WO2018071849A2 - Engineered meganucleases specific for recognition sequences in the hepatitis b virus genome - Google Patents

Engineered meganucleases specific for recognition sequences in the hepatitis b virus genome Download PDF

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Publication number
WO2018071849A2
WO2018071849A2 PCT/US2017/056638 US2017056638W WO2018071849A2 WO 2018071849 A2 WO2018071849 A2 WO 2018071849A2 US 2017056638 W US2017056638 W US 2017056638W WO 2018071849 A2 WO2018071849 A2 WO 2018071849A2
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WIPO (PCT)
Prior art keywords
seq
hbv
meganuclease
engineered meganuclease
engineered
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Ceased
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PCT/US2017/056638
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English (en)
French (fr)
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WO2018071849A3 (en
Inventor
Derek Jantz
James Jefferson Smith
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Precision Biosciences Inc
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Precision Biosciences Inc
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Priority to JP2019520125A priority Critical patent/JP6811857B2/ja
Priority to KR1020247026203A priority patent/KR20240123417A/ko
Priority to EP23164434.5A priority patent/EP4234691A3/en
Priority to BR112019007450-3A priority patent/BR112019007450A2/pt
Priority to US16/342,169 priority patent/US10662416B2/en
Priority to EP17804977.1A priority patent/EP3526323B1/en
Priority to MX2019004349A priority patent/MX2019004349A/es
Priority to DK17804977.1T priority patent/DK3526323T5/da
Priority to IL317537A priority patent/IL317537A/en
Priority to KR1020257040268A priority patent/KR20260004503A/ko
Priority to KR1020217029958A priority patent/KR20210118240A/ko
Priority to KR1020237000425A priority patent/KR20230010826A/ko
Priority to KR1020197013312A priority patent/KR102305215B1/ko
Priority to FIEP17804977.1T priority patent/FI3526323T3/fi
Priority to IL308894A priority patent/IL308894A/en
Priority to AU2017342536A priority patent/AU2017342536A1/en
Priority to CN202311305067.1A priority patent/CN117402852A/zh
Priority to SG11201903042VA priority patent/SG11201903042VA/en
Priority to EA201990792A priority patent/EA201990792A1/ru
Application filed by Precision Biosciences Inc filed Critical Precision Biosciences Inc
Priority to IL265921A priority patent/IL265921B2/en
Priority to PE2019000817A priority patent/PE20191353A1/es
Priority to CA3040143A priority patent/CA3040143A1/en
Priority to CN201780074346.8A priority patent/CN110023495A/zh
Priority to CR20190181A priority patent/CR20190181A/es
Publication of WO2018071849A2 publication Critical patent/WO2018071849A2/en
Publication of WO2018071849A3 publication Critical patent/WO2018071849A3/en
Priority to PH12019500788A priority patent/PH12019500788A1/en
Priority to CONC2019/0003675A priority patent/CO2019003675A2/es
Anticipated expiration legal-status Critical
Priority to US16/852,296 priority patent/US10851358B2/en
Priority to US17/083,171 priority patent/US11274285B2/en
Priority to US17/665,265 priority patent/US20220243187A1/en
Priority to AU2023263542A priority patent/AU2023263542A1/en
Priority to US18/424,277 priority patent/US20240271111A1/en
Priority to US19/029,948 priority patent/US20250154486A1/en
Priority to IL325517A priority patent/IL325517A/en
Priority to AU2026201532A priority patent/AU2026201532A1/en
Ceased legal-status Critical Current

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    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/22—Ribonucleases [RNase]; Deoxyribonucleases [DNase]
    • A—HUMAN NECESSITIES
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    • A61K38/46—Hydrolases (3)
    • A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
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    • C12N2730/00011—Details
    • C12N2730/10011—Hepadnaviridae
    • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
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Definitions

