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238 Olema Road, Fairfox, CA 94930 A61P3/00 (2006.01) A61K 48/00 (2006.01) (US) ( 1 (51) International Patent Classification: COLOSI, Peter; 238 Olema Road, Fairfox, CA 94930 A61P3/00 (2006.01) A61K 48/00 (2006.01) (US). C12N 15/86 (2006.0 1) C12N 9/02 (2006.0 1) (74) Agent: RIEGER, Dale, L. et al.; Jones Day, 250 Vesey (21) International Application Number: Street, New York, NY 10281-1047 (US). PCT/US20 19/03 1252 (81) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of national protection av ailable) . AE, AG, AL, AM, 08 May 2019 (08.05.2019) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (25) Filing Language: English DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (26) Publication Language: English HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (30) Priority Data: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 62/669,292 09 May 2018 (09.05.2018) US OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 62/755,207 02 November 2018 (02. 11.2018) US SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 62/802,608 07 February 2019 (07.02.2019) US TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 62/819,414 15 March 2019 (15.03.2019) US (84) Designated States (unless otherwise indicated, for every (71) Applicant: BIOMARIN PHARMACEUTICAL INC. kind of regional protection available) . ARIPO (BW, GH, [US/US]; 105 Digital Drive, Novato, CA 94949 (US). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, , , , , o (57) Abstract: Provided herein are methods of treating phenylketonuria by normalizing levels of amino acids, neurotransmitters, and neurotransmitter metabolites in a subject having phenylketonuria. & [Continued on next page] W O 2019/217513 A2 TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: without international search report and to be republished upon receipt of that report (Rule 48.2(g)) METHODS OF TREATING PHENYLKETONURIA 1. FIELD [0001] Provided herein is a use of amino acid, neurotransmitter, and neurotransmitter metabolite levels in subjects having phenylketonuria (PKU) to optimize an effective dose of a PKU therapeutic. Also provided are methods of treating subjects having PKU comprising administering an effective amount of a PKU therapeutic where the effective amount is one that normalizes levels of amino acids, neurotransmitters, and neurotransmitter metabolites in the subject. Also provided herein is an optimized coding sequence of phenylalanine hydroxylase (PAH), which may be used in such vectors as recombinant adeno-associated virus (rAAV) vectors to achieve long term expression of PAH, the enzyme responsible for the metabolism of phenylalanine, in the liver of a subject. Also provided are methods of treatment utilizing the vectors in a gene replacement approach. 2. BACKGROUND [0002] Phenylketonuria (PKU) is an inborn error of amino acid metabolism that results from impaired activity of hepatic phenylalanine hydroxylase (PAH), the enzyme responsible for the metabolism of phenylalanine. Patients with PAH mutations that lead to PKU and hyperphenylalaninemia (HPA) display elevated levels of phenylalanine, impaired neurophysiologic functioning, and reduced cognitive development. For patients with severe PKU, there is the potential for irreversible mental retardation unless phenylalanine levels are maintained at low levels using dietary restrictions. The neurological symptoms of PKU are caused by the abnormal production of a number of neurotransmitters in subjects having PKU resulting from a loss of PAH which is required to convert phenylalanine into the precursor metabolite required for the synthesis of a number of neurotransmitters. [0003] Current treatment for PKU includes the lifetime adherence to a diet that is low in the amino acid phenylalanine. This dietary therapy is difficult to maintain and does not always eliminate the damaging neurological effects that can be caused by elevated phenylalanine levels. Less than ideal dietary control during pregnancy can lead to birth defects. In addition, it is very difficult for PKU/HPA patients to live a normal life while following the restricted diet, and dietary therapy can be associated with deficiencies of several nutrients, some of which are detrimental for brain development. Most low phenylalanine diet products have organoleptic properties sufficiently unsatisfactory that compliance with this treatment is compromised. Therefore, development of a therapeutic treatment would replace or supplement the current dietary treatment and prevent the neurological damages inflicted on those individuals with PKU, particularly for those patients with the most severe forms of the disease. However, an optimal PKU therapeutic would be one that normalizes levels of amino acids, neurotransmitters, and neurotransmitter metabolites whose levels are altered as a result of insufficient PAH activity. Accordingly, there is a clinical need for PKU therapeutics that when delivered