GpppCpC, m7GpppCpG, m7GpppCpU, m7GpppGpA, m7GpppGpC, m7GpppGpG, m7GpppGpU, m7GpppUpA, m7GpppUpC, m7GpppUpG, and m7GpppUpU. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, a cap comprises m7GpppApA. In some embodiments, a cap comprises m7GpppApC. In some embodiments, a cap comprises m7GpppApG. In some embodiments, a cap comprises m7GpppApU. In some embodiments, a cap comprises m7GpppCpA. In some embodiments, a cap comprises m7GpppCpC. In some embodiments, a cap comprises m7GpppCpG. In some embodiments, a cap comprises m7GpppCpU. In some embodiments, a cap comprises m7GpppGpA. In some embodiments, a cap comprises m7GpppGpC. In some embodiments, a cap comprises m7GpppGpG. In some embodiments, a cap comprises m7GpppGpU. In some embodiments, a cap comprises m7GpppUpA. In some embodiments, a cap comprises m7GpppUpC. In some embodiments, a cap comprises m7GpppUpG. In some embodiments, a cap comprises m7GpppUpU. A cap, in some embodiments, comprises a sequence selected from the following sequences: m7G3 ^OMepppApA, m7G3 ^OMepppApC, m7G3 ^OMepppApG, m7G3 ^OMepppApU, m7G3 ^OMepppCpA, m7G3 ^OMepppCpC, m7G3 ^OMepppCpG, m7G3^OMepppCpU, m7G3^OMepppGpA, m7G3^OMepppGpC, m7G3^OMepppGpG, m7G3^OMepppGpU, m7G3^OMepppUpA, m7G3^OMepppUpC, m7G3^OMepppUpG, and m7G3 ^OMepppUpU. In some embodiments, a cap comprises m7G3 ^OMepppApA. In some embodiments, a cap comprises m7G3^OMepppApC. In some embodiments, a cap comprises m7G3^OMepppApG. In some embodiments, a cap comprises m7G3 ^OMepppApU. In some embodiments, a cap comprises m7G3 ^OMepppCpA. In some embodiments, a cap comprises m7G3 ^OMepppCpC. In some embodiments, a cap comprises m7G3^OMepppCpG. In some embodiments, a cap comprises m7G3^OMepppCpU. In some embodiments, a cap comprises m7G3^OMepppGpA. In some embodiments, a cap comprises m7G3 ^OMepppGpC. In some embodiments, a cap comprises m7G3 ^OMepppGpG. In some embodiments, a cap comprises m7G3^OMepppGpU. In some embodiments, a cap comprises m7G3^OMepppUpA. In some embodiments, a cap comprises m7G3^OMepppUpC. In some embodiments, a cap comprises m7G3 ^OMepppUpG. In some embodiments, a cap comprises m7G3 ^OMepppUpU. Attorney Docket No.45817-0152WO1 / MTX975.20 A cap, in other embodiments, comprises a sequence selected from the following sequences: m7G3 ^OMepppA2 ^OMepA, m7G3 ^OMepppA2 ^OMepC, m7G3^OMepppA2^OMepG, m7G3^OMepppA2^OMepU, m7G3^OMepppC2^OMepA, m7G3^OMepppC2^OMepC, m7G3^OMepppC2^OMepG, m7G3^OMepppC2^OMepU, m7G3 ^OMepppG2 ^OMepA, m7G3 ^OMepppG2 ^OMepC, m7G3 ^OMepppG2 ^OMepG, m7G3 ^OMepppG2 ^OMepU, m7G3 ^OMepppU2 ^OMepA, m7G3 ^OMepppU2 ^OMepC, m7G3^OMepppU2^OMepG, and m7G3^OMepppU2^OMepU. In some embodiments, a cap comprises m7G3^OMepppA2^OMepA. In some embodiments, a cap comprises m7G3 ^OMepppA2 ^OMepC. In some embodiments, a cap comprises m7G3 ^OMepppA2 ^OMepG. In some embodiments, a cap comprises m7G3^OMepppA2^OMepU. In some embodiments, a cap comprises m7G3^OMepppC2^OMepA. In some embodiments, a cap comprises m7G3^OMepppC2^OMepC. In some embodiments, a cap comprises m7G3 ^OMepppC2 ^OMepG. In some embodiments, a cap comprises m7G3 ^OMepppC2 ^OMepU. In some embodiments, a cap comprises m7G3^OMepppG2^OMepA. In some embodiments, a cap comprises m7G3^OMepppG2^OMepC. In some embodiments, a cap comprises m7G3 ^OMepppG2 ^OMepG. In some embodiments, a cap comprises m7G3 ^OMepppG2 ^OMepU. In some embodiments, a cap comprises m7G3^OMepppU2^OMepA. In some embodiments, a cap comprises m7G3^OMepppU2^OMepC. In some embodiments, a cap comprises m7G3 ^OMepppU2 ^OMepG. In some embodiments, a cap comprises m7G3 ^OMepppU2 ^OMepU. A cap, in still other embodiments, comprises a sequence selected from the following sequences: m7GpppA2 ^OMepA, m7GpppA2 ^OMepC, m7GpppA2 ^OMepG, m7GpppA2 ^OMepU, m7GpppC2 ^OMepA, m7GpppC2 ^OMepC, m7GpppC2 ^OMepG, m7GpppC2^OMepU, m7GpppG2^OMepA, m7GpppG2^OMepC, m7GpppG2^OMepG, m7GpppG2^OMepU, m7GpppU2^OMepA, m7GpppU2^OMepC, m7GpppU2^OMepG, and m7GpppU2 ^OMepU. In some embodiments, a cap comprises m7GpppA2 ^OMepA. In some embodiments, a cap comprises m7GpppA2^OMepC. In some embodiments, a cap Attorney Docket No.45817-0152WO1 / MTX975.20 comprises m7GpppA2^OMepG. In some embodiments, a cap comprises m7GpppA2 ^OMepU. In some embodiments, a cap comprises m7GpppC2 ^OMepA. In some embodiments, a cap comprises m7GpppC2 ^OMepC. In some embodiments, a cap comprises m7GpppC2^OMepG. In some embodiments, a trinucleotide cap comprises m7GpppC2^OMepU. In some embodiments, a cap comprises m7GpppG2^OMepA. In some embodiments, a cap comprises m7GpppG2 ^OMepC. In some embodiments, a cap comprises m7GpppG2 ^OMepG. In some embodiments, a cap comprises m7GpppG2^OMepU. In some embodiments, a cap comprises m7GpppU2^OMepA. In some embodiments, a cap comprises m7GpppU2^OMepC. In some embodiments, a cap comprises m7GpppU2 ^OMepG. In some embodiments, a cap comprises m7GpppU2 ^OMepU. In some embodiments, a cap comprises m7Gpppm6A2’OmepG. In some embodiments, a cap comprises m7Gpppe6A2’OmepG. In some embodiments, a cap comprises GAG. In some embodiments, a cap comprises GCG. In some embodiments, a cap comprises GUG. In some embodiments, a cap comprises GGG. In some embodiments, a cap comprises any one of the following structures: or Attorney Docket No.45817-0152WO1 / MTX975.20 . In some embodiments, the cap comprisesm7GpppN1N2N3, where N1, N2, and N3are optional (i.e., can be absent or one or more can be present) and are independently a natural, a modified, or an unnatural nucleoside base. In some embodiments,m7G is further methylated, e.g., at the 3’ position. In some embodiments, them7G comprises an O-methyl at the 3’ position. In some embodiments N1, N2, and N3if present, optionally, are independently an adenine, a uracil, a guanidine, a thymine, or a cytosine. In some embodiments, one or more (or all) of N1, N2, and N3, if present, are methylated, e.g., at the 2’ position. In some embodiments, one or more (or all) of N1, N2, and N3, if present have an O-methyl at the 2’ position. In some embodiments, the cap comprises the following structure: unnatural nucleoside based; and R1, R2, R3, and R4are independently OH or O- methyl. In some embodiments, R3 is O-methyl and R4 is OH. In some embodiments, Attorney Docket No.45817-0152WO1 / MTX975.20 R3 and R4 are O-methyl. In some embodiments, R4 is O-methyl. In some embodiments, R1is OH, R2is OH, R3is O-methyl, and R4is OH. In some embodiments, R1 is OH, R2 is OH, R3 is O-methyl, and R4 is O-methyl. In some embodiments, at least one of R1and R2is O-methyl, R3is O-methyl, and R4is OH. In some embodiments, at least one of R1 and R2 is O-methyl, R3 is O-methyl, and R4 is O-methyl. In some embodiments, B1, B3, and B3 are natural nucleoside bases. In some embodiments, at least one of B1, B2, and B3is a modified or unnatural base. In some embodiments, at least one of B1, B2, and B3 is N6-methyladenine. In some embodiments, B1is adenine, cytosine, thymine, or uracil. In some embodiments, B1is adenine, B2 is uracil, and B3 is adenine. In some embodiments, R1 and R2 are OH, R3and R4are O-methyl, B1is adenine, B2is uracil, and B3is adenine. In some embodiments the cap comprises a sequence selected from the following sequences: GAAA, GACA, GAGA, GAUA, GCAA, GCCA, GCGA, GCUA, GGAA, GGCA, GGGA, GGUA, GUCA, and GUUA. In some embodiments the cap comprises a sequence selected from the following sequences: GAAG, GACG, GAGG, GAUG, GCAG, GCCG, GCGG, GCUG, GGAG, GGCG, GGGG, GGUG, GUCG, GUGG, and GUUG. In some embodiments the cap comprises a sequence selected from the following sequences: GAAU, GACU, GAGU, GAUU, GCAU, GCCU, GCGU, GCUU, GGAU, GGCU, GGGU, GGUU, GUAU, GUCU, GUGU, and GUUU. In some embodiments the cap comprises a sequence selected from the following sequences: GAAC, GACC, GAGC, GAUC, GCAC, GCCC, GCGC, GCUC, GGAC, GGCC, GGGC, GGUC, GUAC, GUCC, GUGC, and GUUC. A cap, in some embodiments, comprises a sequence selected from the following sequences: m7G3 ^OMepppApApN, m7G3 ^OMepppApCpN, m7G3^OMepppApGpN, m7G3^OMepppApUpN, m7G3^OMepppCpApN, m7G3^OMepppCpCpN, m7G3^OMepppCpGpN, m7G3^OMepppCpUpN, m7G3 ^OMepppGpApN, m7G3 ^OMepppGpCpN, m7G3 ^OMepppGpGpN, m7G3^OMepppGpUpN, m7G3^OMepppUpApN, m7G3^OMepppUpCpN, m7G3^OMepppUpGpN, and m7G3^OMepppUpUpN, where N is a natural, a modified, or an unnatural nucleoside base. Attorney Docket No.45817-0152WO1 / MTX975.20 A cap, in other embodiments, comprises a sequence selected from the following sequences: m7G3 ^OMepppA2 ^OMepApN, m7G3 ^OMepppA2 ^OMepCpN, m7G3^OMepppA2^OMepGpN, m7G3^OMepppA2^OMepUpN, m7G3^OMepppC2^OMepApN, m7G3^OMepppC2^OMepCpN, m7G3^OMepppC2^OMepGpN, m7G3^OMepppC2^OMepUpN, m7G3 ^OMepppG2 ^OMepApN, m7G3 ^OMepppG2 ^OMepCpN, m7G3 ^OMepppG2 ^OMepGpN, m7G3 ^OMepppG2 ^OMepUpN, m7G3 ^OMepppU2 ^OMepApN, m7G3 ^OMepppU2 ^OMepCpN, m7G3^OMepppU2^OMepGpN, and m7G3^OMepppU2^OMepUpN, where N is a natural, a modified, or an unnatural nucleoside base. A cap, in still other embodiments, comprises a sequence selected from the following sequences: m7GpppA2^OMepApN, m7GpppA2^OMepCpN, m7GpppA2 ^OMepGpN, m7GpppA2 ^OMepUpN, m7GpppC2 ^OMepApN, m7GpppC2 ^OMepCpN, m7GpppC2 ^OMepGpN, m7GpppC2 ^OMepUpN, m7GpppG2^OMepApN, m7GpppG2^OMepCpN, m7GpppG2^OMepGpN, m7GpppG2^OMepUpN, m7GpppU2^OMepApN, m7GpppU2^OMepCpN, m7GpppU2 ^OMepGpN, and m7GpppU2 ^OMepUpN, where N is a natural, a modified, or an unnatural nucleoside base. A cap, in other embodiments, comprises a sequence selected from the following sequences: m7G3^OMepppA2^OMepA2^OMepN, m7G3^OMepppA2^OMepC2^OMepN, m7G3^OMepppA2^OMepG2^OMepN, m7G3^OMepppA2^OMepU2^OMepN, m7G3 ^OMepppC2 ^OMepA2 ^OMepN, m7G3 ^OMepppC2 ^OMepC2 ^OMepN, m7G3 ^OMepppC2 ^OMepG2 ^OMepN, m7G3 ^OMepppC2 ^OMepU2 ^OMepN, m7G3^OMepppG2^OMepA2^OMepN, m7G3^OMepppG2^OMepC2^OMepN, m7G3^OMepppG2^OMepG2^OMepN, m7G3^OMepppG2^OMepU2^OMepN, m7G3 ^OMepppU2 ^OMepA2 ^OMepN, m7G3 ^OMepppU2 ^OMepC2 ^OMepN, m7G3 ^OMepppU2 ^OMepG2 ^OMepN, and m7G3 ^OMepppU2 ^OMepU2 ^OMepN, where N is a natural, a modified, or an unnatural nucleoside base. A cap, in still other embodiments, comprises a sequence selected from the following sequences: m7GpppA2^OMepA2^OMepN, m7GpppA2^OMepC2^OMepN, m7GpppA2^OMepG2^OMepN, m7GpppA2^OMepU2^OMepN, m7GpppC2^OMepA2^OMepN, m7GpppC2 ^OMepC2 ^OMepN, m7GpppC2 ^OMepG2 ^OMepN, m7GpppC2 ^OMepU2 ^OMepN, Attorney Docket No.45817-0152WO1 / MTX975.20 m7GpppG2^OMepA2^OMepN, m7GpppG2^OMepC2^OMepN, m7GpppG2^OMepG2^OMepN, m7GpppG2 ^OMepU2 ^OMepN, m7GpppU2 ^OMepA2 ^OMepN, m7GpppU2 ^OMepC2 ^OMepN, m7GpppU2 ^OMepG2 ^OMepN, and m7GpppU2 ^OMepU2 ^OMepN, where N is a natural, a modified, or an unnatural nucleoside base. In some embodiments, a cap comprises GGAG. In some embodiments, a cap comprises the following structure: polynucleotide comprising a nucleotide sequence encoding a PAH polypeptide) further comprise a poly-A tail. In further embodiments, terminal groups on the poly-A tail can be incorporated for stabilization. In other embodiments, a poly-A tail comprises des-3′ hydroxyl tails. During RNA processing, a long chain of adenine nucleotides (poly-A tail) can be added to a polynucleotide such as an mRNA molecule in order to increase stability. Immediately after transcription, the 3′ end of the transcript can be cleaved to free a 3′ hydroxyl. Then poly-A polymerase adds a chain of adenine nucleotides to the RNA. The process, called polyadenylation, adds a poly-A tail that can be between, for example, approximately 80 to approximately 250 residues long, including approximately 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, Attorney Docket No.45817-0152WO1 / MTX975.20 220, 230, 240 or 250 residues long. In one embodiment, the poly-A tail is 100 nucleotides in length (SEQ ID NO:195). PolyA tails can also be added after the construct is exported from the nucleus. According to the present invention, terminal groups on the poly A tail can be incorporated for stabilization. Polynucleotides of the present invention can include des-3′ hydroxyl tails. They can also include structural moieties or 2'-Omethyl modifications as taught by Junjie Li, et al. (Current Biology, Vol.15, 1501–1507, August 23, 2005, the contents of which are incorporated herein by reference in its entirety). The polynucleotides of the present invention can be designed to encode transcripts with alternative polyA tail structures including histone mRNA. According to Norbury, "Terminal uridylation has also been detected on human replication- dependent histone mRNAs. The turnover of these mRNAs is thought to be important for the prevention of potentially toxic histone accumulation following the completion or inhibition of chromosomal DNA replication. These mRNAs are distinguished by their lack of a 3ʹ poly(A) tail, the function of which is instead assumed by a stable stem–loop structure and its cognate stem–loop binding protein (SLBP); the latter carries out the same functions as those of PABP on polyadenylated mRNAs" (Norbury, "Cytoplasmic RNA: a case of the tail wagging the dog," Nature Reviews Molecular Cell Biology; AOP, published online 29 August 2013; doi:10.1038 / nrm3645) the contents of which are incorporated herein by reference in its entirety. Unique poly-A tail lengths provide certain advantages to the polynucleotides of the present invention. Generally, the length of a poly-A tail, when present, is greater than 30 nucleotides in length. In another embodiment, the poly-A tail is greater than 35 nucleotides in length (e.g., at least or greater than about 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, and 3,000 nucleotides). In some embodiments, the polynucleotide or region thereof includes from about 30 to about 3,000 nucleotides (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 750, from 30 to 1,000, from 30 to 1,500, from 30 to Attorney Docket No.45817-0152WO1 / MTX975.20 2,000, from 30 to 2,500, from 50 to 100, from 50 to 250, from 50 to 500, from 50 to 750, from 50 to 1,000, from 50 to 1,500, from 50 to 2,000, from 50 to 2,500, from 50 to 3,000, from 100 to 500, from 100 to 750, from 100 to 1,000, from 100 to 1,500, from 100 to 2,000, from 100 to 2,500, from 100 to 3,000, from 500 to 750, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 2,500, from 500 to 3,000, from 1,000 to 1,500, from 1,000 to 2,000, from 1,000 to 2,500, from 1,000 to 3,000, from 1,500 to 2,000, from 1,500 to 2,500, from 1,500 to 3,000, from 2,000 to 3,000, from 2,000 to 2,500, and from 2,500 to 3,000). In some embodiments, the poly-A tail is designed relative to the length of the overall polynucleotide or the length of a particular region of the polynucleotide. This design can be based on the length of a coding region, the length of a particular feature or region or based on the length of the ultimate product expressed from the polynucleotides. In this context, the poly-A tail can be 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% greater in length than the polynucleotide or feature thereof. The poly-A tail can also be designed as a fraction of the polynucleotides to which it belongs. In this context, the poly-A tail can be 10, 20, 30, 40, 50, 60, 70, 80, or 90% or more of the total length of the construct, a construct region or the total length of the construct minus the poly-A tail. Further, engineered binding sites and conjugation of polynucleotides for Poly-A binding protein can enhance expression. Additionally, multiple distinct polynucleotides can be linked together via the PABP (Poly-A binding protein) through the 3′-end using modified nucleotides at the 3′-terminus of the poly-A tail. Transfection experiments can be conducted in relevant cell lines at and protein production can be assayed by ELISA at 12hr, 24hr, 48hr, 72hr and day 7 post-transfection. In some embodiments, the polynucleotides of the present invention are designed to include a polyA-G Quartet region. The G-quartet is a cyclic hydrogen bonded array of four guanine nucleotides that can be formed by G-rich sequences in both DNA and RNA. In this embodiment, the G-quartet is incorporated at the end of the poly-A tail. The resultant polynucleotide is assayed for stability, protein production and other parameters including half-life at various time points. It has been discovered that the polyA-G quartet results in protein production from an mRNA Attorney Docket No.45817-0152WO1 / MTX975.20 equivalent to at least 75% of that seen using a poly-A tail of 120 nucleotides alone (SEQ ID NO:196). In some embodiments, the polyA tail comprises an alternative nucleoside, e.g., inverted thymidine. PolyA tails comprising an alternative nucleoside, e.g., inverted thymidine, may be generated as described herein. For instance, mRNA constructs may be modified by ligation to stabilize the poly(A) tail. Ligation may be performed using 0.5-1.5 mg / mL mRNA (5′ Cap1, 3′ A100), 50 mM Tris-HCl pH 7.5, 10 mM MgCl2, 1 mM TCEP, 1000 units / mL T4 RNA Ligase 1, 1 mM ATP, 20% w / v polyethylene glycol 8000, and 5:1 molar ratio of modifying oligo