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(12) Patent Application Publication (10) Pub. No.: US 2016/0251665 A1 Lindquist Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0251665 A1 Lindquist Et Al US 2016025 1665A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0251665 A1 Lindquist et al. (43) Pub. Date: Sep. 1, 2016 (54) CELLS EXPRESSINGAPOLIPOPROTEINE (52) U.S. Cl. AND USES THEREOF CPC ................ CI2N 15/81 (2013.01); G0IN33/92 (2013.01); C07K 14/775 (2013.01); C07K (71) Applicant: Whitehead Institute for Biomedical 14/4711 (2013.01); G0IN 2500/10 (2013.01); Research, Cambridge, MA (US) G0IN 2800/50 (2013.01); G0IN 2800/709 (2013.01); C07K 2319/02 (2013.01); A61 K (72) Inventors: Susan L. Lindquist, Cambridge, MA 38/00 (2013.01) (US); Priyanka Narayan, Cambridge, MA (US) (57) ABSTRACT (21) Appl. No.: 14/851,662 Disclosed are yeast cells expressing a polypeptide compris ing a signal sequence and a human ApoE protein. In some 1-1. embodiments the polypeptide comprises ApoE2. In some (22) Filed: Sep. 11, 2015 embodiments the polypeptide comprises ApoE3. In some Related U.S. Application Data embodiments the polypeptide comprises ApoE4. Also dis closed are methods of screening yeast cells to identify com (60) Provisional application No. 62/050,045, filed on Sep. pounds that prevent or Suppress Apo-induced toxicity. Com 12, 2014. pounds identified by Such screens can be used to treat or prevent neurodegenerative disorders such as Alzheimer's dis Publication Classification ease. Also disclosed are methods of Screening yeast cells to identify genetic Suppressors or enhancers of ApoE-induced (51) Int. Cl. toxicity. Also disclosed are genetic Suppressors or enhancers CI2N 15/8 (2006.01) of ApoE-induced toxicity identified using the methods, and C07K I4/775 (2006.01) human homologs thereof. Also disclosed are methods of iden C07K I4/47 (2006.01) tifying compounds that modulate expression or activity of GOIN33/92 (2006.01) genetic modifiers of ApoE-induced toxicity. Patent Application Publication Sep. 1, 2016 Sheet 1 of 19 US 2016/0251665 A1 VVZqeuÐJ??pQe?)suuuogos!??uu??u?SÐUuoOHOdV Suo???SOd Patent Application Publication Sep. 1, 2016 Sheet 2 of 19 US 2016/0251665 A1 3. 888wis88 stair: 33, 8:23, KS334-ai-kai 3-&ix:{{** Fig. 2A 8883: {{{: 8: 88:3 (8888:8: A3:3:38:3: (3:3888. A8: *{38: {:8:338. 8338.*.38: Fig. 2B Patent Application Publication Sep. 1, 2016 Sheet 3 of 19 US 2016/0251665 A1 set f:::::::::::::::: x Apar 82 x Apat 8:3 x Apex: 84. ine in Fig. 2C Patent Application Publication Sep. 1, 2016 Sheet 4 of 19 US 2016/0251665 A1 SIÐAÐIU???OJ) Patent Application Publication US 2016/0251665 A1 Patent Application Publication Sep. 1, 2016 Sheet 6 of 19 US 2016/0251665 A1 gG-61-I Patent Application Publication Sep. 1, 2016 Sheet 7 of 19 US 2016/0251665 A1 Patent Application Publication Sep. 1, 2016 Sheet 8 of 19 US 2016/0251665 A1 Patent Application Publication Sep. 1, 2016 Sheet 9 of 19 US 2016/0251665 A1 L198ZHOdwº |198£30dw. |198#73odv Patent Application Publication Sep. 1, 2016 Sheet 10 of 19 US 2016/0251665 A1 Su?eu?S6u?uÐ?uDS O09CO Patent Application Publication Sep. 1, 2016 Sheet 12 of 19 US 2016/0251665 A1 Transform pooled library into ApoEyeast strains Pooled library of plasmids encoding - ~5500 genes in the yeast ORFeome APOE2 Fig. 9B Patent Application Publication Sep. 1, 2016 Sheet 13 of 19 US 2016/0251665 A1 6666 9 9 9 (66.6666 9 9 g 9 66666666 ge 9 (6666666666 Q Q 9 9 GSGSGSaaSGSGSGSGSGS 9 9 (6'666'6666 e Q 9 9 GSGS6666 9 9 Q 9 6666 9 9 9 9 (5666 (66.6666 (566.66666 (6666,666,666 (SaaSaaaaaaaS e e 66666666 : (a6666 6666 (66.666 66666666 (S666666666 GGGGGS66666 (SGSGSGS6666 666666 6666 (66.666 66666666 (5666666666 6666666666 (6'666'6666 : 666666 GSGSGSS Fig. 9C Patent Application Publication Sep. 1, 2016 Sheet 14 of 19 US 2016/0251665 A1 won NA3. II- Coquino s 3.5 3. S d 8 3 3 Concentration (R) Fig. 10 Patent Application Publication Sep. 1, 2016 Sheet 15 of 19 US 2016/0251665 A1 ( ELL‘61-I snouu36opua) (Je?ououd Patent Application Publication Sep. 1, 2016 Sheet 16 of 19 US 2016/0251665 A1 HL),‘fil Patent Application Publication Sep. 1, 2016 Sheet 17 of 19 US 2016/0251665 A1 9LI‘61-I Patent Application Publication Sep. 1, 2016 Sheet 19 of 19 US 2016/0251665 A1 US 2016/025 1665 A1 Sep. 1, 2016 CELLS EXPRESSINGAPOLIPOPROTEINE embodiments, expression of the nucleic acid and production AND USES THEREOF of the polypeptide renders the yeast cell non-viable. In some embodiments the human ApoE protein is a human ApoE2 SEQUENCE LISTING protein. In some embodiments the human ApoE protein is a 0001. The instant application contains a Sequence Listing human ApoE3 protein. In some embodiments the human which has been submitted electronically in ASCII format and ApoE protein is a human ApoE4 protein. is hereby incorporated by reference in its entirety. Said ASCII 0006. In some embodiments the expression construct