in an effective amount are able to normalize levels of particular amino acids, neurotransmitters, and neurotransmitter metabolites in subjects having PKU. [0004] Gene therapy offers the potential of a cure through continuous endogenous production of PAH following a single administration of vector. This would represent a major clinical advance with significant implications for other congenital disorders that lack effective treatment. Adeno-associated virus (AAV) is a small, replication-defective, non-enveloped animal virus that infects humans and some other primate species. Several features of AAV make this virus an attractive vehicle for delivery of therapeutic proteins by gene therapy, including, for example, that AAV is not known to cause human disease and induces a mild immune response, and that AAV vectors can infect both dividing and quiescent cells without integrating into the host cell genome. Gene therapy vectors using AAV have been successfully used in some clinical trials, for example, for the delivery of human Factor IX (FIX) to the liver of adults for the treatment of Hemophilia B . [0005] Despite their positive features, AAV gene therapy vectors do have some drawbacks. In particular, the cloning capacity of AAV vectors is limited as a consequence of the DNA packaging capacity of the virus. The single-stranded DNA genome of wild-type AAV is about 4.7 kilobases (kb). In practice, AAV genomes of up to about 5.0 kb appear to be completely packaged, i.e., be full-length, into AAV virus particles. With the requirement that the nucleic acid genome in AAV vectors must have two AAV inverted terminal repeats (ITRs) of about 145 bases, the DNA packaging capacity of an AAV vector is such that a maximum of about 4.4 kb of protein-coding sequence can be encapsidated. [0006] PKU poses several new challenges due to the distinct molecular and biochemical properties of PAH relating to the size of the PAH cDNA and efficiency of PAH protein expression, as well as the unique functional properties of the enzyme, such as cellular localization, regulation of activity, and potential for heterodimerization with mutant PAH. Several attempts of vector-mediated PAH expression have been performed on mice. See, e.g., Harding et al, Complete correction of hyperphenylalaninemia following liver-directed, recombinant AAV2/8 vector mediated gene therapy in murine phenylketonuria Gene Ther. 2006 Mar; l3(5):457-6 and Viecelli et al, Treatment of Phenylketonuria Using Minicircle-Based Naked-DNA Gene Transfer to Murine Liver Hepatology. 2014 Sep; 60(3): 1035-1043 (see also WO20181261 12). However, the evaluations of delivery efficiency, immune stimulation, long term expression stability and safety are either lacking or not optimal. Thus, more efficient AAV.hPAH vectors are needed for PKU treatment. 3. SUMMARY [0007] The embodiments described herein relate to an AAV gene therapy vector for delivering functional human phenylalanine hydroxylase (PAH) to a subject in need thereof. [0008] In one aspect, provided is the use of a replication deficient adeno-associated virus (AAV) to deliver a human phenylalanine hydroxylase (PAH) gene to liver cells of patients (human subjects) diagnosed with PKU. The recombinant AAV vector (rAAV) used for delivering the hPAH gene ("rAAV.hPAH" or “AAV-PAH”) should have a tropism for the liver (e.g., an rAAV bearing an AAV5 capsid), and the hPAH transgene should be controlled by liver- specific expression control elements. In one embodiment, the expression control elements include one or more of the following: an enhancer; a promoter; an intron; and a polyA signal. Such elements are further described herein. [0009] In one embodiment, the hPAH transgene is contained within a recombinant adeno- associated virus (rAAV) vector genome which comprises (a) an AAV 5' inverted terminal repeat (ITR) sequence; (b) a promoter; (c) a codon optimized sequence encoding a human phenylalanine hydroxylase (hPAH); and (d) an AAV 3' ITR. In a specific embodiment, the codon optimized PAH sequence is SEQ ID NO: 7 . The promoter may be a synthetic promoter sequence comprising portions of an hAAT promoter, a hepatic control region (HCR) enhancer, and an ApoE enhancer. In a specific embodiment, the sequence of the promoter is SEQ ID NO: 6 . The AAV 5' ITR and/or AAV 3' ITR may be from a heterologous AAV pseudotype. In a specific embodiment, the ITR sequences are derived from AAV2. In another embodiment, the vector genome further comprises a polyadenylation signal sequence, which may be a bovine growth hormone (bGH) polyadenylation signal. In yet another embodiment, the vector genome further comprises an intron. In certain embodiments, the intron is a composite globin/AIAT intron sequence. In a specific embodiment, the intron sequence is SEQ ID NO: 14. The vector genome may be about 4 kb to about 5 kb in size. In a specific embodiment, the vector genome sequence is SEQ ID NO: 18.
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