to mRNA. Modifying oligo has a sequence of 5’-phosphate-AAAAAAAAAAAAAAAAAAAA- (inverted deoxythymidine (idT) (SEQ ID NO:209)) (see below). Ligation reactions are mixed and incubated at room temperature (~22°C) for, e.g., 4 hours. Stable tail mRNA are purified by, e.g., dT purification, reverse phase purification, hydroxyapatite purification, ultrafiltration into water, and sterile filtration. The resulting stable tail-containing mRNAs contain the following structure at the 3’end, starting with the polyA region: A100-UCUAGAAAAAAAAAAAAAAAAAAAA- inverted deoxythymidine (SEQ ID NO:211). Modifying oligo to stabilize tail (5’-phosphate- AAAAAAAAAAAAAAAAAAAA-(inverted deoxythymidine)(SEQ ID NO:209)): UCUAG-A20-inverted deoxy-thymidine (SEQ ID NO:211). In some instances, the polyA tail consists of A100-UCUAG-A20-inverted deoxy-thymidine (SEQ ID NO:211). Attorney Docket No.45817-0152WO1 / MTX975.20 Start codon region The invention also includes a polynucleotide that comprises both a start codon region and the polynucleotide described herein (e.g., a polynucleotide comprising a nucleotide sequence encoding a PAH polypeptide). In some embodiments, the polynucleotides of the present invention can have regions that are analogous to or function like a start codon region. In some embodiments, the translation of a polynucleotide can initiate on a codon that is not the start codon AUG. Translation of the polynucleotide can initiate on an alternative start codon such as, but not limited to, ACG, AGG, AAG, CTG / CUG, GTG / GUG, ATA / AUA, ATT / AUU, TTG / UUG (see Touriol et al. Biology of the Cell 95 (2003) 169-178 and Matsuda and Mauro PLoS ONE, 2010 5:11; the contents of each of which are herein incorporated by reference in its entirety). As a non-limiting example, the translation of a polynucleotide begins on the alternative start codon ACG. As another non-limiting example, polynucleotide translation begins on the alternative start codon CTG or CUG. As yet another non- limiting example, the translation of a polynucleotide begins on the alternative start codon GTG or GUG. Nucleotides flanking a codon that initiates translation such as, but not limited to, a start codon or an alternative start codon, are known to affect the translation efficiency, the length and / or the structure of the polynucleotide. (See, e.g., Matsuda and Mauro PLoS ONE, 20105:11; the contents of which are herein incorporated by reference in its entirety). Masking any of the nucleotides flanking a codon that initiates translation can be used to alter the position of translation initiation, translation efficiency, length and / or structure of a polynucleotide. In some embodiments, a masking agent can be used near the start codon or alternative start codon in order to mask or hide the codon to reduce the probability of translation initiation at the masked start codon or alternative start codon. Non-limiting examples of masking agents include antisense locked nucleic acids (LNA) polynucleotides and exon-junction complexes (EJCs) (See, e.g., Matsuda and Mauro Attorney Docket No.45817-0152WO1 / MTX975.20 describing masking agents LNA polynucleotides and EJCs (PLoS ONE, 20105:11); the contents of which are herein incorporated by reference in its entirety). In another embodiment, a masking agent can be used to mask a start codon of a polynucleotide in order to increase the likelihood that translation will initiate on an alternative start codon. In some embodiments, a masking agent can be used to mask a first start codon or alternative start codon in order to increase the chance that translation will initiate on a start codon or alternative start codon downstream to the masked start codon or alternative start codon. In some embodiments, a start codon or alternative start codon can be located within a perfect complement for a miRNA binding site. The perfect complement of a miRNA binding site can help control the translation, length and / or structure of the polynucleotide similar to a masking agent. As a non-limiting example, the start codon or alternative start codon can be located in the middle of a perfect complement for a miRNA binding site. The start codon or alternative start codon can be located after the first nucleotide, second nucleotide, third nucleotide, fourth nucleotide, fifth nucleotide, sixth nucleotide, seventh nucleotide, eighth nucleotide, ninth nucleotide, tenth nucleotide, eleventh nucleotide, twelfth nucleotide, thirteenth nucleotide, fourteenth nucleotide, fifteenth nucleotide, sixteenth nucleotide, seventeenth nucleotide, eighteenth nucleotide, nineteenth nucleotide, twentieth nucleotide or twenty-first nucleotide. In another embodiment, the start codon of a polynucleotide can be removed from the polynucleotide sequence in order to have the translation of the polynucleotide begin on a codon that is not the start codon. Translation of the polynucleotide can begin on the codon following the removed start codon or on a downstream start codon or an alternative start codon. In a non-limiting example, the start codon ATG or AUG is removed as the first 3 nucleotides of the polynucleotide sequence in order to have translation initiate on a downstream start codon or alternative start codon. The polynucleotide sequence where the start codon was removed can further comprise at least one masking agent for the downstream start codon and / or alternative start codons in order to control or attempt to control the initiation of translation, the length of the polynucleotide and / or the structure of the polynucleotide. Attorney Docket No.45817-0152WO1 / MTX975.20 Stop Codon Region The invention also includes a polynucleotide that comprises both a stop codon region and the polynucleotide described herein (e.g., a polynucleotide comprising a nucleotide sequence encoding a PAH polypeptide). In some embodiments, the polynucleotides of the present invention can include at least two stop codons before the 3′ untranslated region (UTR). The stop codon can be selected from TGA, TAA and TAG in the case of DNA, or from UGA, UAA and UAG in the case of RNA. In some embodiments, the polynucleotides of the present invention include the stop codon TGA in the case or DNA, or the stop codon UGA in the case of RNA, and one additional stop codon. In a further embodiment the addition stop codon can be TAA or UAA. In another embodiment, the polynucleotides of the present invention include three consecutive stop codons, four stop codons, or more. Combination of mRNA elements Any of the polynucleotides disclosed herein can comprise one, two, three, or all of the following elements: (a) a 5’-UTR, e.g., as described herein; (b) a coding region comprising a stop element (e.g., as described herein); (c) a 3’-UTR (e.g., as described herein) and; optionally (d) a 3’ stabilizing region, e.g., as described herein. Also disclosed herein are LNP compositions comprising the same. In an embodiment, a polynucleotide of the disclosure comprises (a) a 5’ UTR described in Table 1 or a variant or fragment thereof and (b) a coding region comprising a stop element provided herein. In an embodiment, the polynucleotide further comprises a cap structure, e.g., as described herein, or a poly A tail, e.g., as described herein. In an embodiment, the polynucleotide further comprises a 3’ stabilizing region, e.g., as described herein. In an embodiment, a polynucleotide of the disclosure comprises (a) a 5’ UTR described in Table 1 or a variant or fragment thereof and (c) a 3’ UTR described in Table 2 or a variant or fragment thereof. In an embodiment, the polynucleotide further comprises a cap structure, e.g., as described herein, or a poly A tail, e.g., as Attorney Docket No.45817-0152WO1 / MTX975.20 described herein. In an embodiment, the polynucleotide further comprises a 3’ stabilizing region, e.g., as described herein. In an embodiment, a polynucleotide of the disclosure comprises (c) a 3’ UTR described in Table 2 or a variant or fragment thereof and (b) a coding region comprising a stop element provided herein. In an embodiment, the polynucleotide comprises a sequence provided in Table 3. In an embodiment, the polynucleotide further comprises a cap structure, e.g., as described herein, or a poly A tail, e.g., as described herein. In an embodiment, the polynucleotide further comprises a 3’ stabilizing region, e.g., as described herein. In an embodiment, a polynucleotide of the disclosure comprises (a) a 5’ UTR described in Table 1 or a variant or fragment thereof; (b) a coding region comprising a stop element provided herein; and (c) a 3’ UTR described in Table 2 or a variant or fragment thereof. In an embodiment, the polynucleotide further comprises a cap structure, e.g., as described herein, or a poly A tail, e.g., as described herein. In an embodiment, the polynucleotide further comprises a 3’ stabilizing region, e.g., as described herein. Table 3: Exemplary 3’ UTR and stop element sequences SEQ ID Sequence NO information Sequence C C A C C A C C A C C A C C Attorney Docket No.45817-0152WO1 / MTX975.20 SEQ ID Sequence NO information Sequence A C C A C C A C C A C C A G C C U A C G A C U C G A C U C C G C U C G Attorney Docket No.45817-0152WO1 / MTX975.20 SEQ ID Sequence NO information Sequence A G A C C A G C U Polynucleotide Comprising an mRNA Encoding a PAH Polypeptide In certain embodiments, a polynucleotide of the present disclosure, for example a polynucleotide comprising an mRNA nucleotide sequence encoding a PAH polypeptide, comprises from 5′ to 3′ end: (i) a 5′ cap such as provided above; (ii) a 5′ UTR, such as the sequences provided above; (iii) an ORF encoding a PAH polypeptide (e.g., SEQ ID NO:1), wherein the ORF has at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO:10; (iv) at least one stop codon; (v) a 3′ UTR, such as the sequences provided above; and (vi) a poly-A tail provided above. In some embodiments, the polynucleotide further comprises a miRNA binding site, e.g., a miRNA binding site that binds to miRNA-142. In some embodiments, the 5′ UTR comprises the miRNA binding site. In some embodiments, the 3′ UTR comprises the miRNA binding site. In some embodiments, a polynucleotide of the present disclosure comprises a nucleotide sequence encoding a polypeptide sequence at least 70%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, Attorney Docket No.45817-0152WO1 / MTX975.20 at least 94%, at least 95%, at least 96% , at least 97%, at least 98%, at least 99%, or 100% identical to a PAH protein sequence having the amino acid sequence of SEQ ID NO:1. In some embodiments, a polynucleotide of the present disclosure, for example a polynucleotide comprising an mRNA nucleotide sequence encoding a polypeptide, comprises (1) a 5′ cap such as provided above, for example, m7Gp-ppGm-A, (2) a 5′ UTR, (3) a nucleotide sequence ORF of SEQ ID NO:10, (3) a stop codon, (4) a 3′UTR, and (5) a poly-A tail provided above, for example, a poly-A tail of SEQ ID NO:195 or A100-UCUAG-A20-inverted deoxy-thymidine (SEQ ID NO:211). An exemplary PAH nucleotide construct is described: SEQ ID NO:11 consists from 5’ to 3’ end: 5' UTR of SEQ ID NO:56, ORF Sequence of SEQ ID NO:10, and 3' UTR of SEQ ID NO:108. In certain embodiments, in a construct with SEQ ID NO:11, all uracils therein are N1-methylpseudouracils. An exemplary PAH nucleotide construct is SEQ ID NO:12. In some embodiments, a polynucleotide of the present disclosure, for example a polynucleotide comprising an mRNA nucleotide sequence encoding a PAH polypeptide, comprises (1) a 5′ cap such as provided above, for example, m7Gp- ppGm-A, (2) a nucleotide sequence of SEQ ID NO:11, and (3) a poly-A tail provided above, for example, a poly A tail of ~100 residues, e.g., SEQ ID NO:195 or A100- UCUAG-A20-inverted deoxy-thymidine (SEQ ID NO:211). In certain embodiments, in constructs with SEQ ID NO:11, all uracils therein are N1-methylpseudouracils. Methods of Making Polynucleotides The present disclosure also provides methods for making a polynucleotide of the invention (e.g., a polynucleotide comprising a nucleotide sequence encoding a PAH polypeptide) or a complement thereof. In some aspects, a polynucleotide (e.g., a RNA, e.g., an mRNA) disclosed herein, and encoding a PAH polypeptide, can be constructed using in vitro transcription (IVT). In other aspects, a polynucleotide (e.g., a RNA, e.g., an mRNA) Attorney Docket No.45817-0152WO1 / MTX975.20 disclosed herein, and encoding a PAH polypeptide, can be constructed by chemical synthesis using an oligonucleotide synthesizer. In other aspects, a polynucleotide (e.g., a RNA, e.g., an mRNA) disclosed herein, and encoding a PAH polypeptide is made by using a host cell. In certain aspects, a polynucleotide (e.g., a RNA, e.g., an mRNA) disclosed herein, and encoding a PAH polypeptide is made by one or more combination of the IVT, chemical synthesis, host cell expression, or any other methods known in the art. Naturally occurring nucleosides, non-naturally occurring nucleosides, or combinations thereof, can totally or partially naturally replace occurring nucleosides present in the candidate nucleotide sequence and can be incorporated into a sequence- optimized nucleotide sequence (e.g., a RNA, e.g., an mRNA) encoding a PAH polypeptide. The resultant polynucleotides, e.g., mRNAs, can then be examined for their ability to produce protein and / or produce a therapeutic outcome. Pharmaceutical Compositions and Formulations The present invention provides pharmaceutical compositions and formulations that comprise any of the polynucleotides described above. In some embodiments, the composition or formulation further comprises a delivery agent. In some embodiments, the composition or formulation can contain a polynucleotide comprising a sequence optimized nucleic acid sequence disclosed herein which encodes a PAH polypeptide. In some embodiments, the composition or formulation can contain a polynucleotide (e.g., a RNA, e.g., an mRNA) comprising a polynucleotide (e.g., an ORF) having significant sequence identity to a sequence optimized nucleic acid sequence disclosed herein which encodes a PAH polypeptide. In some embodiments, the polynucleotide further comprises a miRNA binding site, e.g., a miRNA binding site that binds miR-126, miR-142, miR-144, miR-146, miR- 150, miR-155, miR-16, miR-21, miR-223, miR-24, miR-27 and miR-26a. Pharmaceutical compositions or formulation can optionally comprise one or more additional active substances, e.g., therapeutically and / or prophylactically active substances. Pharmaceutical compositions or formulation of the present invention can be sterile and / or pyrogen-free. General considerations in the formulation and / or Attorney Docket No.45817-0152WO1 / MTX975.20 manufacture of pharmaceutical agents can be found, for example, in Remington: The Science and Practice of Pharmacy 21sted., Lippincott Williams & Wilkins, 2005 (incorporated herein by reference in its entirety). In some embodiments, compositions are administered to humans, human patients or subjects. For the purposes of the present disclosure, the phrase "active ingredient" generally refers to polynucleotides to be delivered as described herein. Formulations and pharmaceutical compositions described herein can be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of associating the active ingredient with an excipient and / or one or more other accessory ingredients, and then, if necessary and / or desirable, dividing, shaping and / or packaging the product into a desired single- or multi-dose unit. A pharmaceutical composition or formulation in accordance with the present disclosure can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. As used herein, a "unit dose" refers to a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject and / or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition in accordance with the present disclosure can vary, depending upon the identity, size, and / or condition of the subject being treated and further depending upon the route by which the composition is to be administered. In some embodiments, the compositions and formulations described herein can contain at least one polynucleotide of the invention. As a non-limiting example, the composition or formulation can contain 1, 2, 3, 4 or 5 polynucleotides of the invention. In some embodiments, the compositions or formulations described herein can comprise more than one type of polynucleotide. In some embodiments, the composition or formulation can comprise a polynucleotide in linear and circular form. In another embodiment, the composition or formulation can comprise a circular polynucleotide and an in vitro transcribed (IVT) polynucleotide. In yet another Attorney Docket No.45817-0152WO1 / MTX975.20 embodiment, the composition or formulation can comprise an IVT polynucleotide, a chimeric polynucleotide and a