comprises a promoteroperably linked to a nucleic acid encod copy, created on Oct. 13, 2015, is named 26495-0017001 ing a polypeptide comprising a signal sequence and a human SL.txt and is 14,498 bytes in size. ApoE protein, wherein expression of the nucleic acid and BACKGROUND production of the polypeptide in the cell results in a decrease in growth or viability of the cell. In some embodiments, 0002 Alzheimer's disease is a neurodegenerative disorder expression of the nucleic acid and production of the polypep characterized by neurofibrillary tangles and plaques contain tide renders the yeast cell non-viable. A signal sequence ing amyloid beta peptides. Patients with Alzheimer's disease causes a polypeptide to be targeted to the endoplasmic reticu (AD) exhibit progressive dementia and personality dysfunc lum within a cell, whence it enters the secretory pathway. In tion. Proteolytic cleavage of the amyloid precursor protein Some embodiments, the signal sequence is located at the (APP) results in the generation of an amyloid beta (AB) amino terminus of the polypeptide encoded by the expression peptide having a length ranging from 38 to 43 amino acids. construct. In some embodiments, the signal sequence is one The amyloid beta 1-42 peptide is particularly prone to self that directs co-translational transport of the encoded polypep aggregation and is strongly linked to development of Alzhe tide. The signal sequence can be identical to a naturally occur imer's disease. ring signal sequence or can be an artificial (non-naturally 0003 Human apolipoprotein E is a 299 amino acid occurring) signal sequence. In some embodiments, the signal secreted glycoprotein that plays important roles in lipid trans sequence is identical to the signal sequence of a naturally port and metabolism. ApoE is synthesized primarily in the occurring yeast protein (e.g., identical to the yeast Kar2p liver but also in a number of other organs and tissues, includ signal sequence. In some embodiments, the signal sequence ing the brain. In the central nervous system, ApoE is produced is identical to the signal sequence of a naturally occurring mainly by astrocytes and microglia and transports cholesterol mammalian protein (e.g., a human protein). to neurons via ApoE receptors. The APOE gene has three 0007. In some embodiments, the polypeptide encoded by common polymorphicalleles—e2, e3 and e4—which encode an expression construct described herein comprises or con the ApoE isoforms known as ApoE2, ApoE3, and ApoE4. sists of a signal sequence and a human ApoE protein. In some respectively. The most common isoform, ApoE3, contains embodiments, the polypeptide encoded by an expression con cysteine and arginine at positions 112 and 158, respectively, struct described herein comprises or consists of a signal whereas ApoE2 has cysteine at both positions and ApoE4 has sequence, a linker peptide sequence, and a human ApoE arginine at both positions. Although these isoforms differ by protein. only one or two amino acids, the differences have a number of 0008. In some embodiments, cleavage of the polypeptide implications. The e4 allele of APOE is the most highly vali comprising a human ApoE protein, thus removing the signal dated genetic risk factor for late onset Alzheimer's disease sequence, may occur before translation of the entire polypep and is also associated with increased risk of early-onset AD tide is complete. This phenomenon is encompassed by the and with a variety of other diseases that affect the central phrase “production of the polypeptide in the cell results in a nervous system. The e2 allele of APOE is associated with the decrease in growth or viability of the cell, so long as at least lowest risk of developing AD, while the e3 allele confers an the human ApoE protein portion of the polypeptide is trans intermediate risk of developing the disease. lated and results in a decrease in growth or viability of the cell. SUMMARY 0009. In some embodiments, a polypeptide encoded by an expression construct described herein may contain a human 0004. The invention relates at least in part to the discovery ApoE protein and one or more heterologous peptide that human Apollipoprotein E (ApoE) protein is toxic when sequences. In some embodiments, a polypeptide encoded by expressed in a yeast cell. The discovery of ApoE-mediated an expression construct described herein may contain a signal toxicity in yeast permits the carrying out of screening assays sequence, a human ApoE protein, and one or more heterolo using ApoE-expressing yeast cells to identify compounds or gous peptide sequences. A "heterologous peptide sequence' genetic factors that modulate ApoE-induced toxicity. Com refers to any polypeptide sequence that is not an ApoE protein pounds identified by such screens can be used for the treat sequence or a signal sequence.
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