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WO 2016/040794 Al 17 March 2016 (17.03.2016) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/040794 Al 17 March 2016 (17.03.2016) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, C12N 1/19 (2006.01) C12Q 1/02 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, C12N 15/81 (2006.01) C07K 14/47 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, PCT/US20 15/049674 MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 11 September 2015 ( 11.09.201 5) SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 62/050,045 12 September 2014 (12.09.2014) US TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant: WHITEHEAD INSTITUTE FOR BIOMED¬ DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, ICAL RESEARCH [US/US]; Nine Cambridge Center, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Cambridge, Massachusetts 02142-1479 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventors: LINDQUIST, Susan L.; 75 E. Cambridge Pkwy, Cambridge, Massachusetts 02142 (US). NARAY- Published: AN, Priyanka; 353 Harvard St., Apt. 2, Cambridge, Mas — with international search report (Art. 21(3)) sachusetts 02 138 (US). — before the expiration of the time limit for amending the (74) Agent: BRENNAN, Jack; Fish & Richardson P.C., P.O. claims and to be republished in the event of receipt of Box 1022, Minneapolis, Minnesota 55440-1022 (US). amendments (Rule 48.2(h)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (54) Title: CELLS EXPRESSING APOLIPOPROTEIN E AND USES THEREOF ApoE comes in three isoforms that differ at 2 AA positions © © (57) Abstract: Disclosed are yeast cells expressing a polypeptide comprising a signal sequence and a human ApoE protein. In some embodiments the polypeptide comprises ApoE2. In some embodiments the polypeptide comprises ApoE3. In some embodiments the v polypeptide comprises ApoE4. Also disclosed are methods of screening yeast cells to identify compounds that prevent or suppress o Apo-induced toxicity. Compounds identified by such screens can be used to treat or prevent neurodegenerative disorders such as Alzheimer's disease. Also disclosed are methods of screening yeast cells to identify genetic suppressors or enhancers of ApoE-in - duced toxicity. Also disclosed are genetic suppressors or enhancers of ApoE-induced toxicity identified using the methods, and hu o man homologs thereof. Also disclosed are methods of identifying compounds that modulate expression or activity of genetic modifi ers of ApoE- induced toxicity. CELLS EXPRESSING APOLIPOPROTEIN E AND USES THEREOF Background [0001] Alzheimer's disease is a neurodegenerative disorder characterized by neurofibrillary tangles and plaques containing amyloid beta peptides. Patients with Alzheimer's disease (AD) exhibit progressive dementia and personality dysfunction. Proteolytic cleavage of the amyloid precursor protein (APP) results in the generation of an amyloid beta (Α β) peptide having a length ranging from 38 to 43 amino acids. The amyloid beta 1-42 peptide is particularly prone to self- aggregation and is strongly linked to development of Alzheimer's disease. [0002] Human apolipoprotein E is a 299 amino acid secreted glycoprotein that plays important roles in lipid transport and metabolism. ApoE is synthesized primarily in the liver but also in a number of other organs and tissues, including the brain. In the central nervous system, ApoE is produced mainly by astrocytes and microglia and transports cholesterol to neurons via ApoE receptors. The APOE gene has three common polymorphic alleles - ε2, ε3 and ε4 - which encode the ApoE isoforms known as ApoE2, ApoE3, and ApoE4, respectively. The most common isoform, ApoE3, contains cysteine and arginine at positions 112 and 158, respectively, whereas ApoE2 has cysteine at both positions and ApoE4 has arginine at both positions. Although these isoforms differ by only one or two amino acids, the differences have a number of implications. The ε4 allele of APOE is the most highly validated genetic risk factor for late onset Alzheimer's disease and is also associated with increased risk of early-onset AD and with a variety of other diseases that affect the central nervous system. The ε2 allele of APOE is associated with the lowest risk of developing AD, while the ε3 allele confers an intermediate risk of developing the disease. Summary [0003] The invention relates at least in part to the discovery that human Apolipoprotein E (ApoE) protein is toxic when expressed in a yeast cell. The discovery