WO2018200635A1 - Methods of treating rheumatoid arthritis using rna-guided genome editing of hla gene - Google Patents

Methods of treating rheumatoid arthritis using rna-guided genome editing of hla gene Download PDF

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Publication number
WO2018200635A1
WO2018200635A1 PCT/US2018/029302 US2018029302W WO2018200635A1 WO 2018200635 A1 WO2018200635 A1 WO 2018200635A1 US 2018029302 W US2018029302 W US 2018029302W WO 2018200635 A1 WO2018200635 A1 WO 2018200635A1
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WO
WIPO (PCT)
Prior art keywords
cell
drb1
nucleic acid
cells
hla
Prior art date
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Ceased
Application number
PCT/US2018/029302
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English (en)
French (fr)
Inventor
Brian Freed
Kirsten ANDERSON
Christina Roark
Jennifer MATSUDA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Colorado System
University of Colorado Colorado Springs
Original Assignee
University of Colorado System
University of Colorado Colorado Springs
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to HRP20240806TT priority Critical patent/HRP20240806T1/hr
Priority to JP2019558446A priority patent/JP7457302B2/ja
Priority to SI201831109T priority patent/SI3615674T1/sl
Priority to CA3061614A priority patent/CA3061614A1/en
Priority to AU2018258061A priority patent/AU2018258061B2/en
Priority to DK18791113.6T priority patent/DK3615674T3/da
Priority to US16/609,175 priority patent/US11932867B2/en
Priority to EP24162513.6A priority patent/EP4400175A3/en
Priority to ES18791113T priority patent/ES2981611T3/es
Application filed by University of Colorado System, University of Colorado Colorado Springs filed Critical University of Colorado System
Priority to LTEPPCT/US2018/029302T priority patent/LT3615674T/lt
Priority to EP18791113.6A priority patent/EP3615674B1/en
Priority to FIEP18791113.6T priority patent/FI3615674T3/fi
Publication of WO2018200635A1 publication Critical patent/WO2018200635A1/en
Anticipated expiration legal-status Critical
Priority to JP2024033480A priority patent/JP2024075603A/ja
Priority to US18/605,149 priority patent/US20240327862A1/en
Priority to AU2025200803A priority patent/AU2025200803A1/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1138—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against receptors or cell surface proteins
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • C12N15/90—Stable introduction of foreign DNA into chromosome
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    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0647—Haematopoietic stem cells; Uncommitted or multipotent progenitors
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    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/22—Ribonucleases [RNase]; Deoxyribonucleases [DNase]
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0306—Animal model for genetic diseases
    • A01K2267/0325—Animal model for autoimmune diseases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/20—Type of nucleic acid involving clustered regularly interspaced short palindromic repeats [CRISPR]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/15011—Lentivirus, not HIV, e.g. FIV, SIV
    • C12N2740/15041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/15042—Use of virus, viral particle or viral elements as a vector virus or viral particle as vehicle, e.g. encapsulating small organic molecule
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    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/16043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
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    • C12N2750/14011—Parvoviridae
    • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
    • C12N2750/14141—Use of virus, viral particle or viral elements as a vector
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    • C12N2800/00—Nucleic acids vectors
    • C12N2800/80—Vectors containing sites for inducing double-stranded breaks, e.g. meganuclease restriction sites