circular polynucleotide. Although the descriptions of pharmaceutical compositions and formulations provided herein are principally directed to pharmaceutical compositions and formulations that are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to any other animal, e.g., to non-human animals, e.g. non-human mammals. The present invention provides pharmaceutical formulations that comprise a polynucleotide described herein (e.g., a polynucleotide comprising a nucleotide sequence encoding a PAH polypeptide). The polynucleotides described herein can be Formulated using one or more excipients to: (1) increase stability; (2) increase cell transfection; (3) permit the sustained or delayed release (e.g., from a depot formulation of the polynucleotide); (4) alter the biodistribution (e.g., target the polynucleotide to specific tissues or cell types); (5) increase the translation of encoded protein in vivo; and / or (6) alter the release profile of encoded protein in vivo. In some embodiments, the pharmaceutical formulation further comprises a delivery agent comprising, e.g., a compound having the Formula (I), e.g., Compound II, Compound A, or Compound B; or a compound having the Formula (III), (IV), (V), or (VI), e.g., Compound I or VI, or any combination thereof. In some embodiments, the delivery agent comprises an ionizable amino lipid (e.g., Compound II, VI, or A), a helper lipid (e.g., DSPC), a sterol (e.g., Cholesterol), and a PEG lipid (e.g., Compound I or PEG- DMG), e.g., with a mole ratio in the range of about (i) 40-50 mol% ionizable amino lipid (e.g., Compound II, VI, or A), optionally 45-50 mol% ionizable amino lipid, for example, 45-46 mol%, 46-47 mol%, 47-48 mol%, 48-49 mol%, or 49-50 mol% for example about 45 mol%, 45.5 mol%, 46 mol%, 46.5 mol%, 47 mol%, 47.5 mol%, 48 mol%, 48.5 mol%, 49 mol%, or 49.5 mol%; (ii) 30-45 mol% sterol (e.g., cholesterol), optionally 35-42 mol% sterol, for example, 30-31 mol%, 31-32 mol%, 32-33 mol%, 33-34 mol%, 35-35 mol%, 35-36 mol%, 36-37 mol%, 37-38 mol%, 38-39 mol%, or 39-40 mol%, or 40-42 mol% sterol; (iii) 5-15 mol% helper lipid (e.g., DSPC), optionally 10-15 mol% helper lipid, for example, 5-6 mol%, 6-7 mol%, 7-8 mol%, 8- 9 mol%, 9-10 mol%, 10-11 mol%, 11-12 mol%, 12-13 mol%, 13-14 mol%, or 14-15 mol% helper lipid; and (iv) 1-5% PEG lipid (e.g., Compound I or PEG-DMG), Attorney Docket No.45817-0152WO1 / MTX975.20 optionally 1-5 mol% PEG lipid, for example 1.5 to 2.5 mol%, 1-2 mol%, 2-3 mol%, 3-4 mol%, or 4-5 mol% PEG lipid. A pharmaceutically acceptable excipient, as used herein, includes, but are not limited to, any and all solvents, dispersion media, or other liquid vehicles, dispersion or suspension aids, diluents, granulating and / or dispersing agents, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, binders, lubricants or oil, coloring, sweetening or flavoring agents, stabilizers, antioxidants, antimicrobial or antifungal agents, osmolality adjusting agents, pH adjusting agents, buffers, chelants, cyoprotectants, and / or bulking agents, as suited to the particular dosage form desired. Various excipients for Formulating pharmaceutical compositions and techniques for preparing the composition are known in the art (see Remington: The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, MD, 2006; incorporated herein by reference in its entirety). Exemplary diluents include, but are not limited to, calcium or sodium carbonate, calcium phosphate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, etc., and / or combinations thereof. Exemplary surface active agents and / or emulsifiers include, but are not limited to, natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monooleate [TWEEN®80], sorbitan monopalmitate [SPAN®40], glyceryl monooleate, polyoxyethylene esters, polyethylene glycol fatty acid esters (e.g., CREMOPHOR®), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether [BRIJ®30]), PLUORINC®F 68, POLOXAMER®188, etc. and / or combinations thereof. Exemplary binding agents include, but are not limited to, starch, gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol), amino acids (e.g., glycine), natural and synthetic gums (e.g., acacia, sodium alginate), ethylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, etc., and combinations thereof. Attorney Docket No.45817-0152WO1 / MTX975.20 Oxidation is a potential degradation pathway for mRNA, especially for liquid mRNA formulations. In order to prevent oxidation, antioxidants can be added to the formulations. Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, ascorbyl palmitate, benzyl alcohol, butylated hydroxyanisole, m-cresol, methionine, butylated hydroxytoluene, monothioglycerol, sodium or potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, etc., and combinations thereof. Exemplary chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, trisodium edetate, etc., and combinations thereof. Exemplary antimicrobial or antifungal agents include, but are not limited to, benzalkonium chloride, benzethonium chloride, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, benzoic acid, hydroxybenzoic acid, potassium or sodium benzoate, potassium or sodium sorbate, sodium propionate, sorbic acid, etc., and combinations thereof. Exemplary preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, ascorbic acid, butylated hydroxyanisol, ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), etc., and combinations thereof. In some embodiments, the pH of polynucleotide solutions is maintained between pH 5 and pH 8 to improve stability. Exemplary buffers to control pH can include, but are not limited to sodium phosphate, sodium citrate, sodium succinate, histidine (or histidine-HCl), sodium malate, sodium carbonate, etc., and / or combinations thereof. Exemplary lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium or magnesium lauryl sulfate, etc., and combinations thereof. The pharmaceutical composition or formulation described here can contain a cryoprotectant to stabilize a polynucleotide described herein during freezing. Attorney Docket No.45817-0152WO1 / MTX975.20 Exemplary cryoprotectants include, but are not limited to mannitol, sucrose, trehalose, lactose, glycerol, dextrose, etc., and combinations thereof. The pharmaceutical composition or formulation described here can contain a bulking agent in lyophilized polynucleotide formulations to yield a "pharmaceutically elegant" cake, stabilize the lyophilized polynucleotides during long term (e.g., 36 month) storage. Exemplary bulking agents of the present invention can include, but are not limited to sucrose, trehalose, mannitol, glycine, lactose, raffinose, and combinations thereof. In some embodiments, the pharmaceutical composition or formulation further comprises a delivery agent. The delivery agent of the present disclosure can include, without limitation, liposomes, lipid nanoparticles, lipidoids, polymers, lipoplexes, microvesicles, exosomes, peptides, proteins, cells transfected with polynucleotides, hyaluronidase, nanoparticle mimics, nanotubes, conjugates, and combinations thereof. Delivery Agents Lipid Compound The present disclosure provides pharmaceutical compositions with advantageous properties. The lipid compositions described herein may be advantageously used in lipid nanoparticle compositions for the delivery of therapeutic and / or prophylactic agents, e.g., mRNAs, to mammalian cells or organs. For example, the lipids described herein have little or no immunogenicity. For example, the lipid compounds disclosed herein have a lower immunogenicity as compared to a reference lipid (e.g., MC3, KC2, or DLinDMA). For example, a formulation comprising a lipid disclosed herein and a therapeutic or prophylactic agent, e.g., mRNA, has an increased therapeutic index as compared to a corresponding formulation which comprises a reference lipid (e.g., MC3, KC2, or DLinDMA) and the same therapeutic or prophylactic agent. In certain embodiments, the present application provides pharmaceutical compositions comprising: (a) a polynucleotide comprising a nucleotide sequence encoding a PAH polypeptide; and Attorney Docket No.45817-0152WO1 / MTX975.20 (b) a delivery agent. Lipid Nanoparticle Formulations In some embodiments, nucleic acids of the invention (e.g., PAH mRNA) are Formulated in a lipid nanoparticle (LNP). Lipid nanoparticles typically comprise ionizable cationic lipid, non-cationic lipid, sterol and PEG lipid components along with the nucleic acid cargo of interest. The lipid nanoparticles of the invention can be generated using components, compositions, and methods as are generally known in the art, see for example PCT / US2016 / 052352; PCT / US2016 / 068300; PCT / US2017 / 037551; PCT / US2015 / 027400; PCT / US2016 / 047406; PCT / US2016000129; PCT / US2016 / 014280; PCT / US2016 / 014280; PCT / US2017 / 038426; PCT / US2014 / 027077; PCT / US2014 / 055394; PCT / US2016 / 52117; PCT / US2012 / 069610; PCT / US2017 / 027492; PCT / US2016 / 059575 and PCT / US2016 / 069491 all of which are incorporated by reference herein in their entirety. Nucleic acids of the present disclosure (e.g., PAH mRNA) are typically Formulated in lipid nanoparticle. In some embodiments, the lipid nanoparticle comprises at least one ionizable cationic lipid, at least one non-cationic lipid, at least one sterol, and / or at least one polyethylene glycol (PEG)-modified lipid. In some embodiments, the lipid nanoparticle comprises a molar ratio of 20- 60% ionizable cationic lipid. For example, the lipid nanoparticle may comprise a molar ratio of 40-50 mol%, optionally 45-50 mol%, for example, 45-46 mol%, 46-47 mol%, 47-48 mol%, 48-49 mol%, or 49-50 mol%, for example about 45 mol%, 45.5 mol%, 46 mol%, 46.5 mol%, 47 mol%, 47.5 mol%, 48 mol%, 48.5 mol%, 49 mol%, or 49.5 mol% ionizable cationic lipid. In some embodiments, the lipid nanoparticle comprises a molar ratio of 5-25% non-cationic lipid. For example, the lipid nanoparticle may comprise a molar ratio of 5-15 mol%, optionally 10-12 mol%, for example, 5-6 mol%, 6-7 mol%, 7-8 mol%, 8- 9 mol%, 9-10 mol%, 10-11 mol%, 11-12 mol%, 12-13 mol%, 13-14 mol%, or 14-15 mol% non-cationic lipid. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the lipid nanoparticle comprises a molar ratio of 25- 55% sterol. For example, the lipid nanoparticle may comprise a molar ratio of 30-45 mol%, optionally 35-40 mol%, for example, 30-31 mol%, 31-32 mol%, 32-33 mol%, 33-34 mol%, 35-35 mol%, 35-36 mol%, 36-37 mol%, 38-38 mol%, 38-39 mol%, or 39-40 mol% sterol. In some embodiments, the lipid nanoparticle comprises a molar ratio of 0.5- 15% PEG-modified lipid. For example, the lipid nanoparticle may comprise a molar ratio of 1-5%, optionally 1-3 mol%, for example 1.5 to 2.5 mol%, 1-2 mol%, 2-3 mol%, 3-4 mol%, or 4-5 mol% PEG-modified lipid. In some embodiments, the lipid nanoparticle comprises a molar ratio of 20- 60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid. In some embodiments, the lipid nanoparticle comprises a molar ratio of 40- 50% ionizable cationic lipid, 5-15% non-cationic lipid, 30-45% sterol, and 1-5% PEG-modified lipid. In some embodiments, the lipid nanoparticle comprises a molar ratio of 45- 50% ionizable cationic lipid, 10-12% non-cationic lipid, 35-40% sterol, and 1-3% PEG-modified lipid. In some embodiments, the lipid nanoparticle comprises a molar ratio of 45- 50% ionizable cationic lipid, 10-12% non-cationic lipid, 35-40% sterol, and 1.5-2.5% PEG-modified lipid. Ionizable amino lipids In some aspects, the disclosure relates to a compound of Formula (I): or its N-oxide, or a salt or isomer thereof, Attorney Docket No.45817-0152WO1 / MTX975.20 R’brancheddenotes a point of attachment; wherein selected from the group consisting of H, 12 12 R2and R3are each independently selected from the group consisting of C1-14alkyl and C2-14R4is selected from the group consisting of -(CH2)nOH, wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, , wherein denotes a point R10is N each R is independently selected from the group consisting of C1-6alkyl, C2-3alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R5is independently selected from the group consisting of C1-3alkyl, C2-3 alkenyl, and H; each R6is independently selected from the group consisting of C1-3alkyl, C2-3 alkenyl, and H; M and M’ are each independently selected from the group consisting of - C(O)O- and -OC(O)-; R’ is a C1-12 alkyl or C2-12 alkenyl; l is selected from the group consisting of 1, 2, 3, 4, and 5; and m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13. In some embodiments of the compounds of Formula (I), R’ais R’branched; R’branched denotes a point of attachment; Raα, Raβ, Raγ, and Raδare each H; R2and R3 C1-14alkyl; R4is -(CH2)nOH; n is 2; each Attorney Docket No.45817-0152WO1 / MTX975.20 R5is H; each R6is H; M and M’ are each -C(O)O-; R’ is a C1-12 alkyl; l is 5; and m is 7. In some embodiments of the compounds of Formula (I), R’ais R’branched; denotes a point of attachment; Raα, Raβ, Raγ, C1-14 alkyl; R4is -(CH2)nOH; n is 2; each 5 R is are -C(O)O-; R’ is a C1-12 alkyl; l is 3; and m is 7. In some embodiments of the compounds of Formula (I), R’ais R’branched; denotes a point of attachment; Raαis C2-12alkyl; R3are each C1-14 alkyl; R4is ; R10NH(C1-6 alkyl); n2 is 2; R5is H; each R6is H; M and M’ are a C1-12 alkyl; l is 5; and m is 7. In some embodiments of the compounds of Formula (I), R’ais R’branched; denotes a point of attachment; Raα, Raβ, and R3are each C1-14 alkyl; R4is -(CH2)nOH; n is 2; each R5is H; each R6is H; M and M’ are each -C(O)O-; R’ is a C1-12alkyl; l is 5; and m is 7. In some embodiments, the compound of Formula (I) is selected from: , Attorney Docket No.45817-0152WO1 / MTX975.20 In some (Compound II). In (I) is: . In some . In some (Compound B). In some aspects, the disclosure relates to a compound of Formula (Ia): Attorney Docket No.45817-0152WO1 / MTX975.20 its N-oxide, or a salt or isomer thereof, denotes a point of attachment; selected from the group 12 12R2and R3are each independently selected from the group consisting of C1-14 alkyl and C2-14 alkenyl; R4is selected from the group consisting of -(CH2)nOH wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, , wherein denotes a point R10is N each R is independently selected from the group consisting of C1-6 alkyl, C2-3 alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R5is independently selected from the group consisting of C1-3 alkyl, C2-3alkenyl, and H; each R6is independently selected from the group consisting of C1-3 alkyl, C2-3alkenyl, and H; M and M’ are each independently selected from the group consisting of - C(O)O- and -OC(O)-; R’ is a C1-12alkyl or C2-12alkenyl; l is selected from the group consisting of 1, 2, 3, 4, and 5; and m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13. Attorney Docket No.45817-0152WO1 / MTX975.20 In some aspects, the disclosure relates to a compound of Formula (Ib): or its N-oxide, or a salt or isomer thereof, denotes a point of attachment; selected from the group consisting of H, C2-12 alkyl, and C2-12 alkenyl; R2and R3are each independently selected from the group consisting of C1-14alkyl and C2-14alkenyl; R4is -(CH2)nOH, wherein n is selected from the group consisting of 1, 2, 3, 4, and 5; each R5is independently selected from the group consisting of C1-3 alkyl, C2-3alkenyl, and H; each R6is independently selected from the group consisting of C1-3 alkyl, C2-3alkenyl, and H; M and M’ are each independently selected from the group consisting of - C(O)O- and -OC(O)-; R’ is a C1-12alkyl or C2-12alkenyl; l is selected from the group consisting of 1, 2, 3, 4, and 5; and m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13. In some embodiments of Formula (I) or (Ib), R’ais R’branched; R’branchedis denotes a point of attachment; Raβ, Raγ, and Raδare each H; 14 alkyl; R4is -(CH2)nOH; n is 2; each R5is H; each R6is H; M and M’ are each -C(O)O-; R’ is a C1-12alkyl; l is 5; and m is 7. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments of Formula (I) or (Ib), R’ais R’branched; R’branchedis denotes a point of attachment; Raβ, Raγ, and Raδare each H; alkyl; R4is -(CH2)nOH; n is 2; each R5is H; each R6is H; M are - ; R’ is a C1-12 alkyl; l is 3; and m is 7. Insome embodiments of Formula (I) or (Ib), R’ais R’branched; R’branchedis denotes a point of attachment; Raβand Raδare each H; Raγis are each C1-14alkyl; R4is -(CH2)nOH; n is 2; each R5is H; each R6is H; M and M’ are each -C(O)O-; R’ is a C1-12 alkyl; l is 5; and m is 7. In some aspects, the disclosure relates to a compound of Formula (Ic): its N-oxide, or a salt or isomer thereof, R’branched; wherein denotes a point of attachment; wherein are each independently selected from the group consisting of H, C2-12alkyl, and C2-12alkenyl; R2and R3are each independently selected from the group consisting of C1-14 alkyl and C2-14 alkenyl;