  • the viral DNA is found in the nucleus soon after infection of the cell.
  • the partially double-stranded DNA is rendered fully double-stranded by completion of the (+) sense strand and removal of a protein molecule from the (-) sense strand and a short sequence of RNA from the (+) sense strand.
  • Non-coding bases are removed from the ends of the (-) sense strand and the ends are rejoined.
  • the first subunit can comprise an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or more, sequence identity to residues 7-153 of SEQ ID NO: 18 or 19 or residues 198-344 of SEQ ID NO: 20 or 21, and the second subunit can comprise an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or more, sequence identity to residues 198-344 of SEQ ID NO: 18 or 19 or residues 7-153 of SEQ ID NO: 20 or 21.
  • the first subunit can comprise residues 7-153 of SEQ ID NO: 18 or 19 or residues 198-344 of SEQ ID NO: 20 or 21.
  • the second subunit can comprise residues 198-344 of SEQ ID NO: 18 or 19 or residues 7-153 of SEQ ID NO: 20 or 21.
  • the viral vector comprises two or more cassettes, wherein each cassette comprises a promoter and a nucleic acid sequence encoding an engineered meganuclease described herein, and wherein each engineered meganuclease has specificity for a different HBV recognition sequence disclosed herein.
  • the viral vector comprises one cassette comprising a promoter and a polycistronic nucleic acid sequence, wherein the promoter drives expression of the polycistronic nucleic acid sequence to generate a polycistronic mRNA described herein in a target cell.
  • the pharmaceutical composition can comprise two or more engineered meganuclease proteins described herein, wherein the engineered
  • the methods of treatment for HBV infection or HCC comprise administering to the subject any pharmaceutical composition of the invention described herein which comprises, at least, a pharmaceutically acceptable carrier and (a) a nucleic acid encoding an engineered meganuclease described herein, wherein the engineered meganuclease is expressed in a target cell in vivo; or (b) an engineered meganuclease protein described herein.
  • Figure 9 Evaluation of HBV meganucleases for their ability to recognize and cleave recognition sequences within episomal DNA plasmids in an E. coli reporter system.
  • Figure 9A shows plasmid pARCUS and plasmid pHBVa.
  • Figure 9B shows the number of colonies present on each selective plate, providing evidence of the ability of HBV
  • the cells were washed and 24 hours later (day 2 post-infection) were transduced with either a lentivirus encoding RFP, HBV 5-6x.33, HBV l l-12x.26, or a 1 : 1 mixture of the lentiviruses encoding the HBV meganucleases.
  • infected cells were treated with DMSO.
  • Cell supernatants were harvested and medium was replaced on days 4, 8, 11, and 13 post-transduction.
  • HBsAg and HBeAg was measured in the cell supernatants by ELISA. Extracellular DNA in the supernatant was also measured at day 13 post-infection.
  • SEQ ID NO: 25 sets forth the amino acid sequence of the HBV 5-6x.4 meganuclease.
  • SEQ ID NO: 51 sets forth the amino acid sequence of the HBV 5-6x.4 meganuclease HBV5-binding subunit.
  • SEQ ID NO: 85 sets forth the nucleic acid sequence of the recognition sequence present in HBV genotype F that corresponds to the HBV 5-6 recognition sequence in HBV genotype A with a G to C substitution at position -3 of the first half-site.
  • SEQ ID NO: 86 sets forth the nucleic acid sequence of the recognition sequence present in HBV genotype E that corresponds to the HBV 7-8 recognition sequence in HBV genotype A with a C to T substitution at position -1 of the first half-site.
  • DNA-binding affinity or "binding affinity” means the tendency of a meganuclease to non-covalently associate with a reference DNA molecule (e.g., a recognition sequence or an arbitrary sequence). Binding affinity is measured by a dissociation constant, Kd.
  • Kd dissociation constant
  • a nuclease has "altered” binding affinity if the Kd of the nuclease for a reference recognition sequence is increased or decreased by a statistically significant (p ⁇ 0.05) amount relative to a reference nuclease.