Definitions

  • this disclosure provides methods of modifying a eukaryotic cell with a three- component system including guide RNA complementary to genomic DNA, and an enzyme that interacts with the RNA, and a template nucleic acid that contains at least a portion of the genomic DNA.
  • the guide RNA and the enzyme are expressed by the cell.
  • the guide RNA of the RNA/enzyme complex binds to complementary genomic DNA and cleaves the genomic DNA.
  • the enzyme cleaves genomic sequences targeted by the guide RNA sequences. A portion of the template nucleic acid is substituted into the genomic DNA, thereby creating a genome-altered eukaryotic cell.
  • the disclosure provides a method of treating RA in a subject by introducing into a cell of the subject one or more nucleic acids encoding a nuclease that targets a portion of the human leukocyte antigen (HLA)-DRBI gene containing an allele associated with RA, wherein the nuclease creates a double stranded break in the DRB1 gene; a guide RNA molecule comprising a nucleotide sequence complementary to a target nucleic acid sequence within HLA-DRB1 locus; and an isolated template nucleic acid comprising a nucleic acid comprising at least a portion of an HLA-DRB1 allele, optionally flanked by nucleic acid sequences homologous to the nucleic acid sequences upstream and downstream of the double stranded break in the DRB1 gene, and wherein the resultant modified DRB1 gene, upon expression, confers resistance to the development of RA in the subject or a reduction of RA progression in the subject, comparable to a subject
  • CRISPR Clustered Regularly Interspaced Short Palindromic Repeats
  • Cas CRISPR Associated Nucleases
  • the target cells from the subject are eukaryotic cells that may be stem cells, and specifically hematopoietic stem cells (HSCs), as hematopoietic cells likely represent the main cell source of DRB1 gene products that present modified peptides and trigger RA.
  • HSCs hematopoietic stem cells
  • the nucleic acids may be introduced into a cell as part of a vector molecule having additional sequences, such as replication origins, promoters and genes encoding antibiotic resistance.
  • the nucleic acids can be introduced as naked nucleic acid, as nucleic acid complexed with an agent such as a liposome or poloxamer, or can be delivered by viruses (e.g., adenovirus, AAV, herpesvirus, retrovirus, lentivirus).
  • viruses e.g., adenovirus, AAV, herpesvirus, retrovirus, lentivirus.
  • this disclosure includes vectors that may encode one or more of the nuclease (e.g., Cas9 nuclease), guide RNA (which may be encoded as a tracrRNA-crRNA fusion), and a template nucleic acid.
  • the vector may be an adenovirus vector, an integration-deficient lentiviral vector (IDLV), or an integration-deficient foamyviral vector
  • the modified cells are preferably autologous cells, i.e., a cell or cells taken from a subject who is in need of altering a DRB1 target polynucleotide sequence in the cell or cells (i.e., the donor and recipient are the same individual).
  • At least one administration of the modified DRB1-expressing cells may be sufficient to generate a pharmacologically relevant response.
  • at least two administrations, at least three administrations, or at least four administrations, or more, of the modified DRB1 -expressing cells may be utilized to ensure a pharmacologically relevant response.
  • the maintenance dose may be a lower dose than the initial dose, including for example, a maintenance dose that is about 3 ⁇ 4, about 3 ⁇ 4, about 1 ⁇ 2, about 1 ⁇ 2, about 1 ⁇ 4, about 1 ⁇ 4, about 1/10, about 1/20, about 1/25, about 1/50, about 1/100, about 1/1 ,000, about 1/10,000, about 1/100,000, or about 1/1 ,000,000 (weight/weight) of the initial dose.
  • Examples are provided of an ex vivo gene modification strategies that can be performed without the use of viral vectors. Genetic materials are delivered to modify DRB1*04:01 allele to express a protein having a glutamic acid residue at position 71 (DRB1*04:01 K7 E ) in HSCs derived from a human RA patient using electroporation and Cas9 nuclease.
  • PBMCs Peripheral blood mononuclear cells
  • BOECs cells are established in culture for 4 weeks with daily medium changes but with no passaging. The first passaging occurs at 4 weeks, after approximately a 100-fold expansion. In the next step, 0.025% trypsin is used for passaging cells and tissue culture plates coated with collagen-l as substrate. Following this initial 4-week establishment of the cells in culture, the BOECs are passaged again 4 days later (day 32) and 4 days after that (day 36), after which time the cells should number 1 million cells or more.
  • cells are transfected with 0.1-10 micrograms per million cells of a vector encoding a Cas9 nuclease, a template nucleic acid, and a guide RNA encoding crRNA comprising the coding sequence GGACCUCGUCUUCGCCCGGCGCC (SEQ ID NO:1) that targets codon 71 in the HLA allele DRB1*04:01.
  • Transfection is done by electroporation, liposome-mediated transfection, polycation-mediated transfection, commercially available proprietary reagents for transfection, or other transfection methods using standard protocols. Following transfection, BOECs are cultured as described above for three days.