[0004] Attorney Docket No.45817-0152WO1 / MTX975.20 R10is N(R)2; each R is independently selected from the group consisting of C1-6alkyl, C2-3alkenyl, and H; n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R5is independently selected from the group consisting of C1-3alkyl, C2-3 alkenyl, and H; each R6is independently selected from the group consisting of C1-3alkyl, C2-3 alkenyl, and H; M and M’ are each independently selected from the group consisting of - C(O)O- and -OC(O)-; R’ is a C1-12 alkyl or C2-12 alkenyl; l is selected from the group consisting of 1, 2, 3, 4, and 5; and m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13. In some embodiments, R’ais R’branched; R’branched; denotes a point of attachment; Raβ, Raγ, and Raδare each H; Raαis C2-12 and R3are each C1-14 alkyl; R4denotes a point of attachment; R10is NH(C1- is H; each R6is H; M and M’ are each -C(O)O-; R’ is a C1-12 alkyl; l is 5; and m is 7. In some embodiments, the compound of Formula (Ic) is: . (II): Attorney Docket No.45817-0152WO1 / MTX975.20 Raγand Raδare each independently selected from the group consisting of H, C1-12alkyl, and C2-12alkenyl, wherein at least one of Raγand Raδis selected from the group consisting of C1-12 alkyl and C2-12 alkenyl; Rbγand Rbδare each independently selected from the group consisting of H, C1-12 alkyl, and C2-12 alkenyl, wherein at least one of Rbγand Rbδis selected from the group consisting of C1-12alkyl and C2-12alkenyl; R2and R3are each independently selected from the group consisting of C1-14 alkyl and C2-14 alkenyl; R4is selected from the group consisting of -(CH2)nOH wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, , wherein denotes a point of attachment; wherein R10is N(R)2; each R is independently selected from the group consisting of C1-6alkyl, C2-3alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Attorney Docket No.45817-0152WO1 / MTX975.20 each R’ independently is a C1-12 alkyl or C2-12 alkenyl; Yais a C3-6carbocycle; R*”ais selected from the group consisting of C1-15 alkyl and C2-15 alkenyl; and s is 2 or 3; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9. In some aspects, the disclosure relates to a compound of Formula (II-a): ; Raγand Raδare each independently selected from the group consisting of H, C1-12alkyl, and C2-12alkenyl, wherein at least one of Raγand Raδis selected from the group consisting of C1-12 alkyl and C2-12 alkenyl; Rbγand Rbδare each independently selected from the group consisting of H, C1-12 alkyl, and C2-12 alkenyl, wherein at least one of Rbγand Rbδis selected from the group consisting of C1-12alkyl and C2-12alkenyl; R2and R3are each independently selected from the group consisting of C1-14 alkyl and C2-14 alkenyl; R4is selected from the group consisting of -(CH2)nOH wherein n is selected from the group consisting of , wherein a Attorney Docket No.45817-0152WO1 / MTX975.20 R10is N(R)2; each R is independently selected from the group consisting of C1-6alkyl, C2-3alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R’ independently is a C1-12alkyl or C2-12alkenyl; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9. In some aspects, the disclosure relates to a compound of Formula (II-b): ; Raγand each independently selected from the group consisting of C1-12alkyl and C2-12 alkenyl; R2and R3are each independently selected from the group consisting of C1-14alkyl and C2-14alkenyl; R4is selected from the group consisting of -(CH2)nOH wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, , wherein denotes a point each R is independently selected from the group C2-3alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R’ independently is a C1-12 alkyl or C2-12 alkenyl; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; Attorney Docket No.45817-0152WO1 / MTX975.20 l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9. In some aspects, the disclosure relates to a compound of Formula (II-c): its N-oxide, or a salt or isomer thereof, ; wherein selected from the group consisting of C1-12 alkyl and C2-12 alkenyl; R2and R3are each independently selected from the group consisting of C1-14 alkyl and C2-14 alkenyl; R4is selected from the group consisting of -(CH2)nOH wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, , wherein denotes a point R10is N(R)2; each R is independently selected from the group consisting of C1-6alkyl, C2-3alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; R’ is a C1-12alkyl or C2-12alkenyl; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9. In some aspects, the disclosure relates to a compound of Formula (II-d): Attorney Docket No.45817-0152WO1 / MTX975.20 wherein Rbγare each independently selected from the group consisting of C1-12 alkyl and C2-12 alkenyl; R4is selected from the group consisting of -(CH2)nOH wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, , wherein denotes a point R10is N each R is independently selected from the group consisting of C1-6alkyl, C2-3alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R’ independently is a C1-12alkyl or C2-12alkenyl; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9. In some aspects, the disclosure relates to a compound of Formula (II-e): R’branched; Attorney Docket No.45817-0152WO1 / MTX975.20 wherein denotes a point of attachment; wherein Raγis selected from the group consisting of C1-12 alkyl and C2-12 alkenyl; R2and R3are each independently selected from the group consisting of C1-14 alkyl and C2-14alkenyl; R4is -(CH2)nOH wherein n is selected from the group consisting of 1, 2, 3, 4, and 5; R’ is a C1-12 alkyl or C2-12 alkenyl; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), m and l are each independently selected from 4, 5, and 6. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), m and l are each 5. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), each R’ independently is a C1-12 alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), each R’ independently is a C2-5 alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’bis: and R2and R3are each independently a C1-14alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’bis: and R2and R3are each independently a C6-10 alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’bis: and R2and R3are each a C8 alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’branched12 Attorney Docket No.45817-0152WO1 / MTX975.20 alkyl and R2and R3are each independently a C6-10 alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’branchedis: R3are each Formula (II), is: , a6are a some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’branchedRbγare each a C1-12 alkyl. is: b), (II-c), (II-d), or (II-e), m and l are each independently selected from 4, 5, and 6 and each R’ independently is a C1-12alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), m and l are each 5 and each R’ independently is a C2-5alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), are and Raγand Rbγare each a C1-12alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’branched Attorney Docket No.45817-0152WO1 / MTX975.20 is: , m and l are each 5, each R’ independently is a C2-5alkyl, and Raγand Rbγare each a C2-6 alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’branchedis: and R’bis: , m and l are each independently selected from is a C1-12 alkyl, Raγis a C1-12 alkyl and R23 and R are each independently a C6-10alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’branchedb and R’ , m and l are each 5, R’ is a C2-5 alkyl, Raγis a C2-6 alkyl, and R2and R3are alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), , wherein R10is NH(C1-6alkyl) and n2 is 2. Formula (II), (II-a), (II-b), (II-c), (II-d), or , wherein R10is NH(CH3) and n2 is 2. the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’branchedare each independently Raγand Rbγare each a C1-12alkyl, and R4, wherein R10is NH(C1-6 alkyl), and n2 is 2. In some of Formula (II), Attorney Docket No.45817-0152WO1 / MTX975.20 is: , m and l are each 5, each R’ independently is a C2-5alkyl, Raγand Rbγare each a C2-6alkyl, and R4is , wherein R10is NH(CH3) and n2 is 2. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’branchedl are each independently selected each independently a C6-10 alkyl, Raγis a C1-12 alkyl, and , wherein R10is NH(C1-6alkyl) and n2 is 2. In some of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’branched R’bis: , m and l are each 5, R’ is a C2-5 alkyl, Raγis a C2-6 alkyl, R2and R3are each a C8alkyl, and R4, wherein R10is NH(CH3) and n2 is 2. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R4is -(CH2)nOH and n is 2, 3, or 4. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R4is -(CH2)nOH and n is 2. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’branchedare each independently Raγand Rbγare each a C1- - embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’ n In some aspects, the disclosure relates to a compound of Formula (II-f): the group consisting of 1, 2, 3, 4, and 5; R’ is a C1-12alkyl; m is selected from 4, 5, and 6; and l is selected from 4, 5, and 6. In some embodiments of the compound of Formula (II-f), m and l are each 5, and n is 2, 3, or 4. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments of the compound of Formula (II-f) R’ is a C2-5 alkyl, Raγis a C2-6alkyl, and R2and R3are each a C6-10alkyl. In some embodiments of the compound of Formula (II-f), m and l are each 5, n is 2, 3, or 4, R’ is a C2-5alkyl, Raγis a C2-6alkyl, and R2and R3are each a C6-10alkyl. In some aspects, the disclosure relates to a compound of Formula (II-g): group - nOH wherein n is selected from the group consisting of 3, 4, and 5, , wherein denotes a point of 6 alkyl), and n2 is selected from consisting of 1, 2, and 3. In some aspects, the disclosure relates to a compound of Formula (II-h): each R’ independently is a C2-5 alkyl; and R4is selected from the group consisting of -(CH2)nOH wherein n is selected from the group consisting of 3, 4, and 5, , wherein denotes a point of attachment, R10is NH(C1-6 alkyl), and n2 is selected from consisting of 1, 2, and 3. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments of the compound of Formula (II-g) or (II-h), R4is of the compound of Formula (II-g) or (II-h), R4is - (CH2)2OH. In some aspects, the disclosure relates to a compound having the Formula (III): , or a salt or R1, R2, R3, R4, and R5 are independently selected from the group consisting of C5-20alkyl, C5-20alkenyl, -R”MR’, -R*YR”, -YR”, and -R*OR”; each M is independently selected from the group consisting of -C(O)O-, -OC(O)-, -OC(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-, an aryl group, and a heteroaryl group; X1, X2, and X3are independently selected from the group consisting of a bond, -CH2-, -(CH2)2-, -CHR-, -CHY-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)-CH2-, -CH2-C(O)-, -C(O)O-CH2-, -OC(O)-CH2-, -CH2-C(O)O-, -CH2-OC(O)-, -CH(OH)-, -C(S)-, and -CH(SH)-; each Y is independently a C3-6carbocycle; each R* is independently selected from the group consisting of C1-12 alkyl and C2-12alkenyl; each R is independently selected from the group consisting of C1-3 alkyl and a C3-6carbocycle; Attorney Docket No.45817-0152WO1 / MTX975.20 each R’ is independently selected from the group consisting of C1-12 alkyl, C2-12alkenyl, and H; and each R” is independently selected from the group consisting of C3-12 alkyl and C3-12alkenyl, and wherein: i) at least one of X1, X2, and X3is not -CH2-; and / or ii) at least one of R1, R2, R3, R4, and R5is -R”MR’. In some embodiments, R1, R2, R3, R4, and R5 are each C5-20 alkyl; X1is -CH2-; and X2and X3are each -C(O)-. In some embodiments, the compound of Formula (III) is: (Compound VI), or a Phospholipids The lipid composition of the lipid nanoparticle composition disclosed herein can comprise one or more phospholipids, for example, one or more saturated or (poly)unsaturated phospholipids or a combination thereof. In general, phospholipids comprise a phospholipid moiety and one or more fatty acid moieties. A phospholipid moiety can be selected, for example, from the non-limiting group consisting of phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl glycerol, phosphatidyl serine, phosphatidic acid, 2-lysophosphatidyl choline, and a sphingomyelin. A fatty acid moiety can be selected, for example, from the non-limiting group consisting of lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, alpha-linolenic acid, erucic acid, phytanoic acid, arachidic acid, arachidonic acid, eicosapentaenoic acid, behenic acid, docosapentaenoic acid, and docosahexaenoic acid. Particular phospholipids can facilitate fusion to a membrane. For example, a cationic phospholipid can interact with one or more negatively charged phospholipids of a membrane (e.g., a cellular or intracellular membrane). Fusion of a phospholipid to a membrane can allow one or more elements (e.g., a therapeutic agent) of a lipid- Attorney Docket No.45817-0152WO1 / MTX975.20 containing composition (e.g., LNPs) to pass through the membrane permitting, e.g., delivery of the one or more elements to a target tissue. Non-natural phospholipid species including natural species with modifications and substitutions including branching, oxidation, cyclization, and alkynes are also contemplated. For example, a phospholipid can be functionalized with or cross-linked to one or more alkynes (e.g., an alkenyl group in which one or more double bonds is replaced with a triple bond). Under appropriate reaction conditions, an alkyne group can undergo a copper-catalyzed cycloaddition upon exposure to an azide. Such reactions can be useful in functionalizing a lipid bilayer of a nanoparticle composition to facilitate membrane permeation or cellular recognition or in conjugating a nanoparticle composition to a useful component such as a targeting or imaging moiety (e.g., a dye). Phospholipids include, but are not limited to, glycerophospholipids such as phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phosphatidylinositols, phosphatidy glycerols, and phosphatidic acids. Phospholipids also include phosphosphingolipid, such as sphingomyelin. In some embodiments, a phospholipid of the invention comprises 1,2- distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3- phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-gly cero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3- phosphocholine (DOPC), l,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2- diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero- 3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2 cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2- dilinolenoyl-sn-glycero-3-phosphocholine,1,2-diarachidonoyl-sn-glycero-3- phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2- diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn- glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero- 3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, Attorney Docket No.45817-0152WO1 / MTX975.20 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), sphingomyelin, and mixtures thereof. In certain embodiments, a phospholipid useful or potentially useful in the present invention is an analog or variant of DSPC. In certain embodiments, a phospholipid useful or potentially useful in the present invention is a compound of Formula (IV): or a salt thereof, wherein: each R1is independently optionally substituted alkyl; or optionally two R1are joined together with the intervening atoms to form optionally substituted monocyclic carbocyclyl or optionally substituted monocyclic heterocyclyl; or optionally three R1are joined together with the intervening atoms to form optionally substituted bicyclic carbocyclyl or optionally substitute bicyclic heterocyclyl; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; A is of the ; each instance of L2 substituted C1-6 alkylene, wherein one methylene unit of the optionally substituted C1-6alkylene is optionally replaced with O, N(RN), S, C(O), C(O)N(RN), NRNC(O), C(O)O, OC(O), OC(O)O, OC(O)N(RN), NRNC(O)O, or NRNC(O)N(RN); each instance of R2is independently optionally substituted C1-30 alkyl, optionally substituted C1-30alkenyl, or optionally substituted C1-30alkynyl; optionally wherein one or more methylene units of R2are independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, N(RN), O, S, C(O), - C(O)N(RN), NRNC(O), NRNC(O)N(RN), C(O)O, OC(O), OC(O)O, OC(O)N(RN), - Attorney Docket No.45817-0152WO1 / MTX975.20 NRNC(O)O, C(O)S, SC(O), C(=NRN), C(=NRN)N(RN), NRNC(=NRN), - NRNC(=NRN)N(RN), C(S), C(S)N(RN), NRNC(S), NRNC(S)N(RN), S(O), OS(O), - , - or Ring B is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and p is 1 or 2; provided that the compound is not of the Formula: , wherein each alkyl, unsubstituted alkenyl, or unsubstituted alkynyl. In some embodiments, the phospholipids may be one or more of the phospholipids described in U.S. Application No.62 / 520,530. Phospholipid Head Modifications In certain embodiments, a phospholipid useful or potentially useful in the present invention comprises a modified phospholipid head (e.g., a modified choline group). In certain embodiments, a phospholipid with a modified head is DSPC, or analog thereof, with a modified quaternary amine. For example, in embodiments of Formula (IV), at least one of R1is not methyl. In certain embodiments, at least one of R1is not hydrogen or methyl. In certain embodiments, the compound of Formula (IV) is of one of the following Formulae: Attorney Docket No.45817-0152WO1 / MTX975.20 , or each u is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each v is independently 1, 2, or 3. In certain embodiments, a compound of Formula (IV) is of Formula (IV-a): potentially useful in the present invention comprises a cyclic moiety in place of the glyceride moiety. In certain embodiments, a phospholipid useful in the present invention is DSPC, or analog thereof, with a cyclic moiety in place of the glyceride moiety. In certain embodiments, the compound of Formula (IV) is of Formula (IV-b): , or a salt thereof. Phospholipid Tail Modifications In certain embodiments, a phospholipid useful or potentially useful in the present invention comprises a modified tail. In certain embodiments, a phospholipid useful or potentially useful in the present invention is DSPC, or analog thereof, with a Attorney Docket No.45817-0152WO1 / MTX975.20 modified tail. As described herein, a “modified tail” may be a tail with shorter or longer aliphatic chains, aliphatic chains with branching introduced, aliphatic chains with substituents introduced, aliphatic chains wherein one or more methylenes are replaced by cyclic or heteroatom groups, or any combination thereof. For example, in certain embodiments, the compound of (IV) is of Formula (IV-a), or a salt thereof, wherein at least one instance of R2is each instance of R2is optionally substituted C1-30 alkyl, wherein one or more methylene units of R2are independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, N(RN), O, S, - C(O), C(O)N(RN), NRNC(O), NRNC(O)N(RN), C(O)O, OC(O), OC(O)O, - , c): c), or a salt thereof, wherein: each x is independently an integer between 0-30, inclusive; and each instance is G is independently selected from the group consisting of optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, N(RN), O, S, - C(O), C(O)N(RN), NRNC(O), NRNC(O)N(RN), C(O)O, OC(O), OC(O)O, - , separate embodiment of the present invention. Attorney Docket No.45817-0152WO1 / MTX975.20 In certain embodiments, a phospholipid useful or potentially useful in the present invention comprises a modified phosphocholine moiety, wherein the alkyl chain linking the quaternary amine to the phosphoryl group is not ethylene (e.g., n is not 2). Therefore, in certain embodiments, a phospholipid useful or potentially useful in the present invention is a compound of Formula (IV), wherein n is 1, 3, 4, 5, 6, 7, 8, 9, or 10. For example, in certain embodiments, a compound of Formula (IV) is of one of the following Formulae: , In certain embodiments, a phospholipid useful or potentially useful in the present invention comprises a modified phosphocholine moiety, wherein the alkyl chain linking the quaternary amine to the phosphoryl group is not ethylene (e.g., n is not 2). Therefore, in certain embodiments, a phospholipid useful. In certain embodiments, an alternative lipid is used in place of a phospholipid of the present disclosure. In certain embodiments, an alternative lipid of the invention is oleic acid. In certain embodiments, the alternative lipid is one of the following: , , Attorney Docket No.45817-0152WO1 / MTX975.20 , Structural Lipids The lipid composition of a pharmaceutical composition disclosed herein can comprise one or more structural lipids. As used herein, the term "structural lipid" refers to sterols and also to lipids containing sterol moieties. Incorporation of structural lipids in the lipid nanoparticle may help mitigate aggregation of other lipids in the particle. Structural lipids can be selected from the group including but not limited to, cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, tomatine, ursolic acid, alpha- tocopherol, hopanoids, phytosterols, steroids, and mixtures thereof. In some Attorney Docket No.45817-0152WO1 / MTX975.20 embodiments, the structural lipid is a sterol. As defined herein, "sterols" are a subgroup of steroids consisting of steroid alcohols. In certain embodiments, the structural lipid is a steroid. In certain embodiments, the structural lipid is cholesterol. In certain embodiments, the structural lipid is an analog of cholesterol. In certain embodiments, the structural lipid is alpha-tocopherol. In some embodiments, the structural lipids may be one or more of the structural lipids described in U.S. Application No.62 / 520,530. Polyethylene Glycol (PEG)-Lipids The lipid composition of a pharmaceutical composition disclosed herein can comprise one or more a polyethylene glycol (PEG) lipid. As used herein, the term “PEG-lipid” refers to polyethylene glycol (PEG)- modified lipids. Non-limiting examples of PEG-lipids include PEG-modified phosphatidylethanolamine and phosphatidic acid, PEG-ceramide conjugates (e.g., PEG-CerC14 or PEG-CerC20), PEG-modified dialkylamines and PEG-modified 1,2- diacyloxypropan-3-amines. Such lipids are also referred to as PEGylated lipids. For example, a PEG lipid can be PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, or a PEG-DSPE lipid. In some embodiments, the PEG-lipid includes, but not limited to 1,2- dimyristoyl-sn-glycerol methoxypolyethylene glycol (PEG-DMG), 1,2-distearoyl-sn- glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)] (PEG-DSPE), PEG- disteryl glycerol (PEG-DSG), PEG-dipalmetoleyl, PEG-dioleyl, PEG-distearyl, PEG- diacylglycamide (PEG-DAG), PEG-dipalmitoyl phosphatidylethanolamine (PEG- DPPE), or PEG-l,2-dimyristyloxlpropyl-3-amine (PEG-c-DMA). In one embodiment, the PEG-lipid is selected from the group consisting of a PEG-modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG- modified ceramide, a PEG-modified dialkylamine, a PEG-modified diacylglycerol, a PEG-modified dialkylglycerol, and mixtures thereof. In some embodiments, the lipid moiety of the PEG-lipids includes those having lengths of from about C14to about C22, preferably from about C14to about C16. In some embodiments, a PEG moiety, for example an mPEG-NH2, has a size of about Attorney Docket No.45817-0152WO1 / MTX975.20 1000, 2000, 5000, 10,000, 15,000 or 20,000 daltons. In one embodiment, the PEG- lipid is PEG2k-DMG. In one embodiment, the lipid nanoparticles described herein can comprise a PEG lipid which is a non-diffusible PEG. Non-limiting examples of non-diffusible PEGs include PEG-DSG and PEG-DSPE. PEG-lipids are known in the art, such as those described in U.S. Patent No. 8158601 and International Publ. No. WO 2015 / 130584 A2, which are incorporated herein by reference in their entirety. In general, some of the other lipid components (e.g., PEG lipids) of various Formulae, described herein may be synthesized as described International Patent Application No. PCT / US2016 / 000129, filed December 10, 2016, entitled “Compositions and Methods for Delivery of Therapeutic Agents,” which is incorporated by reference in its entirety. The lipid component of a lipid nanoparticle composition may include one or more molecules comprising polyethylene glycol, such as PEG or PEG-modified lipids. Such species may be alternately referred to as PEGylated lipids. A PEG lipid is a lipid modified with polyethylene glycol. A PEG lipid may be selected from the non-limiting group including PEG-modified phosphatidylethanolamines, PEG- modified phosphatidic acids, PEG-modified ceramides, PEG-modified dialkylamines, PEG-modified diacylglycerols, PEG-modified dialkylglycerols, and mixtures thereof. For example, a PEG lipid may be PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, or a PEG-DSPE lipid. In some embodiments the PEG-modified lipids are a modified form of PEG DMG. PEG-DMG has the following structure: In one be PEGylated lipids described in International Publication No. WO2012099755, the contents of which is herein incorporated by reference in its entirety. Any of these exemplary PEG lipids described herein may be modified to comprise a hydroxyl Attorney Docket No.45817-0152WO1 / MTX975.20 group on the PEG chain. In certain embodiments, the PEG lipid is a PEG-OH lipid. As generally defined herein, a “PEG-OH lipid” (also referred to herein as “hydroxy- PEGylated lipid”) is a PEGylated lipid having one or more hydroxyl (–OH) groups on the lipid. In certain embodiments, the PEG-OH lipid includes one or more hydroxyl groups on the PEG chain. In certain embodiments, a PEG-OH or hydroxy-PEGylated lipid comprises an –OH group at the terminus of the PEG chain. Each possibility represents a separate embodiment of the present invention. In certain embodiments, a PEG lipid useful in the present invention is a compound of Formula (V). Provided herein are compounds of Formula (V): (V), or salts thereof, wherein: R3is –ORO; ROis hydrogen, optionally substituted alkyl, or an oxygen protecting group; r is an integer between 1 and 100, inclusive; L1is optionally substituted C1-10alkylene, wherein at least one methylene of the optionally substituted C1-10 alkylene is independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, O, N(RN), S, C(O), - C(O)N(RN), NRNC(O), C(O)O, OC(O), OC(O)O, OC(O)N(RN), NRNC(O)O, or - physiological conditions; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; A is of the ; each instance of L2 substituted C1-6 alkylene, wherein one methylene unit of the optionally substituted C1-6alkylene is optionally replaced with O, N(RN), S, C(O), C(O)N(RN), NRNC(O), C(O)O, OC(O), OC(O)O, OC(O)N(RN), NRNC(O)O, or NRNC(O)N(RN); Attorney Docket No.45817-0152WO1 / MTX975.20 each instance of R2is independently optionally substituted C1-30 alkyl, optionally substituted C1-30alkenyl, or optionally substituted C1-30alkynyl; optionally wherein one or more methylene units of R2are independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, N(RN), O, S, - C(O), C(O)N(RN), NRNC(O), NRNC(O)N(RN), C(O)O, OC(O), OC(O)O, - OC N NRNC C SC C C N NRNC , - or a group; Ring B is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and p is 1 or 2. In certain embodiments, the compound of Fomula (V) is a PEG-OH lipid (i.e., R3is –ORO, and ROis hydrogen). In certain embodiments, the compound of Formula (V) is of Formula (V-OH): , or a salt thereof. In certain embodiments, a PEG lipid useful in the present invention is a PEGylated fatty acid. In certain embodiments, a PEG lipid useful in the present invention is a compound of Formula (VI). Provided herein are compounds of Formula (VI): , or a salts thereof, wherein: R3is–ORO; ROis hydrogen, optionally substituted alkyl or an oxygen protecting group; Attorney Docket No.45817-0152WO1 / MTX975.20 r is an integer between 1 and 100, inclusive; R5is optionally substituted C10-40alkyl, optionally substituted C10-40alkenyl, or optionally substituted C10-40 alkynyl; and optionally one or more methylene groups of R5are replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, N(RN), O, S, C(O), C(O)N(RN), NRNC(O), NRNC(O)N(RN), C(O)O, OC(O), - OC OC N NRNC C SC C C N - , - , - or a group. In certain embodiments, the compound of Formula (VI) is of Formula (VI- OH): , In one embodiment, the compound of Formula (VI) is In some aspects, the lipid composition of the pharmaceutical compositions disclosed herein does not comprise a PEG-lipid. In some embodiments, the PEG-lipids may be one or more of the PEG lipids described in U.S. Application No.62 / 520,530. Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, a PEG lipid of the invention comprises a PEG- modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG- modified ceramide, a PEG-modified dialkylamine, a PEG-modified diacylglycerol, a PEG-modified dialkylglycerol, and mixtures thereof. In some embodiments, the PEG-modified lipid is PEG-DMG, PEG-c-DOMG (also referred to as PEG-DOMG), PEG-DSG and / or PEG-DPG. In some embodiments, a LNP of the invention comprises an ionizable cationic lipid of any of Formula I, II or III, a phospholipid comprising DSPC, a structural lipid, and a PEG lipid comprising PEG-DMG. In some embodiments, a LNP of the invention comprises an ionizable cationic lipid of any of Formula I, II or III, a phospholipid comprising DSPC, a structural lipid, and a PEG lipid comprising a compound having Formula VI. In some embodiments, a LNP of the invention comprises an ionizable cationic lipid of Formula I, II or III, a phospholipid comprising a compound having Formula IV, a structural lipid, and the PEG lipid comprising a compound having Formula V or VI. In some embodiments, a LNP of the invention comprises an ionizable cationic lipid of Formula I, II or III, a phospholipid comprising a compound having Formula IV, a structural lipid, and the PEG lipid comprising a compound having Formula V or VI. In some embodiments, a LNP of the invention comprises an ionizable cationic lipid of Formula I, II or III, a phospholipid having Formula IV, a structural lipid, and a PEG lipid comprising a compound having Formula VI. In some embodiments, a LNP of the invention comprises an ionizable cationic lipid of , and a Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, a LNP of the invention comprises an ionizable cationic lipid of , In some embodiments, a LNP of the invention comprises an ionizable cationic lipid of , lipid comprising cholesterol, and a PEG lipid comprising a compound having Formula VI. In some embodiments, a LNP of the invention comprises an ionizable cationic lipid of and a PEG lipid comprising a compound having Formula VI. In some embodiments, a LNP of the invention comprises an ionizable cationic lipid of