  • a variable which is described as having values between 0 and 2 can take the values 0, 1 or 2 if the variable is inherently discrete, and can take the values 0.0, 0.1, 0.01, 0.001, or any other real values ⁇ 0 and ⁇ 2 if the variable is inherently continuous.
  • HBV1 Subunit % and "HBV2 Subunit %" represent the amino acid sequence identity between the HBVl -binding and HBV2-binding subunit regions of each meganuclease and the HBVl -binding and HBV2-binding subunit regions, respectively, of the HBV l-2x.2 meganuclease.
  • HBV7 Subunit % and "HBV8 Subunit %" represent the amino acid sequence identity between the HBV7-binding and HBV8-binding subunit regions of each meganuclease and the HBV7-binding and HBV8-binding subunit regions, respectively, of the HBV 7-8x.2 meganuclease.
  • the recombinant DNA construct can comprise two cassettes, three cassettes, four cassettes, or more.
  • a cassette or combination of cassettes can encode any number or combination of an HBV 1-2 meganuclease, an HBV 5-6 meganuclease, an HBV 7-8 meganuclease, and an HBV 11-12 meganuclease.
  • a single cassette can encode an HBV 1-2 meganuclease, an HBV 5-6 meganuclease, an HBV 7-8 meganuclease, and an HBV 11-12 meganuclease.
  • a cassette or combination of cassettes can encode an HBV 5-6 meganuclease and an HBV 11-12 meganuclease.
  • meganucleases of the invention can be delivered as purified protein or as RNA or DNA encoding the meganuclease.
  • meganuclease proteins, or mRNA, or DNA vectors encoding endonucleases are supplied to target cells (e.g., cells in the liver) via injection directly to the target tissue.
  • endonuclease proteins or DNA/mRNA encoding endonucleases, are coupled covalently or, preferably, non-covalently to a nanoparticle or encapsulated within such a nanoparticle using methods known in the art (Sharma, et al.
  • a retroviral, pseudotype or adenoviral associated vector is constructed which encodes the engineered meganuclease and is administered to the subject.
  • the pharmaceutical composition can comprise one or more mRNAs described herein encapsulated within lipid nanoparticles, which are described elsewhere herein.
  • lipid nanoparticles can comprise two or more mRNAs described herein, each encoding an engineered meganuclease of the invention having specificity for a different HBV recognition sequence described herein.
  • lipid nanoparticles can comprise two, three, or four mRNAs described herein, each encoding an engineered meganuclease of the invention having specificity for a different HBV recognition sequence.
  • lipid nanoparticles can comprise two, three, or four mRNAs described herein, each encoding an engineered meganuclease of the invention having specificity for a different HBV recognition sequence.
  • lipid nanoparticles can comprise two, three, or four mRNAs described herein, each encoding an engineered meganuclease of the invention having specificity for a different HBV recognition sequence.
  • lipid nanoparticles
  • Cationic lipids can include, for example, one or more of the following:
  • palmitoyi-oleoyl-nor-arginine PONA
  • MPDACA GUADACA
  • MC3 heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate)
  • MC3 LenMC3, CP- LenMC3, y-LenMC3, CP-y-LenMC3, MC3MC, MC2MC, MC3 Ether, MC4 Ether, MC3 Amide, Pan-MC3, Pan-MC4 and Pan MC5, l,2-dilinoleyloxy-N,N-dimethylaminopropane (DLinDMA), l,2-dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA), 2,2-dilinoleyl-4- (2-dimethylaminoethyl)-[l,3]-diox
  • the endonuclease can be placed under the control of a tissue-specific promoter that is not active in the packaging cells.
  • a tissue-specific promoter that is not active in the packaging cells.
  • a muscle-specific promoter can be used.
  • muscle-specific promoters include C5-12 (Liu, et al. (2004) Hum Gene Ther. 15:783-92), the muscle-specific creatine kinase (MCK) promoter (Yuasa, et al. (2002) Gene Ther. 9: 1576-88), or the smooth muscle 22 (SM22) promoter (Haase, et al. (2013) BMC Biotechnol.
  • recombinant AAV particles are produced in a mammalian cell line that expresses a transcription repressor that prevents expression of the endonuclease.
  • Transcription repressors are known in the art and include the Tet-Repressor, the Lac-Repressor, the Cro repressor, and the Lambda-repressor.
  • Many nuclear hormone receptors such as the ecdysone receptor also act as transcription repressors in the absence of their cognate hormone ligand.