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PCT/US2018/029302 2017-04-28 2018-04-25 Methods of treating rheumatoid arthritis using rna-guided genome editing of hla gene Ceased WO2018200635A1 (en)

Priority Applications (15)

Application Number Priority Date Filing Date Title
ES18791113T ES2981611T3 (es) 2017-04-28 2018-04-25 Métodos para tratar la artritis reumatoide mediante el uso de la edición del genoma guiada por ARN del gen de HLA
SI201831109T SI3615674T1 (sl) 2017-04-28 2018-04-25 Metoda za zdravljenje revmatoidnega artritisa z rna-vodenim urejanjem genoma gena hla
LTEPPCT/US2018/029302T LT3615674T (lt) 2017-04-28 2018-04-25 Reumatoidinio artrito gydymo būdai, naudojant nukreipiančios rnr hla geno redagavimą genome
AU2018258061A AU2018258061B2 (en) 2017-04-28 2018-04-25 Methods of treating rheumatoid arthritis using RNA-guided genome editing of HLA gene
DK18791113.6T DK3615674T3 (da) 2017-04-28 2018-04-25 Methods of treating rheumatoid arthritis using rna-guided genome editing of hla gene
US16/609,175 US11932867B2 (en) 2017-04-28 2018-04-25 Methods of treating rheumatoid arthritis using RNA-guided genome editing of HLA gene
EP24162513.6A EP4400175A3 (en) 2017-04-28 2018-04-25 Methods of treating rheumatoid arthritis using rna-guided genome editing of hla gene
HRP20240806TT HRP20240806T1 (hr) 2017-04-28 2018-04-25 Metode liječenja reumatoidnog artritisa pomoću rna-vođenog genoma uređivanja hla gena
CA3061614A CA3061614A1 (en) 2017-04-28 2018-04-25 Methods of treating rheumatoid arthritis using rna-guided genome editing of hla gene
JP2019558446A JP7457302B2 (ja) 2017-04-28 2018-04-25 Ｈｌａ遺伝子のｒｎａガイドゲノム編集を使用して関節リウマチを処置する方法
EP18791113.6A EP3615674B1 (en) 2017-04-28 2018-04-25 Methods of treating rheumatoid arthritis using rna-guided genome editing of hla gene
FIEP18791113.6T FI3615674T3 (fi) 2017-04-28 2018-04-25 Menetelmiä reumatoidin artriitin hoitoon HLA-geenin RNA-ohjattua genomin muokkausta käyttämällä
JP2024033480A JP2024075603A (ja) 2017-04-28 2024-03-06 Ｈｌａ遺伝子のｒｎａガイドゲノム編集を使用して関節リウマチを処置する方法
US18/605,149 US20240327862A1 (en) 2017-04-28 2024-03-14 Methods of Treating Rheumatoid Arthritis Using RNA-Guided Genome Editing of HLA Gene
AU2025200803A AU2025200803A1 (en) 2017-04-28 2025-02-06 Methods of treating rheumatoid arthritis using RNA-guided genome editing of HLA gene

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762491487P 2017-04-28 2017-04-28
US62/491,487 2017-04-28

Related Child Applications (2)

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US16/609,175 A-371-Of-International US11932867B2 (en) 2017-04-28 2018-04-25 Methods of treating rheumatoid arthritis using RNA-guided genome editing of HLA gene
US18/605,149 Division US20240327862A1 (en) 2017-04-28 2024-03-14 Methods of Treating Rheumatoid Arthritis Using RNA-Guided Genome Editing of HLA Gene

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EP (2) EP3615674B1 (https=)
JP (2) JP7457302B2 (https=)
AU (2) AU2018258061B2 (https=)
CA (1) CA3061614A1 (https=)
DK (1) DK3615674T3 (https=)
ES (1) ES2981611T3 (https=)
FI (1) FI3615674T3 (https=)
HR (1) HRP20240806T1 (https=)
HU (1) HUE069314T2 (https=)
LT (1) LT3615674T (https=)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230126183A1 (en) * 2021-05-10 2023-04-27 The Regents Of The University Of Colorado, A Body Corporate Methods of Treating Autoimmunity With Engineered HLA Proteins
US11932867B2 (en) 2017-04-28 2024-03-19 National Jewish Health Methods of treating rheumatoid arthritis using RNA-guided genome editing of HLA gene

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JP2024075603A (ja) 2024-06-04
EP3615674A4 (en) 2021-03-24
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CA3061614A1 (en) 2018-11-01
JP2020517289A (ja) 2020-06-18
US20240327862A1 (en) 2024-10-03
US20200199616A1 (en) 2020-06-25
SI3615674T1 (sl) 2025-03-31
ES2981611T3 (es) 2024-10-09
EP3615674A1 (en) 2020-03-04
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EP4400175A3 (en) 2024-09-25
EP4400175A2 (en) 2024-07-17

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