[0005] Attorney Docket No.45817-0152WO1 / MTX975.20 a phospholipid comprising DOPE, a structural lipid comprising cholesterol, and a PEG lipid comprising a compound having Formula VI. In some embodiments, a LNP of the invention comprises an N:P ratio of from about 2:1 to about 30:1. In some embodiments, a LNP of the invention comprises an N:P ratio of about 6:1. In some embodiments, a LNP of the invention comprises an N:P ratio of about 3:1. In some embodiments, a LNP of the invention comprises a wt / wt ratio of the ionizable cationic lipid component to the RNA of from about 10:1 to about 100:1. In some embodiments, a LNP of the invention comprises a wt / wt ratio of the ionizable cationic lipid component to the RNA of about 20:1. In some embodiments, a LNP of the invention comprises a wt / wt ratio of the ionizable cationic lipid component to the RNA of about 10:1. In some embodiments, a LNP of the invention has a mean diameter from about 50nm to about 150nm. In some embodiments, a LNP of the invention has a mean diameter from about 70nm to about 120nm. As used herein, the term "alkyl", "alkyl group", or "alkylene" means a linear or branched, saturated hydrocarbon including one or more carbon atoms (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or more carbon atoms), which is optionally substituted. The notation "C1-14alkyl" means an optionally substituted linear or branched, saturated hydrocarbon including 1-14 carbon atoms. Unless otherwise specified, an alkyl group described herein refers to both unsubstituted and substituted alkyl groups. As used herein, the term "alkenyl", "alkenyl group", or "alkenylene" means a linear or branched hydrocarbon including two or more carbon atoms (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or more carbon atoms) and at least one double bond, which is optionally substituted. The notation "C2-14alkenyl" means an optionally substituted linear or branched hydrocarbon including 2-14 carbon atoms Attorney Docket No.45817-0152WO1 / MTX975.20 and at least one carbon-carbon double bond. An alkenyl group may include one, two, three, four, or more carbon-carbon double bonds. For example, C18alkenyl may include one or more double bonds. A C18 alkenyl group including two double bonds may be a linoleyl group. Unless otherwise specified, an alkenyl group described herein refers to both unsubstituted and substituted alkenyl groups. As used herein, the term "alkynyl", "alkynyl group", or "alkynylene" means a linear or branched hydrocarbon including two or more carbon atoms (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or more carbon atoms) and at least one carbon-carbon triple bond, which is optionally substituted. The notation "C2-14alkynyl" means an optionally substituted linear or branched hydrocarbon including 2- 14 carbon atoms and at least one carbon-carbon triple bond. An alkynyl group may include one, two, three, four, or more carbon-carbon triple bonds. For example, C18 alkynyl may include one or more carbon-carbon triple bonds. Unless otherwise specified, an alkynyl group described herein refers to both unsubstituted and substituted alkynyl groups. As used herein, the term "carbocycle" or "carbocyclic group" means an optionally substituted mono- or multi-cyclic system including one or more rings of carbon atoms. Rings may be three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty membered rings. The notation "C3-6carbocycle" means a carbocycle including a single ring having 3-6 carbon atoms. Carbocycles may include one or more carbon- carbon double or triple bonds and may be non-aromatic or aromatic (e.g., cycloalkyl or aryl groups). Examples of carbocycles include cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, and 1,2 dihydronaphthyl groups. The term "cycloalkyl" as used herein means a non-aromatic carbocycle and may or may not include any double or triple bond. Unless otherwise specified, carbocycles described herein refers to both unsubstituted and substituted carbocycle groups, i.e., optionally substituted carbocycles. As used herein, the term "heterocycle" or "heterocyclic group" means an optionally substituted mono- or multi-cyclic system including one or more rings, where at least one ring includes at least one heteroatom. Heteroatoms may be, for Attorney Docket No.45817-0152WO1 / MTX975.20 example, nitrogen, oxygen, or sulfur atoms. Rings may be three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen membered rings. Heterocycles may include one or more double or triple bonds and may be non- aromatic or aromatic (e.g., heterocycloalkyl or heteroaryl groups). Examples of heterocycles include imidazolyl, imidazolidinyl, oxazolyl, oxazolidinyl, thiazolyl, thiazolidinyl, pyrazolidinyl, pyrazolyl, isoxazolidinyl, isoxazolyl, isothiazolidinyl, isothiazolyl, morpholinyl, pyrrolyl, pyrrolidinyl, furyl, tetrahydrofuryl, thiophenyl, pyridinyl, piperidinyl, quinolyl, and isoquinolyl groups. The term "heterocycloalkyl" as used herein means a non-aromatic heterocycle and may or may not include any double or triple bond. Unless otherwise specified, heterocycles described herein refers to both unsubstituted and substituted heterocycle groups, i.e., optionally substituted heterocycles. As used herein, the term "heteroalkyl", "heteroalkenyl", or "heteroalkynyl", refers respectively to an alkyl, alkenyl, alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. Unless otherwise specified, heteroalkyls, heteroalkenyls, or heteroalkynyls described herein refers to both unsubstituted and substituted heteroalkyls, heteroalkenyls, or heteroalkynyls, i.e., optionally substituted heteroalkyls, heteroalkenyls, or heteroalkynyls. As used herein, a "biodegradable group" is a group that may facilitate faster metabolism of a lipid in a mammalian entity. A biodegradable group may be selected from the group consisting of, but is not limited to, -C(O)O-, -OC(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-, an aryl group, and a heteroaryl group. As used herein, an "aryl group" is an optionally substituted carbocyclic group including one or more aromatic rings. Examples of aryl groups include phenyl and naphthyl groups. As used herein, a "heteroaryl group" is an optionally substituted heterocyclic group including one or more aromatic rings. Examples of heteroaryl groups include pyrrolyl, furyl, thiophenyl, imidazolyl, oxazolyl, and thiazolyl. Both aryl and heteroaryl groups may Attorney Docket No.45817-0152WO1 / MTX975.20 be optionally substituted. For example, M and M' can be selected from the non- limiting group consisting of optionally substituted phenyl, oxazole, and thiazole. In the Formulas herein, M and M' can be independently selected from the list of biodegradable groups above. Unless otherwise specified, aryl or heteroaryl groups described herein refers to both unsubstituted and substituted groups, i.e., optionally substituted aryl or heteroaryl groups. Alkyl, alkenyl, and cyclyl (e.g., carbocyclyl and heterocyclyl) groups may be optionally substituted unless otherwise specified. Optional substituents may be selected from the group consisting of, but are not limited to, a halogen atom (e.g., a chloride, bromide, fluoride, or iodide group), a carboxylic acid (e.g., C(O)OH), an alcohol (e.g., a hydroxyl, OH), an ester (e.g., C(O)OR OC(O)R), an aldehyde (e.g., C(O)H), a carbonyl (e.g., C(O)R, alternatively represented by C=O), an acyl halide (e.g., C(O)X, in which X is a halide selected from bromide, fluoride, chloride, and iodide), a carbonate (e.g., OC(O)OR), an alkoxy (e.g., OR), an acetal (e.g., C(OR)2R"", in which each OR are alkoxy groups that can be the same or different and R"" is an alkyl or alkenyl group), a phosphate (e.g., P(O)43-), a thiol (e.g., SH), a sulfoxide (e.g., S(O)R), a sulfinic acid (e.g., S(O)OH), a sulfonic acid (e.g., S(O)2OH), a thial (e.g., C(S)H), a sulfate (e.g., S(O)42-), a sulfonyl (e.g., S(O)2 ), an amide (e.g., C(O)NR2, or N(R)C(O)R), an azido (e.g., N3), a nitro (e.g., NO2), a cyano (e.g., CN), an isocyano (e.g., NC), an acyloxy (e.g., OC(O)R), an amino (e.g., NR2, NRH, or NH2), a carbamoyl (e.g., OC(O)NR2, OC(O)NRH, or OC(O)NH2), a sulfonamide (e.g., S(O)2NR2, S(O)2NRH, S(O)2NH2, N(R)S(O)2R, N(H)S(O)2R, N(R)S(O)2H, or N(H)S(O)2H), an alkyl group, an alkenyl group, and a cyclyl (e.g., carbocyclyl or heterocyclyl) group. In any of the preceding, R is an alkyl or alkenyl group, as defined herein. In some embodiments, the substituent groups themselves may be further substituted with, for example, one, two, three, four, five, or six substituents as defined herein. For example, a C1-6alkyl group may be further substituted with one, two, three, four, five, or six substituents as described herein. Compounds of the disclosure that contain nitrogens can be converted to N- oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid (mCPBA) and / or hydrogen peroxides) to afford other compounds of the disclosure. Thus, all shown and claimed nitrogen-containing compounds are considered, when Attorney Docket No.45817-0152WO1 / MTX975.20 allowed by valency and structure, to include both the compound as shown and its N- oxide derivative (which can be designated as N ^O or N+-O-). Furthermore, in other instances, the nitrogens in the compounds of the disclosure can be converted to N- hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds can be prepared by oxidation of the parent amine by an oxidizing agent such as m CPBA. All shown and claimed nitrogen-containing compounds are also considered, when allowed by valency and structure, to cover both the compound as shown and its N- hydroxy (i.e., N-OH) and N-alkoxy (i.e., N-OR, wherein R is substituted or unsubstituted C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, 3-14-membered carbocycle or 3-14-membered heterocycle) derivatives. Other Lipid Composition Components The lipid composition of a pharmaceutical composition disclosed herein can include one or more components in addition to those described above. For example, the lipid composition can include one or more permeability enhancer molecules, carbohydrates, polymers, surface altering agents (e.g., surfactants), or other components. For example, a permeability enhancer molecule can be a molecule described by U.S. Patent Application Publication No.2005 / 0222064. Carbohydrates can include simple sugars (e.g., glucose) and polysaccharides (e.g., glycogen and derivatives and analogs thereof). A polymer can be included in and / or used to encapsulate or partially encapsulate a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition in lipid nanoparticle form). A polymer can be biodegradable and / or biocompatible. A polymer can be selected from, but is not limited to, polyamines, polyethers, polyamides, polyesters, polycarbamates, polyureas, polycarbonates, polystyrenes, polyimides, polysulfones, polyurethanes, polyacetylenes, polyethylenes, polyethyleneimines, polyisocyanates, polyacrylates, polymethacrylates, polyacrylonitriles, and polyarylates. The ratio between the lipid composition and the polynucleotide range can be from about 10:1 to about 60:1 (wt / wt). Attorney Docket No.45817-0152WO1 / MTX975.20 In some embodiments, the ratio between the lipid composition and the polynucleotide can be about 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1 or 60:1 (wt / wt). In some embodiments, the wt / wt ratio of the lipid composition to the polynucleotide encoding a therapeutic agent is about 20:1 or about 15:1. In some embodiments, the pharmaceutical composition disclosed herein can contain more than one polypeptides. For example, a pharmaceutical composition disclosed herein can contain two or more polynucleotides (e.g., RNA, e.g., mRNA). In one embodiment, the lipid nanoparticles described herein can comprise polynucleotides (e.g., mRNA) in a lipid:polynucleotide weight ratio of 5:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1 or 70:1, or a range or any of these ratios such as, but not limited to, 5:1 to about 10:1, from about 5:1 to about 15:1, from about 5:1 to about 20:1, from about 5:1 to about 25:1, from about 5:1 to about 30:1, from about 5:1 to about 35:1, from about 5:1 to about 40:1, from about 5:1 to about 45:1, from about 5:1 to about 50:1, from about 5:1 to about 55:1, from about 5:1 to about 60:1, from about 5:1 to about 70:1, from about 10:1 to about 15:1, from about 10:1 to about 20:1, from about 10:1 to about 25:1, from about 10:1 to about 30:1, from about 10:1 to about 35:1, from about 10:1 to about 40:1, from about 10:1 to about 45:1, from about 10:1 to about 50:1, from about 10:1 to about 55:1, from about 10:1 to about 60:1, from about 10:1 to about 70:1, from about 15:1 to about 20:1, from about 15:1 to about 25:1,from about 15:1 to about 30:1, from about 15:1 to about 35:1, from about 15:1 to about 40:1, from about 15:1 to about 45:1, from about 15:1 to about 50:1, from about 15:1 to about 55:1, from about 15:1 to about 60:1 or from about 15:1 to about 70:1. In one embodiment, the lipid nanoparticles described herein can comprise the polynucleotide in a concentration from approximately 0.1 mg / ml to 2 mg / ml such as, but not limited to, 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1.0 mg / ml, 1.1 mg / ml, 1.2 mg / ml, 1.3 mg / ml, 1.4 mg / ml, 1.5 mg / ml, 1.6 mg / ml, 1.7 mg / ml, 1.8 mg / ml, 1.9 mg / ml, 2.0 mg / ml or greater than 2.0 mg / ml. Attorney Docket No.45817-0152WO1 / MTX975.20 Nanoparticle Compositions In some embodiments, the pharmaceutical compositions disclosed herein are Formulated as lipid nanoparticles (LNP). Accordingly, the present disclosure also provides nanoparticle compositions comprising (i) a lipid composition comprising a delivery agent such as compound as described herein, and (ii) a polynucleotide encoding a PAH polypeptide. In such nanoparticle composition, the lipid composition disclosed herein can encapsulate the polynucleotide encoding a PAH polypeptide. Nanoparticle compositions are typically sized on the order of micrometers or smaller and can include a lipid bilayer. Nanoparticle compositions encompass lipid nanoparticles (LNPs), liposomes (e.g., lipid vesicles), and lipoplexes. For example, a nanoparticle composition can be a liposome having a lipid bilayer with a diameter of 500 nm or less. Nanoparticle compositions include, for example, lipid nanoparticles (LNPs), liposomes, and lipoplexes. In some embodiments, nanoparticle compositions are vesicles including one or more lipid bilayers. In certain embodiments, a nanoparticle composition includes two or more concentric bilayers separated by aqueous compartments. Lipid bilayers can be functionalized and / or crosslinked to one another. Lipid bilayers can include one or more ligands, proteins, or channels. In one embodiment, a lipid nanoparticle comprises an ionizable amino lipid, a structural lipid, a phospholipid, and mRNA. In some embodiments, the LNP comprises an ionizable amino lipid, a PEG-modified lipid, a sterol and a structural lipid. In some embodiments, the LNP has a molar ratio of about 40-50% ionizable amino lipid; about 5-15% structural lipid; about 30-45% sterol; and about 1-5% PEG- modified lipid. In some embodiments, the LNP has a polydispersity value of less than 0.4. In some embodiments, the LNP has a net neutral charge at a neutral pH. In some embodiments, the LNP has a mean diameter of 50-150 nm. In some embodiments, the LNP has a mean diameter of 80-100 nm. As generally defined herein, the term “lipid” refers to a small molecule that has hydrophobic or amphiphilic properties. Lipids may be naturally occurring or Attorney Docket No.45817-0152WO1 / MTX975.20 synthetic. Examples of classes of lipids include, but are not limited to, fats, waxes, sterol-containing metabolites, vitamins, fatty acids, glycerolipids, glycerophospholipids, sphingolipids, saccharolipids, and polyketides, and prenol lipids. In some instances, the amphiphilic properties of some lipids leads them to form liposomes, vesicles, or membranes in aqueous media. In some embodiments, a lipid nanoparticle (LNP) may comprise an ionizable amino lipid. As used herein, the term “ionizable amino lipid” has its ordinary meaning in the art and may refer to a lipid comprising one or more charged moieties. In some embodiments, an ionizable amino lipid may be positively charged or negatively charged. An ionizable amino lipid may be positively charged, in which case it can be referred to as “cationic lipid”. In certain embodiments, an ionizable amino lipid molecule may comprise an amine group, and can be referred to as an ionizable amino lipid. As used herein, a “charged moiety” is a chemical moiety that carries a formal electronic charge, e.g., monovalent (+1, or -1), divalent (+2, or -2), trivalent (+3, or -3), etc. The charged moiety may be anionic (i.e., negatively charged) or cationic (i.e., positively charged). Examples of positively-charged moieties include amine groups (e.g., primary, secondary, and / or tertiary amines), ammonium groups, pyridinium group, guanidine groups, and imidizolium groups. In a particular embodiment, the charged moieties comprise amine groups. Examples of negatively- charged groups or precursors thereof, include carboxylate groups, sulfonate groups, sulfate groups, phosphonate groups, phosphate groups, hydroxyl groups, and the like. The charge of the charged moiety may vary, in some cases, with the environmental conditions, for example, changes in pH may alter the charge of the moiety, and / or cause the moiety to become charged or uncharged. In general, the charge density of the molecule may be selected as desired. It should be understood that the terms “charged” or “charged moiety” does not refer to a “partial negative charge" or “partial positive charge" on a molecule. The terms “partial negative charge" and “partial positive charge" are given its ordinary meaning in the art. A “partial negative charge" may result when a functional group comprises a bond that becomes polarized such that electron density is pulled toward one atom of the bond, creating a partial negative charge on the atom. Those of Attorney Docket No.45817-0152WO1 / MTX975.20 ordinary skill in the art will, in general, recognize bonds that can become polarized in this way. The ionizable amino lipid is sometimes referred to in the art as an “ionizable cationic lipid”. In one embodiment, the ionizable amino lipid may have a positively charged hydrophilic head and a hydrophobic tail that are connected via a linker structure. In addition to these, an ionizable amino lipid may also be a lipid including a cyclic amine group. In one embodiment, the ionizable amino lipid may be selected from, but not limited to, an ionizable amino lipid described in International Publication Nos. WO2013086354 and WO2013116126; the contents of each of which are herein incorporated by reference in their entirety. In yet another embodiment, the ionizable amino lipid may be selected from, but not limited to, Formula CLI-CLXXXXII of US Patent No.7,404,969; each of which is herein incorporated by reference in their entirety. In one embodiment, the lipid may be a cleavable lipid such as those described in International Publication No. WO2012170889, herein incorporated by reference in its entirety. In one embodiment, the lipid may be synthesized by methods known in the art and / or as described in International Publication Nos. WO2013086354; the contents of each of which are herein incorporated by reference in their entirety. Nanoparticle compositions can be characterized by a variety of methods. For example, microscopy (e.g., transmission electron microscopy or scanning electron microscopy) can be used to examine the morphology and size distribution of a nanoparticle composition. Dynamic light scattering or potentiometry (e.g., potentiometric titrations) can be used to measure zeta potentials. Dynamic light scattering can also be utilized to determine particle sizes. Instruments such as the Zetasizer Nano ZS (Malvern Instruments Ltd, Malvern, Worcestershire, UK) can also be used to measure multiple characteristics of a nanoparticle composition, such as particle size, polydispersity index, and zeta potential. The size of the nanoparticles can help counter biological reactions such as, but not limited to, inflammation, or can increase the biological effect of the polynucleotide. Attorney Docket No.45817-0152WO1 / MTX975.20 As used herein, “size” or “mean size” in the context of nanoparticle compositions refers to the mean diameter of a nanoparticle composition. In one embodiment, the polynucleotide encoding a PAH polypeptide are Formulated in lipid nanoparticles having a diameter from about 10 to about 100 nm such as, but not limited to, about 10 to about 20 nm, about 10 to about 30 nm, about 10 to about 40 nm, about 10 to about 50 nm, about 10 to about 60 nm, about 10 to about 70 nm, about 10 to about 80 nm, about 10 to about 90 nm, about 20 to about 30 nm, about 20 to about 40 nm, about 20 to about 50 nm, about 20 to about 60 nm, about 20 to about 70 nm, about 20 to about 80 nm, about 20 to about 90 nm, about 20 to about 100 nm, about 30 to about 40 nm, about 30 to about 50 nm, about 30 to about 60 nm, about 30 to about 70 nm, about 30 to about 80 nm, about 30 to about 90 nm, about 30 to about 100 nm, about 40 to about 50 nm, about 40 to about 60 nm, about 40 to about 70 nm, about 40 to about 80 nm, about 40 to about 90 nm, about 40 to about 100 nm, about 50 to about 60 nm, about 50 to about 70 nm, about 50 to about 80 nm, about 50 to about 90 nm, about 50 to about 100 nm, about 60 to about 70 nm, about 60 to about 80 nm, about 60 to about 90 nm, about 60 to about 100 nm, about 70 to about 80 nm, about 70 to about 90 nm, about 70 to about 100 nm, about 80 to about 90 nm, about 80 to about 100 nm and / or about 90 to about 100 nm. In one embodiment, the nanoparticles have a diameter from about 10 to 500 nm. In one embodiment, the nanoparticle has a diameter greater than 100 nm, greater than 150 nm, greater than 200 nm, greater than 250 nm, greater than 300 nm, greater than 350 nm, greater than 400 nm, greater than 450 nm, greater than 500 nm, greater than 550 nm, greater than 600 nm, greater than 650 nm, greater than 700 nm, greater than 750 nm, greater than 800 nm, greater than 850 nm, greater than 900 nm, greater than 950 nm or greater than 1000 nm. In some embodiments, the largest dimension of a nanoparticle composition is 1 µm or shorter (e.g., 1 µm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, 175 nm, 150 nm, 125 nm, 100 nm, 75 nm, 50 nm, or shorter). A nanoparticle composition can be relatively homogenous. A polydispersity index can be used to indicate the homogeneity of a nanoparticle composition, e.g., the particle size distribution of the nanoparticle composition. A small (e.g., less than 0.3) polydispersity index generally indicates a narrow particle size distribution. A Attorney Docket No.45817-0152WO1 / MTX975.20 nanoparticle composition can have a polydispersity index from about 0 to about 0.25, such as 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, or 0.25. In some embodiments, the polydispersity index of a nanoparticle composition disclosed herein can be from about 0.10 to about 0.20. The zeta potential of a nanoparticle composition can be used to indicate the electrokinetic potential of the composition. For example, the zeta potential can describe the surface charge of a nanoparticle composition. Nanoparticle compositions with relatively low charges, positive or negative, are generally desirable, as more highly charged species can interact undesirably with cells, tissues, and other elements in the body. In some embodiments, the zeta potential of a nanoparticle composition disclosed herein can be from about -10 mV to about +20 mV, from about -10 mV to about +15 mV, from about 10 mV to about +10 mV, from about -10 mV to about +5 mV, from about -10 mV to about 0 mV, from about -10 mV to about -5 mV, from about -5 mV to about +20 mV, from about -5 mV to about +15 mV, from about -5 mV to about +10 mV, from about -5 mV to about +5 mV, from about -5 mV to about 0 mV, from about 0 mV to about +20 mV, from about 0 mV to about +15 mV, from about 0 mV to about +10 mV, from about 0 mV to about +5 mV, from about +5 mV to about +20 mV, from about +5 mV to about +15 mV, or from about +5 mV to about +10 mV. In some embodiments, the zeta potential of the lipid nanoparticles can be from about 0 mV to about 100 mV, from about 0 mV to about 90 mV, from about 0 mV to about 80 mV, from about 0 mV to about 70 mV, from about 0 mV to about 60 mV, from about 0 mV to about 50 mV, from about 0 mV to about 40 mV, from about 0 mV to about 30 mV, from about 0 mV to about 20 mV, from about 0 mV to about 10 mV, from about 10 mV to about 100 mV, from about 10 mV to about 90 mV, from about 10 mV to about 80 mV, from about 10 mV to about 70 mV, from about 10 mV to about 60 mV, from about 10 mV to about 50 mV, from about 10 mV to about 40 mV, from about 10 mV to about 30 mV, from about 10 mV to about 20 mV, from about 20 mV to about 100 mV, from about 20 mV to about 90 mV, from about 20 mV to about 80 mV, from about 20 mV to about 70 mV, from about 20 mV to about 60 mV, from about 20 mV to about 50 mV, from about 20 mV to about 40 mV, from Attorney Docket No.45817-0152WO1 / MTX975.20 about 20 mV to about 30 mV, from about 30 mV to about 100 mV, from about 30 mV to about 90 mV, from about 30 mV to about 80 mV, from about 30 mV to about 70 mV, from about 30 mV to about 60 mV, from about 30 mV to about 50 mV, from about 30 mV to about 40 mV, from about 40 mV to about 100 mV, from about 40 mV to about 90 mV, from about 40 mV to about 80 mV, from about 40 mV to about 70 mV, from about 40 mV to about 60 mV, and from about 40 mV to about 50 mV. In some embodiments, the zeta potential of the lipid nanoparticles can be from about 10 mV to about 50 mV, from about 15 mV to about 45 mV, from about 20 mV to about 40 mV, and from about 25 mV to about 35 mV. In some embodiments, the zeta potential of the lipid nanoparticles can be about 10 mV, about 20 mV, about 30 mV, about 40 mV, about 50 mV, about 60 mV, about 70 mV, about 80 mV, about 90 mV, and about 100 mV. The term “encapsulation efficiency” of a polynucleotide describes the amount of the polynucleotide that is encapsulated by or otherwise associated with a nanoparticle composition after preparation, relative to the initial amount provided. As used herein, “encapsulation” can refer to complete, substantial, or partial enclosure, confinement, surrounding, or encasement. Encapsulation efficiency is desirably high (e.g., close to 100%). The encapsulation efficiency can be measured, for example, by comparing the amount of the polynucleotide in a solution containing the nanoparticle composition before and after breaking up the nanoparticle composition with one or more organic solvents or detergents. Fluorescence can be used to measure the amount of free polynucleotide in a solution. For the nanoparticle compositions described herein, the encapsulation efficiency of a polynucleotide can be at least 50%, for example 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. In some embodiments, the encapsulation efficiency can be at least 80%. In certain embodiments, the encapsulation efficiency can be at least 90%. The amount of a polynucleotide present in a pharmaceutical composition disclosed herein can depend on multiple factors such as the size of the polynucleotide, desired target and / or application, or other properties of the nanoparticle composition as well as on the properties of the polynucleotide. Attorney Docket No.45817-0152WO1 / MTX975.20 For example, the amount of an mRNA useful in a nanoparticle composition can depend on the size (expressed as length, or molecular mass), sequence, and other characteristics of the mRNA. The relative amounts of a polynucleotide in a nanoparticle composition can also vary. The relative amounts of the lipid composition and the polynucleotide present in a lipid nanoparticle composition of the present disclosure can be optimized according to considerations of efficacy and tolerability. For compositions including an mRNA as a polynucleotide, the N:P ratio can serve as a useful metric. As the N:P ratio of a nanoparticle composition controls both expression and tolerability, nanoparticle compositions with low N:P ratios and strong expression are desirable. N:P ratios vary according to the ratio of lipids to RNA in a nanoparticle composition. In general, a lower N:P ratio is preferred. The one or more RNA, lipids, and amounts thereof can be selected to provide an N:P ratio from about 2:1 to about 30:1, such as 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 14:1, 16:1, 18:1, 20:1, 22:1, 24:1, 26:1, 28:1, or 30:1. In certain embodiments, the N:P ratio can be from about 2:1 to about 8:1. In other embodiments, the N:P ratio is from about 5:1 to about 8:1. In certain embodiments, the N:P ratio is between 5:1 and 6:1. In one specific aspect, the N:P ratio is about is about 5.67:1. In addition to providing nanoparticle compositions, the present disclosure also provides methods of producing lipid nanoparticles comprising encapsulating a polynucleotide. Such method comprises using any of the pharmaceutical compositions disclosed herein and producing lipid nanoparticles in accordance with methods of production of lipid nanoparticles known in the art. See, e.g., Wang et al. (2015) “Delivery of oligonucleotides with lipid nanoparticles” Adv. Drug Deliv. Rev.87:68- 80; Silva et al. (2015) “Delivery Systems for Biopharmaceuticals. Part I: Nanoparticles and Microparticles” Curr. Pharm. Technol.16: 940-954; Naseri et al. (2015) “Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: Structure, Preparation and Application” Adv. Pharm. Bull.5:305-13; Silva et al. (2015) “Lipid nanoparticles for the delivery of biopharmaceuticals” Curr. Pharm. Biotechnol. 