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Tepzz¥5Z5 8 a T (19) TZZ¥Z___T (11) EP 3 505 181 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 03.07.2019 Bulletin 2019/27 A61K 38/46 (2006.01) C12N 9/16 (2006.01) (21) Application number: 18248241.4 (22) Date of filing: 28.12.2018 (84) Designated Contracting States: (72) Inventors: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • DICKSON, Patricia GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Torrance, CA California 90502 (US) PL PT RO RS SE SI SK SM TR • CHOU, Tsui-Fen Designated Extension States: Torrance, CA California 90502 (US) BA ME • EKINS, Sean Designated Validation States: Brooklyn, NY New York 11215 (US) KH MA MD TN • KAN, Shih-Hsin Torrance, CA California 90502 (US) (30) Priority: 28.12.2017 US 201762611472 P • LE, Steven 05.04.2018 US 201815946505 Torrance, CA California 90502 (US) • MOEN, Derek R. (71) Applicants: Torrance, CA California 90502 (US) • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (74) Representative: J A Kemp Torrance, CA 90502 (US) 14 South Square • Phoenix Nest Inc. Gray’s Inn Brooklyn NY 11215 (US) London WC1R 5JJ (GB) (54) PREPARATION OF ENZYME REPLACEMENT THERAPY FOR MUCOPOLYSACCHARIDOSIS IIID (57) The present disclosure relates to compositions for use in a method of treating Sanfilippo syndrome (also known as Sanfilippo disease type D, Sanfilippo D, mu- copolysaccharidosis type IIID, MPS IIID). The method can entail injecting to the spinal fluid of a MPS IIID patient an effective amount of a composition comprising a re- combinant human acetylglucosamine-6-sulfatase (GNS) protein comprising the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 1 and having the en- zymatic activity of the human GNS protein. The compo- sition can be tested in a testing buffer comprising less than 500 mM sodium, less than 100 mM citrate, less than 100 mM phosphate, less than 100 mM sulfate, and at least 0.005% Triton X-100 at a pH of about 5.6. EP 3 505 181 A1 Printed by Jouve, 75001 PARIS (FR) EP 3 505 181 A1 Description STATEMENT AS TO FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 5 [0001] This invention was made with government support under 1R41NS89061-01, 2R42NS089061-02, and 2R44NS089061-04 awarded by National Institute of Neurological Disorders and Stroke at National Institute of Health. The government has certain rights in the invention. BACKGROUND 10 [0002] Sanfilippo disease (mucopolysaccharidosis type III; MPS III) is a devastating neurodegenerative lysosomal storage disorder of childhood. Babies appear normal at birth, learn to walk and talk, but then gradually, progressively, deteriorate to a vegetative state over the span of 10 or 20 years. The central pathologic features of MPS III are neurologic: there is a slowing of development, severe behavioral problems, progressive cognitive decline, dementia, and decline in 15 motor skills that steadily lead to immobility, unresponsiveness, and death. [0003] The fundamental cause of MPS III is an inherited mutation in one of the 4 enzymes required to catabolize heparan sulfate (HS), a glycosaminoglycan which plays important structural and functional roles in the brain and else- where. Each type of MPS III (A to D) is due to deficiency of a different enzyme in the HS breakdown pathway. Because MPS III is rare and affects the brain (which is difficult to treat), motivation for pharmaceutical and biotechnology companies 20 to develop new therapies has been limited. [0004] There is no cure or effective treatment available for MPS IIID, and there is therefore an unmet need for developing such a treatment. SUMMARY 25 [0005] The present disclosure provides methods and compositions of treating Sanfilippo syndrome (also known as Sanfilippo diseasetype D, Sanfilippo D, mucopolysaccharidosistype IIID, MPS IIID) by,e.g., intrathecal (IT) administration of an alpha-N-acetylglucosamine-6-sulfatase (GNS) protein. A suitable GNS protein can be a recombinant, gene-acti- vated or natural protein. In some embodiments, a suitable GNS protein is a recombinant GNS protein. In some embod- 30 iments, a recombinant GNS protein is a protein containing a GNS domain and a lysosomal targeting moiety. [0006] In one embodiment, the disclosure provides a method of treating mucopolysaccharidosis type IIID (MPS IIID) in a human patient in need thereof, comprising injecting to the spinal fluid of the patient an effective amount of a composition comprising a recombinant polypeptide comprising the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence (a) having at least 95% sequence identity to SEQ ID NO: 1 and (b) having the enzymatic activity of GNS, 35 wherein the composition is provided in an artificial cerebrospinal fluid. [0007] In some embodiments, about 1 mg to about 100 mg of the recombinant polypeptide is administered to the patient each time (or each day when administration is conducted). In some embodiments, the administration is conducted once every 2 to 26 weeks (or every 2 weeks to every 6 months). In some embodiments, the recombinant polypeptide comprises the amino acid sequence of SEQ ID NO: 2, 5 or 6. 