of ApoE-mediated toxicity in yeast permits the carrying out of screening assays using ApoE-expressing yeast cells to identify compounds or genetic factors that modulate ApoE-induced toxicity. Compounds identified by such screens can be used for the treatment or prevention of diseases in which one or more isoforms of ApoE plays a pathological role. For example, compounds identified by such screens can be used for the treatment of diseases and disorders affecting the nervous system in which ApoE4 plays a role, e.g., neurodegenerative diseases such as Alzheimer's disease. [0004] In some aspects, described herein is a yeast cell comprising an expression construct comprising a promoter operably linked to a nucleic acid encoding a polypeptide comprising a human ApoE protein, wherein expression of the nucleic acid and production of the polypeptide in the cell results in a decrease in growth or viability of the cell. In some embodiments, expression of the nucleic acid and production of the polypeptide renders the yeast cell non viable. In some embodiments the human ApoE protein is a human ApoE2 protein. In some embodiments the human ApoE protein is a human ApoE3 protein. In some embodiments the human ApoE protein is a human ApoE4 protein. [0005] In some embodiments the expression construct comprises a promoter operably linked to a nucleic acid encoding a polypeptide comprising a signal sequence and a human ApoE protein, wherein expression of the nucleic acid and production of the polypeptide in the cell results in a decrease in growth or viability of the cell. In some embodiments, expression of the nucleic acid and production of the polypeptide renders the yeast cell non-viable. A signal sequence causes a polypeptide to be targeted to the endoplasmic reticulum within a cell, whence it enters the secretory pathway. In some embodiments, the signal sequence is located at the amino terminus of the polypeptide encoded by the expression construct. In some embodiments, the signal sequence is one that directs co-translational transport of the encoded polypeptide. The signal sequence can be identical to a naturally occurring signal sequence or can be an artificial (non-naturally occurring) signal sequence. In some embodiments, the signal sequence is identical to the signal sequence of a naturally occurring yeast protein (e.g., identical to the yeast Kar2p signal sequence. In some embodiments, the signal sequence is identical to the signal sequence of a naturally occurring mammalian protein (e.g., a human protein). [0006] In some embodiments, the polypeptide encoded by an expression construct described herein comprises or consists of a signal sequence and a human ApoE protein. In some embodiments, the polypeptide encoded by an expression construct described herein comprises or consists of a signal sequence, a linker peptide sequence, and a human ApoE protein. [0007] In some embodiments, cleavage of the polypeptide comprising a human ApoE protein, thus removing the signal sequence, may occur before translation of the entire polypeptide is complete. This phenomenon is encompassed by the phrase "production of the polypeptide in the cell results in a decrease in growth or viability of the cell," so long as at least the human ApoE protein portion of the polypeptide is translated and results in a decrease in growth or viability of the cell. [0008] In some embodiments, a polypeptide encoded by an expression construct described herein may contain a human ApoE protein and one or more heterologous peptide sequences. In some embodiments, a polypeptide encoded by an expression construct described herein may contain a signal sequence, a human ApoE protein, and one or more heterologous peptide sequences. A "heterologous peptide sequence" refers to any polypeptide sequence that is not an ApoE protein sequence or a signal sequence. A heterologous peptide sequence can be present at the amino terminus of the polypeptide, between the signal sequence and the human ApoE protein, at the carboxy terminus of the human ApoE protein, and/or at the carboxy terminus of the polypeptide. In some embodiments the heterologous peptide sequence comprises a "detection protein," which term refers to a protein that serves as a detectable label (e.g., a fluorescent protein, an enzyme, or an epitope tag). In some embodiments the polypeptide is a fusion protein containing a human ApoE protein and a detection protein (e.g., a fluorescent protein, an enzyme, or an epitope tag).
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