16:291-302, and references cited therein. Attorney Docket No.45817-0152WO1 / MTX975.20 Methods of Use The polynucleotides, pharmaceutical compositions and formulations described above are used in the preparation, manufacture and therapeutic use of to treat and / or prevent PAH-related diseases, disorders or conditions. In some embodiments, the polynucleotides, compositions and formulations of the present disclosure are used to treat and / or prevent PKU. In some embodiments, the polynucleotides, pharmaceutical compositions and formulations of the invention are used in methods for reducing the levels of phenylalanine in a subject in need thereof. For instance, one aspect of the invention provides a method of alleviating the symptoms of PKU in a subject comprising the administration of a composition or formulation comprising a polynucleotide encoding a variant PAH to that subject (e.g., an mRNA encoding an PAH polypeptide). In some embodiments, the polynucleotides, pharmaceutical compositions and formulations of the invention are used to reduce the level of phenylalanine, the method comprising administering to the subject an effective amount of a polynucleotide encoding a PAH polypeptide. In some embodiments, the administration of the polynucleotide, pharmaceutical composition or formulation of the invention results in reduction in the level of phenylalanine to less than 1,200 µM (e.g., 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1025, 1050, 1075, 1100, 1125, 1150, 1175 µM), within a short period of time (e.g., within about 6 hours, within about 8 hours, within about 12 hours, within about 16 hours, within about 20 hours, or within about 24 hours) after administration of the polynucleotide, pharmaceutical composition or formulation of the invention. In some embodiments, the polynucleotides, pharmaceutical compositions and formulations of the invention are used to increase the level of tyrosine, the method comprising administering to the subject an effective amount of a polynucleotide encoding a PAH polypeptide. Replacement therapy is a potential treatment for PKU. Thus, in certain aspects of the present disclosure, the polynucleotides, e.g., mRNA, disclosed herein comprise Attorney Docket No.45817-0152WO1 / MTX975.20 one or more sequences encoding an PAH polypeptide that is suitable for use in gene replacement therapy for PKU. In some embodiments, the present disclosure treats a lack of PAH or PAH activity, or decreased or abnormal PAH activity in a subject by providing a polynucleotide, e.g., mRNA, that encodes an PAH polypeptide to the subject. In some embodiments, the polynucleotide is sequence-optimized. In some embodiments, the polynucleotide (e.g., an mRNA) comprises a nucleic acid sequence (e.g., an ORF) encoding an PAH polypeptide, wherein the nucleic acid is sequence- optimized, e.g., by modifying its G / C, uridine, or thymidine content, and / or the polynucleotide comprises at least one chemically modified nucleoside. In some embodiments, the polynucleotide comprises a miRNA binding site, e.g., a miRNA binding site that binds miRNA-142. In some embodiments, the administration of a composition or formulation comprising polynucleotide, pharmaceutical composition or formulation of the invention to a subject results in a decrease in phenylalanine in blood / plasma to a level at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or to 100% lower than the level observed prior to the administration of the composition or formulation. In some embodiments, the administration of the polynucleotide, pharmaceutical composition or formulation of the invention results in expression of PAH in cells of the subject. In some embodiments, administering the polynucleotide, pharmaceutical composition or formulation of the invention results in an increase of PAH expression and / or enzymatic activity in the subject. For example, in some embodiments, the polynucleotides of the present invention are used in methods of administering a composition or formulation comprising an mRNA encoding a PAH polypeptide to a subject, wherein the method results in an increase of PAH expression and / or enzymatic activity in at least some cells of a subject. In some embodiments, the administration of a composition or formulation comprising an mRNA encoding an PAH polypeptide to a subject results in an increase of PAH enzymatic activity in cells subject to a level at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least Attorney Docket No.45817-0152WO1 / MTX975.20 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or to 100% or more of the activity level expected in a normal subject, e.g., a human not suffering from PKU. In another embodiment, the polynucleotides, pharmaceutical compositions, or formulations of the present disclosure can be repeatedly administered such that PAH protein is expressed at a therapeutic level for a period of time sufficient to have a beneficial biological effect as described herein. In some embodiments, the expression of the encoded polypeptide is increased. In some embodiments, the polynucleotide increases PAH expression levels in cells when introduced into those cells, e.g., by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or to 100% with respect to the PAH expression level in the cells before the polypeptide is introduced in the cells. In some embodiments, the method or use comprises administering a polynucleotide, e.g., mRNA, comprising a nucleotide sequence having sequence similarity to a polynucleotide of SEQ ID NO:10, wherein the polynucleotide encodes a PAH polypeptide (e.g., SEQ ID NO:1). The present disclosure also provides methods to increase PAH activity in a subject in need thereof, e.g., a subject with PKU, comprising administering to the subject a therapeutically effective amount of a composition or formulation comprising mRNA encoding an PAH polypeptide disclosed herein or a fusion protein comprising PAH. In some aspects, the PAH activity measured after administration to a subject in need thereof, e.g., a subject with PKU, is at least the normal PAH activity level observed in healthy human subjects. In some aspects, the PAH activity measured after administration is at higher than the PAH activity level observed in PKU patients, e.g., untreated PKU patients. In some aspects, the increase in PAH activity in a subject in need thereof, e.g., a subject with PKU, after administering to the subject a therapeutically effective amount of a composition or formulation comprising mRNA encoding an PAH polypeptide disclosed herein is at least about 5, at least about 10, at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, Attorney Docket No.45817-0152WO1 / MTX975.20 at least about 40, at least about 45, at least about 50, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 85, at least about 90, at least about 95, at least about 100, or greater than 100 percent of the normal PAH activity level observed in healthy human subjects. In some aspects, the increase in PAH activity above the PAH activity level observed in PKU patients after administering to the subject a composition or formulation comprising an mRNA encoding an PAH polypeptide disclosed herein (e.g., after a single dose administration) is maintained for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 12 days, at least 14 days, at least 21 days, or at least 28 days. The present disclosure also provides a method to treat, prevent, or ameliorate the symptoms of PKU (e.g., high levels of phenylalanine in the blood) in a PKU patient comprising administering to the subject a therapeutically effective amount of a composition or formulation comprising mRNA encoding an PAH polypeptide disclosed herein. In some aspects, the administration of a therapeutically effective amount of a composition or formulation comprising mRNA encoding an PAH polypeptide disclosed herein to subject in need of treatment for PKU results in reducing the symptoms of PKU. In some embodiments, the polynucleotides (e.g., mRNA), pharmaceutical compositions and formulations used in the methods of the invention comprise a uracil-modified sequence encoding a PAH polypeptide disclosed herein and a miRNA binding site disclosed herein, e.g., a miRNA binding site that binds to miR-142 and / or a miRNA binding site that binds to miR-126. In some embodiments, the uracil- modified sequence encoding a PAH polypeptide comprises at least one chemically modified nucleobase, e.g., N1-methylpseudouracil or 5-methoxyuracil. In some embodiments, at least 95% of a type of nucleobase (e.g., uracil) in a uracil-modified sequence encoding a PAH polypeptide of the invention are modified nucleobases. In some embodiments, the polynucleotide (e.g., a RNA, e.g., a mRNA) disclosed herein is Formulated with a delivery agent comprising, e.g., a compound having the Formula (I), e.g., Compound II, Compound A, or Compound B; or a compound having the Formula (III), (IV), (V), or (VI), e.g., Compound I or Compound VI, or any combination thereof. In some embodiments, the delivery agent comprises an Attorney Docket No.45817-0152WO1 / MTX975.20 ionizable amino lipid (e.g., Compound II, VI, or A), a helper lipid (e.g., DSPC), a sterol (e.g., Cholesterol), and a PEG lipid (e.g., Compound I or PEG-DMG), e.g., with a mole ratio in the range of about (i) 40-50 mol% ionizable amino lipid (e.g., Compound II, VI, or A), optionally 45-50 mol% ionizable amino lipid, for example, 45-46 mol%, 46-47 mol%, 47-48 mol%, 48-49 mol%, or 49-50 mol% for example about 45 mol%, 45.5 mol%, 46 mol%, 46.5 mol%, 47 mol%, 47.5 mol%, 48 mol%, 48.5 mol%, 49 mol%, or 49.5 mol%; (ii) 30-45 mol% sterol (e.g., cholesterol), optionally 35-42 mol% sterol, for example, 30-31 mol%, 31-32 mol%, 32-33 mol%, 33-34 mol%, 35-35 mol%, 35-36 mol%, 36-37 mol%, 37-38 mol%, 38-39 mol%, or 39-40 mol%, or 40-42 mol% sterol; (iii) 5-15 mol% helper lipid (e.g., DSPC), optionally 10-15 mol% helper lipid, for example, 5-6 mol%, 6-7 mol%, 7-8 mol%, 8- 9 mol%, 9-10 mol%, 10-11 mol%, 11-12 mol%, 12-13 mol%, 13-14 mol%, or 14-15 mol% helper lipid; and (iv) 1-5% PEG lipid (e.g., Compound I or PEG-DMG), optionally 1-5 mol% PEG lipid, for example 1.5 to 2.5 mol%, 1-2 mol%, 2-3 mol%, 3-4 mol%, or 4-5 mol% PEG lipid. The skilled artisan will appreciate that the therapeutic effectiveness of a drug or a treatment of the instant invention can be characterized or determined by measuring the level of expression of an encoded protein (e.g., enzyme) in a sample or in samples taken from a subject (e.g., from a preclinical test subject (rodent, primate, etc.) or from a clinical subject (human). Likewise, the therapeutic effectiveness of a drug or a treatment of the instant invention can be characterized or determined by measuring the level of activity of an encoded protein (e.g., enzyme) in a sample or in samples taken from a subject (e.g., from a preclinical test subject (rodent, primate, etc.) or from a clinical subject (human). Furthermore, the therapeutic effectiveness of a drug or a treatment of the instant invention can be characterized or determined by measuring the level of an appropriate biomarker in sample(s) taken from a subject. Levels of protein and / or biomarkers can be determined post-administration with a single dose of an mRNA therapeutic of the invention or can be determined and / or monitored at several time points following administration with a single dose or can be determined and / or monitored throughout a course of treatment, e.g., a multi-dose treatment. Attorney Docket No.45817-0152WO1 / MTX975.20 PKU is associated with an impaired ability to convert phenylalanine to tyrosine. Accordingly, PKU patients commonly show high levels of phenylalanine in their blood. PKU is an autosomal recessive inborn error of amino acid metabolism characterized by the inability to convert phenylalanine to tyrosine. Accordingly, PKU patients can be asymptomatic carriers of the disorder or suffer from the various symptoms associated with the disease. PKU patients commonly show high levels of phenylketones (produced via alternative pathways when phenylalanine metabolism is impaired) in their plasma, serum, urine, and / or tissue (e.g., liver). Unless otherwise specified, the methods of treating PKU patients or human subjects disclosed herein include treatment of both asymptomatic carriers and those individuals with abnormal levels of biomarkers. PAH Protein Expression Levels Certain aspects of the invention feature measurement, determination and / or monitoring of the expression level or levels of PAH protein in a subject. PAH protein expression levels can be measured or determined by any art- recognized method for determining protein levels in biological samples, e.g., from blood samples or a needle biopsy. The term "level" or "level of a protein" as used herein, preferably means the weight, mass or concentration of the protein within a sample or a subject. It will be understood by the skilled artisan that in certain embodiments the sample may be subjected, e.g., to any of the following: purification, precipitation, separation, e.g. centrifugation and / or HPLC, and subsequently subjected to determining the level of the protein, e.g., using mass and / or spectrometric analysis. In exemplary embodiments, enzyme-linked immunosorbent assay (ELISA) can be used to determine protein expression levels. In other exemplary embodiments, protein purification, separation and LC-MS can be used as a means for determining the level of a protein according to the invention. In some embodiments, an mRNA therapy of the invention (e.g., a single intravenous dose) results in increased PAH protein expression levels in the liver tissue of the subject (e.g., 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold increase and / or increased to at least 50%, at least 60%, at least 70%, at least 75%, 80%, at least Attorney Docket No.45817-0152WO1 / MTX975.20 85%, at least 90%, at least 95%, or at least 100% of normal levels) for at least 6 hours, at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 60 hours, at least 72 hours, at least 84 hours, at least 96 hours, at least 108 hours, at least 122 hours after administration of a single dose of the mRNA therapy. In some embodiments, an mRNA therapy of the invention (e.g., a single intravenous dose) results in decreased phenylalanine expression levels in the blood, plasma, or liver tissue of the subject (e.g., less than 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1025, 1050, 1075, 1100, 1125, 1150, 1175 or 1,200 µM) for at least 6 hours, at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 60 hours, at least 72 hours, at least 84 hours, at least 96 hours, at least 108 hours, at least 122 hours after administration of a single dose of the mRNA therapy. PAH Protein Activity In PKU patients, PAH enzymatic activity is reduced compared to a normal physiological activity level. Further aspects of the invention feature measurement, determination and / or monitoring of the activity level(s) (i.e., enzymatic activity level(s)) of PAH protein in a subject, for example, in an animal (e.g., rodent, primate, and the like) or in a human subject. Activity levels can be measured or determined by any art-recognized method for determining enzymatic activity levels in biological samples. The term "activity level" or "enzymatic activity level" as used herein, preferably means the activity of the enzyme per volume, mass or weight of sample or total protein within a sample. In exemplary embodiments, the "activity level" or "enzymatic activity level" is described in terms of units per milliliter of fluid (e.g., bodily fluid, e.g., serum, plasma, urine and the like) or is described in terms of units per weight of tissue or per weight of protein (e.g., total protein) within a sample. Units (“U”) of enzyme activity can be described in terms of weight or mass of substrate hydrolyzed per unit time. In certain embodiments of the invention feature PAH activity described in terms of U / ml plasma or U / mg protein (tissue), where units (“U”) are described in terms of nmol substrate hydrolyzed per hour (or nmol / hr). Attorney Docket No.45817-0152WO1 / MTX975.20 PAH Biomarkers Further aspects of the invention feature determining the level (or levels) of a biomarker determined in a sample as compared to a level (e.g., a reference level) of the same or another biomarker in another sample, e.g., from the same patient, from another patient, from a control and / or from the same or different time points, and / or a physiologic level, and / or an elevated level, and / or a supraphysiologic level, and / or a level of a control. The skilled artisan will be familiar with physiologic levels of biomarkers, for example, levels in normal or wildtype animals, normal or healthy subjects, and the like, in particular, the level or levels characteristic of subjects who are healthy and / or normal functioning. As used herein, the phrase “elevated level” means amounts greater than normally found in a normal or wildtype preclinical animal or in a normal or healthy subject, e.g. a human subject. As used herein, the term “supraphysiologic” means amounts greater than normally found in a normal or wildtype preclinical animal or in a normal or healthy subject, e.g. a human subject, optionally producing a significantly enhanced physiologic response. As used herein, the term "comparing" or "compared to" preferably means the mathematical comparison of the two or more values, e.g., of the levels of the biomarker(s). It will thus be readily apparent to the skilled artisan whether one of the values is higher, lower or identical to another value or group of values if at least two of such values are compared with each other. Comparing or comparison to can be in the context, for example, of comparing to a control value, e.g., as compared to a reference blood, serum, plasma, and / or tissue (e.g., liver) phenylalanine level, in said subject prior to administration (e.g., in a person suffering from PKU) or in a normal or healthy subject. Comparing or comparison to can also be in the context, for example, of comparing to a control value, e.g., as compared to a reference blood, serum, plasma and / or tissue (e.g., liver) Phe level in said subject prior to administration (e.g., in a person suffering from PKU) or in a normal or healthy subject. As used herein, a “control” is preferably a sample from a subject wherein the PKU status of said subject is known. In one embodiment, a control is a sample of a healthy patient. In another embodiment, the control is a sample from at least one subject having a known PKU status, for example, a severe, mild, or healthy PKU Attorney Docket No.45817-0152WO1 / MTX975.20 status, e.g. a control patient. In another embodiment, the control is a sample from a subject not being treated for PKU. In a still further embodiment, the control is a sample from a single subject or a pool of samples from different subjects and / or samples taken from the subject(s) at different time points. The term "level" or "level of a biomarker" as used herein, preferably means the mass, weight or concentration of a biomarker of the invention within a sample or a subject. It will be understood by the skilled artisan that in certain embodiments the sample may be subjected to, e.g., one or more of the following: substance purification, precipitation, separation, e.g. centrifugation and / or HPLC and subsequently subjected to determining the level of the biomarker, e.g. using mass spectrometric analysis. In certain embodiments, LC-MS can be used as a means for determining the level of a biomarker according to the invention. The term "determining the level" of a biomarker as used herein can mean methods which include quantifying an amount of at least one substance in a sample from a subject, for example, in a bodily fluid from the subject (e.g., serum, plasma, urine, lymph, etc.) or in a tissue of the subject (e.g., liver, etc.). The term "reference level" as used herein can refer to levels (e.g., of a biomarker) in a subject prior to administration of an mRNA therapy of the invention (e.g., in a person suffering from PKU) or in a normal or healthy subject. As used herein, the term “normal subject” or “healthy subject” refers to a subject not suffering from symptoms associated with PKU. Moreover, a subject will be considered to be normal (or healthy) if it has no mutation of the functional portions or domains of the PAH gene and / or no mutation of the PAH gene resulting in a reduction of or deficiency of the enzyme PAH or the activity thereof, resulting in symptoms associated with PKU. Said mutations will be detected if a sample from the subject is subjected to a genetic testing for such PAH mutations. In certain embodiments of the present invention, a sample from a healthy subject is used as a control sample, or the known or standardized value for the level of biomarker from samples of healthy or normal subjects is used as a control. In some embodiments, comparing the level of the biomarker in a sample from a subject in need of treatment for PKU or in a subject being treated for PKU to a control level of the biomarker comprises comparing the level of the biomarker in the Attorney Docket No.45817-0152WO1 / MTX975.20 sample from the subject (in need of treatment or being treated for PKU) to a baseline or reference level, wherein if a level of the biomarker in the sample from the subject (in need of treatment or being treated for PKU) is elevated, increased or higher compared to the baseline or reference level, this is indicative that the subject is suffering from PKU and / or is in need of treatment; and / or wherein if a level of the biomarker in the sample from the subject (in need of treatment or being treated for PKU) is decreased or lower compared to the baseline level this is indicative that the subject is not suffering from, is successfully being treated for PKU, or is not in need of treatment for PKU. The stronger the reduction (e.g., at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 10- fold, at least 20-fold, at least-30 fold, at least 40-fold, at least 50-fold reduction and / or 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% reduction) of