WO2020076614A1 - Artificial expression constructs for selectively modulating gene expression in interneurons - Google Patents

Artificial expression constructs for selectively modulating gene expression in interneurons Download PDF

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Publication number
WO2020076614A1
WO2020076614A1 PCT/US2019/054539 US2019054539W WO2020076614A1 WO 2020076614 A1 WO2020076614 A1 WO 2020076614A1 US 2019054539 W US2019054539 W US 2019054539W WO 2020076614 A1 WO2020076614 A1 WO 2020076614A1
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seq
protein
molecule
expression construct
vector
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English (en)
French (fr)
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Jonathan Ting
Boaz P. LEVI
John K. Mich
Edward Sebastian LEIN
Franck KALUME
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Seattle Childrens Hospital
Allen Institute
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Seattle Childrens Hospital
Allen Institute
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Priority to US17/283,232 priority Critical patent/US12467064B2/en
Priority to EP19870829.9A priority patent/EP3864150A4/en
Priority to CA3115652A priority patent/CA3115652A1/en
Priority to JP2021543981A priority patent/JP7695192B2/ja
Priority to AU2019358806A priority patent/AU2019358806B2/en
Publication of WO2020076614A1 publication Critical patent/WO2020076614A1/en
Anticipated expiration legal-status Critical
Priority to JP2024187194A priority patent/JP7829658B2/ja
Priority to US19/007,152 priority patent/US20250223612A1/en
Priority to AU2025208516A priority patent/AU2025208516A1/en
Ceased legal-status Critical Current

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    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
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    • C12N2750/14141—Use of virus, viral particle or viral elements as a vector
    • C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the product of the coding sequence may be expressed at low levels in non-selected cell types, for example at less than 1 % or 1 %, 2%, 3%, 5%, 10%, 15% or 20% of the levels at which the product is expressed in selected neural cells.
  • the targeted central nervous system cell type is the only cell type that expresses the right combination of transcription factors that bind an enhancer disclosed herein to drive gene expression. Thus, in particular embodiments, expression occurs exclusively within the targeted cell type.
  • Serpinfl Found in many cortical layers, and have molecular overlaps with Sncg and Vip cells, but inconsistent expression of Sncg or Vip, with more consistent expression of Serpinfl
  • L2/3 IT Primarily reside in Layer 2/3 and have mainly intratelencephalic (cortico-cortical) projections.
  • GCaMPs yield distinct fluorescence emission spectra (Zhao et al..Science, 201 1 , 333(6051): 1888-1891).
  • Exemplary GECIs with green fluorescence include GCaMP3, GCaMP5G, GCaMP6s, GCaMP6m, GCaMP6f, jGCaMP7s, jGCaMP7c, jGCaMP7b, andjGCaMP7f.
  • GECIs with red fluorescence include jRGECOIa and jRGECOI b.
  • AAV products containing GECIs are commercially available. For example, Vigene Biosciences provides AAV products including AAV8-CAG-GCaMP3 (Cat.
  • Additional effector elements include Cre, iCre, dgCre, FlpO, and tTA2.
  • iCre refers to a codon-improved Cre.
  • dgCre refers to an enhanced GFP/Cre recombinase fusion gene with an N terminal fusion of the first 159 amino acids of the Escherichia coli K-12 strain chromosomal dihydrofolate reductase gene (DHFR or folA) harboring a G67S mutation and modified to also include the R12Y/Y100I destabilizing domain mutation.
  • FlpO refers to a codon-optimized form of FLPe that greatly increases protein expression and FRT recombination efficiency in mouse cells. Like the Cre/LoxP system, the FLP/FRT system has been widely used for gene expression (and generating conditional knockout mice, mediated by the FLP/FRT system).
  • tTA2 refers to tetracycline transactivator.
  • Adeno-Associated Virus is a parvovirus, discovered as a contamination of adenoviral stocks. It is a ubiquitous virus (antibodies are present in 85% of the US human population) that has not been linked to any disease. It is also classified as a dependovirus, because its replication is dependent on the presence of a helper virus, such as adenovirus. Various serotypes have been isolated, of which AAV-2 is the best characterized. AAV has a single-stranded linear DNA that is encapsidated into capsid proteins VP1 , VP2 and VP3 to form an icosahedral virion of 20 to 24 nm in diameter.
  • Polyadenylation sequences can promote mRNA stability by addition of a poly(A) tail to the 3' end of the coding sequence and thus, contribute to increased translational efficiency.
  • Particular embodiments may utilize BGHpA or SV40pA.
  • a preferred embodiment of an expression construct includes a terminator element. These elements can serve to enhance transcript levels and to minimize read through from the construct into other plasmid sequences.
  • Pharmaceutically-acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like.
  • Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethyl
  • (iii) Cell Lines Including Artificial Expression Constructs The present disclosure includes cells including an artificial expression construct described herein.
  • a cell that has been transformed with an artificial expression construct can be used for many purposes, including in neuroanatomical studies, assessments of functioning and/or non-functioning proteins, and drug screens that assess the regulatory properties of enhancers.
  • the cell is a mammalian neural cell.
  • the enhancer sequence of the artificial expression construct is SEQ ID NO: 3 and/or 7 and/or a CN1390, CN1244, CN1389, CN1203, CN1367, CN1498, CN1499, CN1500, CN1838 or a combination of components depicted in FIG. 16, and the cell line is a human, primate, or murine neural cell.
  • Cell lines which can be utilized for transgenesis in the present disclosure also include primary cell lines derived from living tissue such as rat or mouse brains and organotypic cell cultures, including brain slices from animals such as rats or mice.
  • the PC12 cell line (available from the American Type Culture Collection, ATCC, Manassas, VA) has been shown to express a number of neuronal marker proteins in response to Neuronal Growth Factor (NGF).
  • NGF Neuronal Growth Factor
  • the PC12 cell line is considered to be a neuronal cell line and is applicable for use with this disclosure.
  • JAR cells (available from ATCC) are a platelet derived cell-line that express some neuronal genes, such as the serotonin transporter gene, and may be used with embodiments described herein.
  • Dravet syndrome is a drug-resistant and life-threatening form of epilepsy. It typically begins in the first year of life, with fever- or temperature- induced seizures that evolve into generalized clonic, tonic-clonic, and unilateral seizures. These seizures are often resistant to current anti-epileptic drugs, the first-line therapies for this syndrome; complete seizure control is typically not achieved. As the disease progresses, most affected children also suffer from comorbid conditions including developmental delays, intellectual disabilities, impaired motor control and coordination, autistic behaviors, sleep disturbances, and many die prematurely.