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PCT/US2017/056638 2016-10-14 2017-10-13 Engineered meganucleases specific for recognition sequences in the hepatitis b virus genome Ceased WO2018071849A2 (en)

Priority Applications (34)

Application Number Priority Date Filing Date Title
EA201990792A EA201990792A1 (ru) 2017-06-30 2017-10-13 Сконструированные мегануклеазы, специфичные к последовательностям распознавания в геноме вируса гепатита b
EP23164434.5A EP4234691A3 (en) 2016-10-14 2017-10-13 Engineered meganucleases specific for recognition sequences in the hepatitis b virus genome
BR112019007450-3A BR112019007450A2 (pt) 2016-10-14 2017-10-13 meganucleases modificadas específicas para sequências de reconhecimento no genoma do vírus da hepatite b
US16/342,169 US10662416B2 (en) 2016-10-14 2017-10-13 Engineered meganucleases specific for recognition sequences in the hepatitis B virus genome
EP17804977.1A EP3526323B1 (en) 2016-10-14 2017-10-13 Engineered meganucleases specific for recognition sequences in the hepatitis b virus genome
MX2019004349A MX2019004349A (es) 2016-10-14 2017-10-13 Meganucleasas manipuladas específicamente para el reconocimiento de secuencias en el genoma del virus de la hepatitis b.
DK17804977.1T DK3526323T5 (da) 2016-10-14 2017-10-13 Modificerede meganucleaser der er specifikke for en genkendelsessekvens i hepatitis b virusgenomet
IL317537A IL317537A (en) 2016-10-14 2017-10-13 Engineered megacannolyases specific for recognition sequences in the hepatitis B virus genome
KR1020257040268A KR20260004503A (ko) 2016-10-14 2017-10-13 B형 간염 바이러스 게놈 내의 인식 서열에 대해 특이적인 조작된 메가뉴클레아제
KR1020217029958A KR20210118240A (ko) 2016-10-14 2017-10-13 B형 간염 바이러스 게놈 내의 인식 서열에 대해 특이적인 조작된 메가뉴클레아제
KR1020237000425A KR20230010826A (ko) 2016-10-14 2017-10-13 B형 간염 바이러스 게놈 내의 인식 서열에 대해 특이적인 조작된 메가뉴클레아제
KR1020197013312A KR102305215B1 (ko) 2016-10-14 2017-10-13 B형 간염 바이러스 게놈 내의 인식 서열에 대해 특이적인 조작된 메가뉴클레아제
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CA3040143A CA3040143A1 (en) 2016-10-14 2017-10-13 Engineered meganucleases specific for recognition sequences in the hepatitis b virus genome
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CR20190181A CR20190181A (es) 2016-10-14 2017-10-13 Meganucleasas diseñadas específicamente para el reconocimiento de secuencias en el genoma del virus de la hepatitis b.
PH12019500788A PH12019500788A1 (en) 2016-10-14 2019-04-11 Engineered meganucleases specific for recgonition sequences in the hepatitis b virus genome
CONC2019/0003675A CO2019003675A2 (es) 2016-10-14 2019-04-12 Meganucleasas diseñadas especificamente para el reconocimiento de secuencias en el genoma del virus de la hepatitis b.
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US17/665,265 US20220243187A1 (en) 2016-10-14 2022-02-04 Engineered meganucleases specific for recognition sequences in the hepatitis b virus genome
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