the level of a biomarker, within a certain time period, e.g., within 6 hours, within 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, or 72 hours, and / or for a certain duration of time, e.g., 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, etc. the more successful is a therapy, such as for example an mRNA therapy of the invention (e.g., a single dose or a multiple regimen). A reduction of at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least 100% or more of the level of biomarker, in particular, in bodily fluid (e.g., plasma, serum, urine, e.g., urinary sediment) or in tissue(s) in a subject (e.g., liver), within 1, 2, 3, 4, 5, 6 or more days following administration is indicative of a dose suitable for successful treatment PKU, wherein reduction as used herein, preferably means that the level of biomarker determined at the end of a specified time period (e.g., post-administration, for example, of a single intravenous dose) is compared to the level of the same biomarker determined at the beginning of said time period (e.g., pre-administration of said dose). Exemplary time periods include 12, 24, 48, 72, 96, 120 or 144 hours post administration, in particular 24, 48, 72 or 96 hours post administration. Attorney Docket No.45817-0152WO1 / MTX975.20 A sustained reduction in substrate levels (e.g., biomarkers) is particularly indicative of mRNA therapeutic dosing and / or administration regimens successful for treatment of PKU. Such sustained reduction can be referred to herein as “duration” of effect. In exemplary embodiments, a reduction of at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 100% or more of the level of biomarker, in particular, in a bodily fluid (e.g., plasma, serum, urine, e.g., urinary sediment) or in tissue(s) in a subject (e.g., liver), within 1, 2, 3, 4, 5, 6, 7, 8 or more days following administration is indicative of a successful therapeutic approach. In exemplary embodiments, sustained reduction in substrate (e.g., biomarker) levels in one or more samples (e.g., fluids and / or tissues) is preferred. For example, mRNA therapies resulting in sustained reduction in a biomarker, optionally in combination with sustained reduction of said biomarker in at least one tissue, preferably two, three, four, five or more tissues, is indicative of successful treatment. In some embodiments, each dose of an mRNA therapy of the invention is about 0.4 mg / kg to about 1.7 mg / kg (“mg / kg” refers to mg of mRNA administered per kg of body weight of the treated subject). In some embodiments, each dose of an mRNA therapy of the invention is about 0.4 mg / kg. In some embodiments, each dose of an mRNA therapy of the invention is about 0.5 mg / kg. In some embodiments, each dose of an mRNA therapy of the invention is about 0.6 mg / kg. In some embodiments, each dose of an mRNA therapy of the invention is about 0.7 mg / kg. In some embodiments, each dose of an mRNA therapy of the invention is about 0.8 mg / kg. In some embodiments, each dose of an mRNA therapy of the invention is about 0.9 mg / kg. In some embodiments, each dose of an mRNA therapy of the invention is about 1.0 mg / kg. In some embodiments, each dose of an mRNA therapy of the invention is about 1.1 mg / kg. In some embodiments, each dose of an mRNA therapy of the invention is about 1.2 mg / kg. In some embodiments, each dose of an mRNA therapy of the invention is about 1.3 mg / kg. In some embodiments, each dose of an mRNA therapy of the invention is about 1.4 mg / kg. In some embodiments, each dose of an mRNA therapy of the invention is about 1.5 mg / kg. In some embodiments, each Attorney Docket No.45817-0152WO1 / MTX975.20 dose of an mRNA therapy of the invention is about 1.6 mg / kg. In some embodiments, each dose of an mRNA therapy of the invention is about 1.7 mg / kg. In some embodiments, each dose of an mRNA therapy of the invention is administered about once every week. In some embodiments, each dose of an mRNA therapy of the invention is administered once every week. In some embodiments, each dose of an mRNA therapy of the invention is administered about once every two weeks. In some embodiments, each dose of an mRNA therapy of the invention is administered once every two weeks. In some embodiments, each dose of an mRNA therapy of the invention is administered about once every three weeks. In some embodiments, each dose of an mRNA therapy of the invention is administered once every three weeks. In some embodiments, each dose of an mRNA therapy of the invention is administered about once every four weeks. In some embodiments, each dose of an mRNA therapy of the invention is administered once every four weeks. Compositions and Formulations for Use Certain aspects of the invention are directed to compositions or formulations comprising any of the polynucleotides disclosed above. In some embodiments, the composition or formulation comprises: (i) a polynucleotide (e.g., a RNA, e.g., an mRNA) comprising a sequence- optimized nucleotide sequence (e.g., an ORF) encoding a PAH polypeptide (e.g., SEQ ID NO:1), wherein the polynucleotide comprises at least one chemically modified nucleobase, e.g., N1-methylpseudouracil or 5-methoxyuracil (e.g., wherein at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or 100% of the uracils are N1-methylpseudouracils or 5- methoxyuracils), and wherein the polynucleotide further comprises a miRNA binding site, e.g., a miRNA binding site that binds to miR-142 (e.g., a miR-142-3p or miR- 142-5p binding site) and / or a miRNA binding site that binds to miR-126 (e.g., a miR- 126-3p or miR-126-5p binding site); and (ii) a delivery agent comprising, e.g., a compound having the Formula (I), e.g., Compound II, Compound A, or Compound B; a compound having the Formula (III), Attorney Docket No.45817-0152WO1 / MTX975.20 (IV), (V), or (VI), e.g., Compound I or Compound VI, or any combination thereof. In some embodiments, the delivery agent is a lipid nanoparticle comprising Compound II, Compound VI, a salt or a stereoisomer thereof, or any combination thereof. In some embodiments, the delivery agent comprises an ionizable amino lipid (e.g., Compound II, VI, or A), a helper lipid (e.g., DSPC), a sterol (e.g., Cholesterol), and a PEG lipid (e.g., Compound I or PEG-DMG), e.g., with a mole ratio in the range of about (i) 40-50 mol% ionizable amino lipid (e.g., Compound II, VI, or A), optionally 45-50 mol% ionizable amino lipid, for example, 45-46 mol%, 46-47 mol%, 47-48 mol%, 48-49 mol%, or 49-50 mol% for example about 45 mol%, 45.5 mol%, 46 mol%, 46.5 mol%, 47 mol%, 47.5 mol%, 48 mol%, 48.5 mol%, 49 mol%, or 49.5 mol%; (ii) 30-45 mol% sterol (e.g., cholesterol), optionally 35-42 mol% sterol, for example, 30-31 mol%, 31-32 mol%, 32-33 mol%, 33-34 mol%, 35-35 mol%, 35-36 mol%, 36-37 mol%, 37-38 mol%, 38-39 mol%, or 39-40 mol%, or 40-42 mol% sterol; (iii) 5-15 mol% helper lipid (e.g., DSPC), optionally 10-15 mol% helper lipid, for example, 5-6 mol%, 6-7 mol%, 7-8 mol%, 8-9 mol%, 9-10 mol%, 10-11 mol%, 11-12 mol%, 12-13 mol%, 13-14 mol%, or 14-15 mol% helper lipid; and (iv) 1-5% PEG lipid (e.g., Compound I or PEG-DMG), optionally 1-5 mol% PEG lipid, for example 1.5 to 2.5 mol%, 1-2 mol%, 2-3 mol%, 3-4 mol%, or 4-5 mol% PEG lipid. In some embodiments, the uracil or thymine content of the ORF relative to the theoretical minimum uracil or thymine content of a nucleotide sequence encoding the PAH polypeptide (%UTMor %TTM), is between about 100% and about 150%. In some embodiments, the polynucleotides, compositions or formulations above are used to treat and / or prevent PAH-related diseases, disorders or conditions, e.g., PKU. Definitions In order that the present disclosure can be more readily understood, certain terms are first defined. As used in this application, except as otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application. Attorney Docket No.45817-0152WO1 / MTX975.20 The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. In this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as the terms "one or more," and "at least one" can be used interchangeably herein. In certain aspects, the term "a" or "an" means "single." In other aspects, the term "a" or "an" includes "two or more" or "multiple." Furthermore, "and / or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" as used in a phrase such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone). Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary Of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure. Wherever aspects are described herein with the language "comprising," otherwise analogous aspects described in terms of "consisting of" and / or "consisting essentially of" are also provided. Units, prefixes, and symbols are denoted in their Système International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range. Where a range of values is recited, it is to be understood that each intervening integer value, and each fraction thereof, between the recited upper and lower limits of Attorney Docket No.45817-0152WO1 / MTX975.20 that range is also specifically disclosed, along with each subrange between such values. The upper and lower limits of any range can independently be included in or excluded from the range, and each range where either, neither or both limits are included is also encompassed within the invention. Where a value is explicitly recited, it is to be understood that values which are about the same quantity or amount as the recited value are also within the scope of the invention. Where a combination is disclosed, each subcombination of the elements of that combination is also specifically disclosed and is within the scope of the invention. Conversely, where different elements or groups of elements are individually disclosed, combinations thereof are also disclosed. Where any element of an invention is disclosed as having a plurality of alternatives, examples of that invention in which each alternative is excluded singly or in any combination with the other alternatives are also hereby disclosed; more than one element of an invention can have such exclusions, and all combinations of elements having such exclusions are hereby disclosed. Nucleotides are referred to by their commonly accepted single-letter codes. Unless otherwise indicated, nucleic acids are written left to right in 5′ to 3′ orientation. Nucleobases are referred to herein by their commonly known one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Accordingly, A represents adenine, C represents cytosine, G represents guanine, T represents thymine, U represents uracil. Amino acids are referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Unless otherwise indicated, amino acid sequences are written left to right in amino to carboxy orientation. About: The term "about" as used in connection with a numerical value throughout the specification and the claims denotes an interval of accuracy, familiar and acceptable to a person skilled in the art, such interval of accuracy is ± 10 %. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, Attorney Docket No.45817-0152WO1 / MTX975.20 to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. Approximately: As used herein, the term "approximately," as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term "approximately" refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value). Dosing regimen: As used herein, a "dosing regimen" or a "dosing regimen" is a schedule of administration or physician determined regimen of treatment, prophylaxis, or palliative care. Effective Amount: As used herein, the term "effective amount" of an agent is that amount sufficient to effect beneficial or desired results, for example, clinical results, and, as such, an "effective amount" depends upon the context in which it is being applied. For example, in the context of administering an agent that treats a protein deficiency (e.g., a PAH deficiency), an effective amount of an agent is, for example, an amount of mRNA expressing sufficient PAH to ameliorate, reduce, eliminate, or prevent the symptoms associated with the PAH deficiency, as compared to the severity of the symptom observed without administration of the agent. The term "effective amount" can be used interchangeably with "effective dose," "therapeutically effective amount," or "therapeutically effective dose." PAH Associated Disease: As used herein the terms "PAH-associated disease" or "PAH-associated disorder" refer to diseases or disorders, respectively, which result from aberrant PAH activity (e.g., decreased activity or increased activity). As a non- limiting example, PKU is a PAH associated disease. The terms "PAH enzymatic activity" and "PAH activity," are used interchangeably in the present disclosure and refer to PAH's ability to convert phenylalanine to tyrosine. Accordingly, a PAH polypeptide having PAH enzymatic activity or PAH activity refers to a polypeptide that has measurable enzymatic activity in catalyzing the conversion of phenylalanine to tyrosine. Attorney Docket No.45817-0152WO1 / MTX975.20 Methods of Administration: As used herein, “methods of administration” can include intravenous, intramuscular, intradermal, subcutaneous, or other methods of delivering a composition to a subject. A method of administration can be selected to target delivery (e.g., to specifically deliver) to a specific region or system of a body. Nanoparticle Composition: As used herein, a “nanoparticle composition” is a composition comprising one or more lipids. Nanoparticle compositions are typically sized on the order of micrometers or smaller and can include a lipid bilayer. Nanoparticle compositions encompass lipid nanoparticles (LNPs), liposomes (e.g., lipid vesicles), and lipoplexes. For example, a nanoparticle composition can be a liposome having a lipid bilayer with a diameter of 500 nm or less. The phrase "nucleotide sequence encoding" refers to the nucleic acid (e.g., an mRNA or DNA molecule) coding sequence which encodes a polypeptide. The coding sequence can further include initiation and termination signals operably linked to regulatory elements including a promoter and polyadenylation signal capable of directing expression in the cells of an individual or mammal to which the nucleic acid is administered. The coding sequence can further include sequences that encode signal peptides. Patient: As used herein, "patient" refers to a subject who can seek or be in need of treatment, requires treatment, is receiving treatment, will receive treatment, or a subject who is under care by a trained professional for a particular disease or condition. In some embodiments, the treatment is needed, required, or received to prevent or decrease the risk of developing acute disease, i.e., it is a prophylactic treatment. Pseudouridine: As used herein, pseudouridine (ψ) refers to the C-glycoside isomer of the nucleoside uridine. A "pseudouridine analog" is any modification, variant, isoform or derivative of pseudouridine. For example, pseudouridine analogs include but are not limited to 1-carboxymethyl-pseudouridine, 1-propynyl- pseudouridine, 1-taurinomethyl-pseudouridine, 1-taurinomethyl-4-thio-pseudouridine, 1-methylpseudouridine (m1ψ) (also known as N1-methyl-pseudouridine), 1-methyl-4- thio-pseudouridine (m1s4ψ), 4-thio-1-methyl-pseudouridine, 3-methyl-pseudouridine (m3ψ), 2-thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1- methyl-1-deaza-pseudouridine, dihydropseudouridine, 2-thio-dihydropseudouridine, Attorney Docket No.45817-0152WO1 / MTX975.20 2-methoxyuridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-methoxy- 2-thio-pseudouridine, 1-methyl-3-(3-amino-3-carboxypropyl)pseudouridine (acp3ψ), and 2′-O-methyl-pseudouridine (ψm). Therapeutically effective amount: As used herein, the term "therapeutically effective amount" means an of an agent to be delivered (e.g., nucleic acid, drug, therapeutic agent, diagnostic agent, prophylactic agent, etc.) that is sufficient, when administered to a subject suffering from or susceptible to an infection, disease, disorder, and / or condition, to treat, improve symptoms of, diagnose, prevent, and / or delay the onset of the infection, disease, disorder, and / or condition. Uracil: Uracil is one of the four nucleobases in the nucleic acid of RNA, and it is represented by the letter U. Uracil can be attached to a ribose ring, or more specifically, a ribofuranose via a ^-N1-glycosidic bond to yield the nucleoside uridine. The nucleoside uridine is also commonly abbreviated according to the one letter code of its nucleobase, i.e., U. Thus, in the context of the present disclosure, when a monomer in a polynucleotide sequence is U, such U is designated interchangeably as a "uracil" or a "uridine." Uridine Content: The terms "uridine content" or "uracil content" are interchangeable and refer to the amount of uracil or uridine present in a certain nucleic acid sequence. Uridine content or uracil content can be expressed as an absolute value (total number of uridine or uracil in the sequence) or relative (uridine or uracil percentage respect to the total number of nucleobases in the nucleic acid sequence). Uridine-Modified Sequence: The terms "uridine-modified sequence" refers to a sequence optimized nucleic acid (e.g., a synthetic mRNA sequence) with a different overall or local uridine content (higher or lower uridine content) or with different uridine patterns (e.g., gradient distribution or clustering) with respect to the uridine content and / or uridine patterns of a candidate nucleic acid sequence. In the content of the present disclosure, the terms "uridine-modified sequence" and "uracil-modified sequence" are considered equivalent and interchangeable. Nucleobase: As used herein, the term “nucleobase” (alternatively “nucleotide base” or “nitrogenous base”) refers to a purine or pyrimidine heterocyclic compound found in nucleic acids, including any derivatives or analogs of the naturally occurring Attorney Docket No.45817-0152WO1 / MTX975.20 purines and pyrimidines that confer improved properties (e.g., binding affinity, nuclease resistance, chemical stability) to a nucleic acid or a portion or segment thereof. Adenine, cytosine, guanine, thymine, and uracil are the nucleobases predominately found in natural nucleic acids. Other natural, non-natural, and / or synthetic nucleobases, as known in the art and / or described herein, can be incorporated into nucleic acids. Unless otherwise specified, the nucleobase sequence of a SEQ ID NO described herein encompasses both natural nucleobases and chemically modified nucleobases (e.g., a “U” designation in a SEQ ID NO encompasses both uracil and chemically modified uracil). Nucleoside / Nucleotide: As used herein, the term “nucleoside” refers to a compound containing a sugar molecule (e.g., a ribose in RNA or a deoxyribose in DNA), or derivative or analog thereof, covalently linked to a nucleobase (e.g., a purine or pyrimidine), or a derivative or analog thereof (also referred to herein as “nucleobase”), but lacking an internucleoside linking group (e.g., a phosphate group). As used herein, the term “nucleotide” refers to a nucleoside covalently bonded to an internucleoside linking group (e.g., a phosphate group), or any derivative, analog, or modification thereof that confers improved chemical and / or functional properties (e.g., binding affinity, nuclease resistance, chemical stability) to a nucleic acid or a portion or segment thereof. Nucleic acid: As used herein, the term “nucleic acid” is used in its broadest sense and encompasses any compound and / or substance that includes a polymer of nucleotides, or derivatives or analogs thereof. These polymers are often referred to as “polynucleotides”. Accordingly, as used herein the terms “nucleic acid” and “polynucleotide” are equivalent and are used interchangeably. Exemplary nucleic acids or polynucleotides of the disclosure include, but are not limited to, ribonucleic acids (RNAs), deoxyribonucleic acids (DNAs), DNA-RNA hybrids, RNAi-inducing agents, RNAi agents, siRNAs, shRNAs, mRNAs, modified mRNAs, miRNAs, antisense RNAs, ribozymes, catalytic DNA, RNAs that induce triple helix formation, threose nucleic acids (TNAs), glycol nucleic acids (GNAs), peptide nucleic acids (PNAs), locked nucleic acids (LNAs, including LNA having a β-D-ribo configuration, α-LNA having an α-L-ribo configuration (a diastereomer of LNA), 2'-amino-LNA Attorney Docket No.45817-0152WO1 / MTX975.20 having a 2'-amino functionalization, and 2'-amino-α-LNA having a 2'-amino functionalization) or hybrids thereof. Open Reading Frame: As used herein, the term “open reading frame”, abbreviated as “ORF”, refers to a segment or region of an mRNA molecule that encodes a polypeptide. The ORF comprises a continuous stretch of non-overlapping, in-frame codons, beginning with the initiation codon and ending with a stop codon, and is translated by the ribosome. Equivalents and Scope Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments in accordance with the invention described herein. The scope of the present invention is not intended to be limited to the above Description, but rather is as set forth in the appended claims. In the claims, articles such as "a," "an," and "the" can mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. It is also noted that the term "comprising" is intended to be open and permits but does not require the inclusion of additional elements or steps. When the term "comprising" is used herein, the term "consisting of" is thus also encompassed and disclosed. Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges Attorney Docket No.45817-0152WO1 / MTX975.20 can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. In addition, it is to be understood that any particular embodiment of the present invention that falls within the prior art can be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to one of ordinary skill in the art, they can be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions of the invention (e.g., any nucleic acid or protein encoded thereby; any method of production; any method of use; etc.) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art. All cited sources, for example, references, publications, databases, database entries, and art cited herein, are incorporated into this application by reference, even if not expressly stated in the citation. In case of conflicting statements of a cited source and the instant application, the statement in the instant application shall control. Section and table headings are not intended to be limiting. EXAMPLES EXAMPLE 1: Synthesis of mRNA Encoding Phenylalanine Hydroxylase An mRNA encoding the human M180T phenylalanine hydroxylase (PAH) polypeptide of SEQ ID NO:1 is constructed by using the ORF sequence (nucleotide) provided in SEQ ID NO:10. The mRNA sequence includes both 5' and 3' UTR regions flanking the ORF sequence. In an exemplary construct (SEQ ID NO:11), the 5' UTR and 3' UTR sequences are SEQ ID NO:56 and SEQ ID NO:108, respectively. The PAH mRNA sequences are prepared as modified mRNAs. Specifically, during in vitro transcription, modified mRNAs can be generated using N1- methylpseudouridine-5′-triphosphate to ensure that the mRNAs contain 100% N1- methylpseudouridine instead of uridine. Alternatively, during in vitro transcription, modified mRNA can be generated using N1-methoxyuridine-5′-Triphosphate to ensure that the mRNAs contain 100% 5-methoxyuridine instead of uridine. Further, PAH mRNAs can be synthesized with a primer that introduces a polyA-tail, and a cap Attorney Docket No.45817-0152WO1 / MTX975.20 structure is generated on both mRNAs using co-transcriptional capping to incorporate a m7G-ppp-Gm-AG 5′ cap1. Alternatively, mRNA can be synthesized and the polyA- tail introduced during Gibson assembly of the DNA template. The PAH mRNA is modified by ligation to stabilize the poly(A) tail. Ligation is performed using 0.5-1.5 mg / mL mRNA (5’ Cap1, 3’ A100), 50 mM Tris-HCl pH 7.5, 10 mM MgCl2, 1 mM TCEP, 1000 units / mL T4 RNA Ligase 1, 1 mM ATP, 20% w / v polyethylene glycol 8000, and 5:1 molar ratio of a modifying oligo to mRNA. The modifying oligo has the sequence of 5’-phosphate- AAAAAAAAAAAAAAAAAAAA-(inverted deoxythymidine (idT) (SEQ ID NO:209) (see below). Ligation reactions are mixed and incubated at room temperature (~22°C) for 4 hours. Stable tail mRNA is purified by dT purification, reverse phase purification, hydroxyapatite purification, ultrafiltration into water, and sterile filtration. The resulting stable tail-containing mRNAs contain the following structure at the 3’end, starting with the polyA region: A100- UCUAGAAAAAAAAAAAAAAAAAAAA -inverted deoxythymidine (SEQ ID NO:211). The modifying oligo with stabilized tail (5’-phosphate- AAAAAAAAAAAAAAAAAAAA-(inverted deoxythymidine) (SEQ ID NO:209)) is depicted below: . Attorney Docket No.45817-0152WO1 / MTX975.20 EXAMPLE 2: Production of Phenylalanine Hydroxylase mRNA Nanoparticle Compositions A. Production of nanoparticle compositions Nanoparticles can be made with mixing processes such as microfluidics and T-junction mixing of two fluid streams, one of which contains the polynucleotide and the other has the lipid components. Lipid compositions are prepared by combining an ionizable amino lipid disclosed herein, e.g., a lipid according to Formula (I) such as Compound II, Compound A, or Compound B, a phospholipid (such as Compound I or 1,2 dimyristoyl sn glycerol methoxypolyethylene glycol, also known as PEG-DMG, obtainable from Avanti Polar Lipids, Alabaster, AL), a PEG lipid (such as 1,2 dimyristoyl sn glycerol methoxypolyethylene glycol, also known as PEG-DMG, obtainable from Avanti Polar Lipids, Alabaster, AL), and a structural lipid (such as cholesterol, obtainable from Sigma Aldrich, Taufkirchen, Germany, or a corticosteroid (such as prednisolone, dexamethasone, prednisone, and hydrocortisone), or a combination thereof) at concentrations of about 50 mM in ethanol. Solutions should be refrigerated for storage at, for example, -...