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PCT/US2019/054539 2018-10-08 2019-10-03 Artificial expression constructs for selectively modulating gene expression in interneurons Ceased WO2020076614A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US17/283,232 US12467064B2 (en) 2018-10-08 2019-10-03 Artificial expression constructs for selectively modulating gene expression in interneurons
EP19870829.9A EP3864150A4 (en) 2018-10-08 2019-10-03 ARTIFICIAL EXPRESSION CONSTRUCTS FOR SELECTIVE MODULATION OF GENE EXPRESSION IN INTERNEURONES
CA3115652A CA3115652A1 (en) 2018-10-08 2019-10-03 Artificial expression constructs for selectively modulating gene expression in interneurons
JP2021543981A JP7695192B2 (ja) 2018-10-08 2019-10-03 介在ニューロンにおける遺伝子発現を選択的に調節するための人工発現構築物
AU2019358806A AU2019358806B2 (en) 2018-10-08 2019-10-03 Artificial expression constructs for selectively modulating gene expression in interneurons
JP2024187194A JP7829658B2 (ja) 2018-10-08 2024-10-24 介在ニューロンにおける遺伝子発現を選択的に調節するための人工発現構築物
US19/007,152 US20250223612A1 (en) 2018-10-08 2024-12-31 Artificial expression constructs for selectively modulating gene expression in interneurons
AU2025208516A AU2025208516A1 (en) 2018-10-08 2025-07-25 Artificial Expression Constructs For Selectively Modulating Gene Expression In Interneurons

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US201862742835P 2018-10-08 2018-10-08
US62/742,835 2018-10-08
US201862749012P 2018-10-22 2018-10-22
US62/749,012 2018-10-22
US201962810281P 2019-02-25 2019-02-25
US62/810,281 2019-02-25

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US19/007,152 Continuation US20250223612A1 (en) 2018-10-08 2024-12-31 Artificial expression constructs for selectively modulating gene expression in interneurons

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EP (1) EP3864150A4 (https=)
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Cited By (7)

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WO2021248085A2 (en) 2020-06-04 2021-12-09 Allen Institute Artificial expression constructs for selectively modulating gene expression in inhibitory neocortical neurons
WO2021216778A3 (en) * 2020-04-21 2021-12-16 Allen Institute Artificial expression constructs for selectively modulating gene expression in neocortical layer 5 glutamatergic neurons
WO2022036255A1 (en) * 2020-08-14 2022-02-17 Allen Institute Artificial expression constructs for modulating gene expression in striatal neurons
WO2022049385A1 (en) 2020-09-04 2022-03-10 Asklepios Biopharmaceutical, Inc. Regulatory nucleic acid sequences
WO2023250362A1 (en) * 2022-06-21 2023-12-28 Regel Therapeutics, Inc. Genetic regulatory elements and uses thereof
JP2024505027A (ja) * 2021-02-02 2024-02-02 アレン インスティテュート Ｇａｂａ作動性ニューロン及び星状膠細胞における遺伝子発現の調節のための人工発現構築物
US12121563B2 (en) 2018-04-09 2024-10-22 Allen Institute Rescuing voltage-gated sodium channel function in inhibitory neurons

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JP7695192B2 (ja) * 2018-10-08 2025-06-18 アレン インスティテュート 介在ニューロンにおける遺伝子発現を選択的に調節するための人工発現構築物
CN116286917A (zh) * 2021-12-14 2023-06-23 中国科学院深圳先进技术研究院 重组载体及其构建方法和应用
JP2025520385A (ja) * 2022-06-13 2025-07-03 アレン インスティテュート 中枢神経系の非神経細胞において遺伝子発現を調節するための人工発現コンストラクト
CN119060958A (zh) * 2023-12-15 2024-12-03 中国科学院深圳先进技术研究院 一种携带钙离子报告基因的神经元及其制备方法和应用

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AU2019358806A1 (en) 2021-05-20
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US12467064B2 (en) 2025-11-11
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US20210348195A1 (en) 2021-11-11
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