40 [0008] The artificial cerebrospinal fluid may have a pH of about 6 to 7.5, without limitation. In some embodiments, the artificial cerebrospinal fluid comprises about 130-170 mEq/l sodium, about 2.5-5 mEq/l potassium, about 1-3 mEq/l calcium, about 0.5-3 mEq/l magnesium, about 120-180 mEq/l chloride, and about 0.5-2 mEq/l phosphate. In some aspects, the artificial cerebrospinal fluid comprises about 140-160 mEq/l sodium, about 3.5-4.5 mEq/l potassium, about 2.5-3 mEq/l calcium, about 2-3 mEq/l magnesium, about 120-140 mEq/l chloride, and about 1-2 mEq/l phosphate. In 45 some aspects, the artificial cerebrospinal fluid comprises about 140-160 mEq/l sodium, about 3.5-4.5 mEq/l potassium, about 2.5-3 mEq/l calcium, about 2-3 mEq/l magnesium, about 120-140 mEq/l chloride, about 1-2 mEq/l phosphate, about 18-25 mEq/l bicarbonate, and about 2-3 mEq/l sulfate. In some aspects, the artificial cerebrospinal fluid has an osmolarity of about 250-350 mOsm/l. [0009] In some aspects, the recombinant polypeptide is has maximum enzymatic activity at a pH within 5.4 to 5.8. In 50 some embodiments, the recombinant polypeptide enters a human fibroblast cell when the recombinant polypeptide is incubated with the human fibroblast cell. In some aspects, the composition comprises from about 0.5 mg to about 30 mg of the recombinant protein per ml of the artificial cerebrospinal fluid. [0010] In some aspects, the recombinant polypeptide further comprises a lysosomal targeting moiety. In some aspects, the recombinant polypeptide is glycosylated, which glycosylation adds from 25 kDa to 45 kDa molecular weight to the 55 recombinant polypeptide. [0011] Combination therapies are also provided. In addition to the injection, the patient can further receive a therapy such as bone marrow replacement, or administration of genistein or a chaperone. [0012] Also provided, in one embodiment, is a polynucleotide comprising the nucleic acid sequence of SEQ ID NO: 2 EP 3 505 181 A1 3 or a nucleic acid sequence (a) having at least 85% sequence identify to SEQ ID NO: 3, (b) encoding the amino acid sequence of SEQ ID NO: 1, and (c) having no more than 95% sequence identity to SEQ ID NO: 4. Further provided, in one embodiment, is a cell comprising the polynucleotide of the disclosure. [0013] Thus, the present invention provides a method for preparing a composition for use in a method of treating 5 mucopolysaccharidosis type IIID (MPS IIID) in a human patient in need thereof, comprising testing a recombinant polypeptide in a testing buffer comprising less than 500 mM sodium, less than 100 mM citrate, less than 100 mM phosphate, less than 100 mM sulfate, and at least 0.005% Triton X-100, and providing the recombinant polypeptide in an artificial cerebrospinal fluid to prepare a composition for the use, wherein the recombinant polypeptide comprises the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence (a) having at least 95% sequence identity to SEQ 10 ID NO: 1 and (b) having the enzymatic activity of human acetylglucosamine-6-sulfatase (GNS). [0014] The present invention further provides a method of testing the activity of a recombinant polypeptide, comprising reacting the recombinant polypeptide with para-nitrocatechol sulfate (PNCS) in a testing buffer comprising less than 500 mM sodium, less than 100 mM citrate, less than 100 mM phosphate, less than 100 mM sulfate, and at least 0.005% Triton X-100, wherein the recombinant polypeptide comprises the amino acid sequence of SEQ ID NO: 1 or an amino 15 acid sequence (a) having at least 95% sequence identity to SEQ ID NO: 1 and (b) having the enzymatic activity of human acetylglucosamine-6-sulfatase (GNS). [0015] The method of testing the activity of a recombinant peptide may further comprise stopping the reaction with a base. The method of testing the activity of a recombinant peptide may further comprise stopping the reaction with a phosphate-citrate buffer. The phosphate-citrate buffer may comprise at least 0.4 M Na 2HPO4 in at least 0.2 M citric acid. 20 [0016] In any of the methods of the present invention described herein, the testing buffer may have a pH of about 5 to about 6. In any of the methods of the present invention described herein, the testing buffer may comprise less than 250 mM sodium, less than 50 mM citrate, less than 50 mM phosphate, less than 50 mM sulfate, and/or at least 0.01% Triton X-100.
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