Claims

Attorney Docket No.45817-0152WO1 / MTX975.20 WHAT IS CLAIMED IS:

1. A method of treating phenylketonuria in a human subject in need thereof, the method comprising administering to the human subject by intravenous infusion a lipid nanoparticle comprising a messenger RNA (mRNA) comprising an open reading frame (ORF) encoding the phenylalanine hydroxylase polypeptide of SEQ ID NO:1, wherein the mRNA is administered at a dose of 0.4 mg / kg to 1.7 mg / kg.

2. The method of claim 1, wherein the ORF is at least 80% identical to the nucleotide sequence of SEQ ID NO:

10.

3. The method of claim 1, wherein the ORF is at least 95% identical to the nucleotide sequence of SEQ ID NO:

10.

4. The method of claim 1, wherein the ORF is at least 99% identical to the nucleotide sequence of SEQ ID NO:

10.

5. The method of claim 1, wherein the ORF is 100% identical to the nucleotide sequence of SEQ ID NO:

10.

6. The method of any one of claims 1 to 5, wherein the mRNA comprises a 5' UTR comprising the nucleotide sequence of SEQ ID NO:

56.

7. The method of any one of claims 1 to 6, wherein the mRNA comprises a 3' UTR comprising the nucleotide sequence of SEQ ID NO:

108.

8. The method of claim 1, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:

11.

9. The method of any one of claims 1 to 8, wherein the mRNA comprises a 5′ terminal cap.Attorney Docket No.45817-0152WO1 / MTX975.20 10. The method of claim 9, wherein the 5' terminal cap comprises m7G-ppp- Gm.

11. The method of any one of claims 1 to 10, wherein the mRNA comprises a poly-A region.

12. The method of claim 11, wherein the poly-A region comprises SEQ ID NO:

195.

13. The method of claim 11, wherein the poly-A region comprises A100- UCUAG-A20-inverted deoxy-thymidine (SEQ ID NO:211).

14. The method of any one of claims 1 to 13, wherein all of the uracils of the mRNA are N1-methylpseudouracils.

15. The method of claim 1, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:

12.

16. The method of any one of claims 1 to 15, wherein the mRNA is administered at a dose of about 0.4 mg / kg.

17. The method of any one of claims 1 to 15, wherein the mRNA is administered at a dose of about 0.5 mg / kg.

18. The method of any one of claims 1 to 15, wherein the mRNA is administered at a dose of about 0.6 mg / kg.

19. The method of any one of claims 1 to 15, wherein the mRNA is administered at a dose of about 0.7 mg / kg.

20. The method of any one of claims 1 to 15, wherein the mRNA is administered at a dose of about 0.8 mg / kg.Attorney Docket No.45817-0152WO1 / MTX975.20 21. The method of any one of claims 1 to 15, wherein the mRNA is administered at a dose of about 0.9 mg / kg.

22. The method of any one of claims 1 to 15, wherein the mRNA is administered at a dose of about 1.0 mg / kg.

23. The method of any one of claims 1 to 15, wherein the mRNA is administered at a dose of about 1.1 mg / kg.

24. The method of any one of claims 1 to 15, wherein the mRNA is administered at a dose of about 1.2 mg / kg.

25. The method of any one of claims 1 to 15, wherein the mRNA is administered at a dose of about 1.3 mg / kg.

26. The method of any one of claims 1 to 15, wherein the mRNA is administered at a dose of about 1.4 mg / kg.

27. The method of any one of claims 1 to 15, wherein the mRNA is administered at a dose of about 1.5 mg / kg.

28. The method of any one of claims 1 to 15, wherein the mRNA is administered at a dose of about 1.6 mg / kg.

29. The method of any one of claims 1 to 15, wherein the mRNA is administered at a dose of about 1.7 mg / kg.

30. The method of any one of claims 1 to 29, comprising multiple administrations of the dose.Attorney Docket No.45817-0152WO1 / MTX975.20 31. The method of claim 30, wherein the dose is administered repeatedly at intervals of about once every 1 to 4 weeks.

32. The method of claim 30, wherein the dose is administered repeatedly at intervals of about once every week.

33. The method of claim 30, wherein the dose is administered repeatedly at intervals of about once every 2 weeks.

34. The method of claim 30, wherein the dose is administered repeatedly at intervals of about once every 3 weeks.

35. The method of claim 30, wherein the dose is administered repeatedly at intervals of about once every 4 weeks.

36. The method of any one of claims 1 to 15, wherein the mRNA is administered once every week at a dose of about 0.4 mg / kg.

37. The method of any one of claims 1 to 15, wherein the mRNA is administered once every week at a dose of about 0.5 mg / kg.

38. The method of any one of claims 1 to 15, wherein the mRNA is administered once every week at a dose of about 0.6 mg / kg.

39. The method of any one of claims 1 to 15, wherein the mRNA is administered once every week at a dose of about 0.7 mg / kg.

40. The method of any one of claims 1 to 15, wherein the mRNA is administered once every week at a dose of about 0.8 mg / kg.

41. The method of any one of claims 1 to 15, wherein the mRNA is administered once every week at a dose of about 0.9 mg / kg.Attorney Docket No.45817-0152WO1 / MTX975.20 42. The method of any one of claims 1 to 15, wherein the mRNA is administered once every week at a dose of about 1.0 mg / kg.

43. The method of any one of claims 1 to 15, wherein the mRNA is administered once every week at a dose of about 1.1 mg / kg.

44. The method of any one of claims 1 to 15, wherein the mRNA is administered once every week at a dose of about 1.2 mg / kg.

45. The method of any one of claims 1 to 15, wherein the mRNA is administered once every week at a dose of about 1.3 mg / kg.

46. The method of any one of claims 1 to 15, wherein the mRNA is administered once every week at a dose of about 1.4 mg / kg.

47. The method of any one of claims 1 to 15, wherein the mRNA is administered once every week at a dose of about 1.5 mg / kg.

48. The method of any one of claims 1 to 15, wherein the mRNA is administered once every week at a dose of about 1.6 mg / kg.

49. The method of any one of claims 1 to 15, wherein the mRNA is administered once every week at a dose of about 1.7 mg / kg.

50. The method of any one of claims 1 to 15, wherein the mRNA is administered once every 2 weeks at a dose of about 0.4 mg / kg.

51. The method of any one of claims 1 to 15, wherein the mRNA is administered once every 2 weeks at a dose of about 0.5 mg / kg.Attorney Docket No.45817-0152WO1 / MTX975.20 52. The method of any one of claims 1 to 15, wherein the mRNA is administered once every 2 weeks at a dose of about 0.6 mg / kg.

53. The method of any one of claims 1 to 15, wherein the mRNA is administered once every 2 weeks at a dose of about 0.7 mg / kg.

54. The method of any one of claims 1 to 15, wherein the mRNA is administered once every 2 weeks at a dose of about 0.8 mg / kg.

55. The method of any one of claims 1 to 15, wherein the mRNA is administered once every 2 weeks at a dose of about 0.9 mg / kg.

56. The method of any one of claims 1 to 15, wherein the mRNA is administered once every 2 weeks at a dose of about 1.0 mg / kg.

57. The method of any one of claims 1 to 15, wherein the mRNA is administered once every 2 weeks at a dose of about 1.1 mg / kg.

58. The method of any one of claims 1 to 15, wherein the mRNA is administered once every 2 weeks at a dose of about 1.2 mg / kg.

59. The method of any one of claims 1 to 15, wherein the mRNA is administered once every 2 weeks at a dose of about 1.3 mg / kg.

60. The method of any one of claims 1 to 15, wherein the mRNA is administered once every 2 weeks at a dose of about 1.4 mg / kg.

61. The method of any one of claims 1 to 15, wherein the mRNA is administered once every 2 weeks at a dose of about 1.5 mg / kg.

62. The method of any one of claims 1 to 15, wherein the mRNA is administered once every 2 weeks at a dose of about 1.6 mg / kg.Attorney Docket No.45817-0152WO1 / MTX975.20 63. The method of any one of claims 1 to 15, wherein the mRNA is administered once every 2 weeks at a dose of about 1.7 mg / kg.

64. The method of any one of claims 1 to 63, wherein the human subject is at least 18 years of age.

65. The method of any one of claims 1 to 64, wherein phenylketonuria in the human subject is confirmed by a genetic test identifying a mutation in the phenylalanine hydroxylase gene.

66. The method of any one of claims 1 to 65, wherein the human subject does not have a BH4 deficiency or a DNAJC12 deficiency.

67. The method of any one of claims 1 to 66, wherein prior to treatment the human subject has blood phenylalanine levels of at least 360 μmol / L.

68. The method of any one of claims 1 to 66, wherein prior to treatment the human subject has blood phenylalanine levels of at least 600 μmol / L.

69. The method of any one of claims 1 to 68, wherein the treatment reduces blood phenylalanine levels from baseline.

70. The method of any one of claims 1 to 69, wherein the treatment increases blood tyrosine levels from baseline.

71. The method of any one of claims 1 to 70, wherein the human subject is administered at least one of an H2-receptor blocker, an H1-receptor blocker, or acetaminophen / paracetamol or ibuprofen prior to infusion of the lipid nanoparticle.Attorney Docket No.45817-0152WO1 / MTX975.20 72. The method of any one of claims 1 to 70, wherein the human subject is administered an H2-receptor blocker, an H1-receptor blocker, and acetaminophen / paracetamol or ibuprofen prior to infusion of the lipid nanoparticle.

73. The method of any one of claims 1 to 72, wherein the lipid nanoparticle comprises a compound of Formula (I): or its N-oxide, or a salt or isomer thereof,R’brancheddenotes a point of attachment; whereinselected from the group consisting of H, C2-12alkyl, and C2-12alkenyl; R2and R3are each independently selected from the group consisting of C1-14 alkyl and C2-14 alkenyl; R4is selected from the group consisting of -(CH2)nOH, wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, ,wherein denotes a point R10is Neach R is independently selected from the group consisting of C1-6alkyl, C2-3alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R5is independently selected from the group consisting of C1-3alkyl, C2-3 alkenyl, and H; each R6is independently selected from the group consisting of C1-3 alkyl, C2-3 alkenyl, and H;Attorney Docket No.45817-0152WO1 / MTX975.20 M and M’ are each independently selected from the group consisting of - C(O)O- and -OC(O)-; R’ is a C1-12alkyl or C2-12alkenyl; l is selected from the group consisting of 1, 2, 3, 4, and 5; and m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13.

74. The method of claim 73, wherein the lipid nanoparticle further comprises a phospholipid, a structural lipid, and a PEG-lipid.

75. The method of claim 74, wherein the PEG-lipid is Compound I.

76. The method of claim 74 or 75, wherein the lipid nanoparticle comprises: (i) 40-50 mol% of the compound of Formula (I), 30-45 mol% of the structural lipid, 5-15 mol% of the phospholipid, and 1-5 mol% of the PEG-lipid; or (ii) 45-50 mol% of the compound of Formula (I), 35-45 mol% of the structural lipid, 8-12 mol% of the phospholipid, and 1.5 to 3.5 mol% of the PEG-lipid.

77. The method of any one of claims 1 to 72, wherein the lipid nanoparticle comprises: (i) Compound II, (ii) cholesterol, and (iii) PEG-DMG or Compound I; (i) Compound VI, (ii) cholesterol, and (iii) PEG-DMG or Compound I; (i) Compound II, (ii) DSPC or DOPE, (iii) cholesterol, and (iv) PEG-DMG or Compound I; (i) Compound VI, (ii) DSPC or DOPE, (iii) cholesterol, and (iv) PEG-DMG or Compound I; (i) Compound II, (ii) cholesterol, and (iii) Compound I; (i) Compound II, (ii) DSPC or DOPE, (iii) cholesterol, and (iv) Compound I; (i) Compound B, (ii) cholesterol, and (iii) PEG-DMG or Compound I; (i) Compound B, (ii) DSPC or DOPE, (iii) cholesterol, and (iv) PEG-DMG or Compound I; (i) Compound B, (ii) cholesterol, and (iii) Compound I;Attorney Docket No.45817-0152WO1 / MTX975.20 (i) Compound B, (ii) DSPC or DOPE, (iii) cholesterol, and (iv) Compound I; (i) Compound A, (ii) cholesterol, and (iii) PEG-DMG or Compound I; (i) Compound A, (ii) DSPC or DOPE, (iii) cholesterol, and (iv) PEG-DMG or Compound I; (i) Compound A, (ii) cholesterol, and (iii) Compound I; or (i) Compound A, (ii) DSPC or DOPE, (iii) cholesterol, and (iv) Compound I.

78. The method of any one of claims 1 to 72, wherein the lipid nanoparticle comprises Compound II and Compound I.

79. The method of any one of claims 1 to 72, wherein the lipid nanoparticle comprises Compound II, DSPC, Cholesterol, and Compound I.

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