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Non-human animals having disruption in C9oRF72 locus

A locus, genome technology applied to the domain of non-human animals with disruption of the C9ORF72 locus

Pending Publication Date: 2018-04-17
REGENERON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Given the genetic differences between species, there is a large but unmet need for the development of improved animal models that encompass virtually every human neurodegenerative and / or inflammatory disease

Method used

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  • Non-human animals having disruption in C9oRF72 locus
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  • Non-human animals having disruption in C9oRF72 locus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0212] Example 1. Disruption in the non-human C9ORF72 locus

[0213] This example illustrates targeted disruption of the rodent C9orf72 locus. In particular, this example specifically describes the knockout of the entire coding sequence of the mouse C9orf72 locus using a lacZ reporter gene construct operably linked to the mouse C9orf72 promoter. The C9orf72-lacZ targeting vector used to disrupt the endogenous mouse C9orf72 locus was prepared using a method as previously described (see, for example, U.S. Patent No. 6,586,251; Valenzuela et al., 2003, NatureBiotech.21 (6): 652 -659; and Adams, N.C. and N.W. Gale, in Mammalian and Avian Transgenesis–New Approaches, ed. Lois, S.P.a.C., Springer Verlag, Berlin Heidelberg, 2006). The resulting modified C9orf72 locus is at Figure 1A displayed in the box at the bottom.

[0214] Briefly, targeting vectors were constructed using bacterial artificial chromosome (BAC) clones from the mouse RP23BAC library (Adams, D.J. et al., 2005, Ge...

Embodiment 2

[0227] Example 2. Behavioral Analysis of Non-Human Animals with Disruptions in the C9orf72 Locus

[0228] This example demonstrates, inter alia, that non-human animals described herein (e.g., rodents) develop ALS-like symptoms, e.g., due to disruption of the rodent C9orf72 locus (e.g., mice) as described in Example 1, leading to weight loss Reduced and marked motor abnormalities.

[0229] Phenotypic studies of C9orf72-disrupted mice as described above were performed at 8 weeks, 18 weeks, 37 weeks (female) and 57-60 weeks (male). Body weight was measured every two weeks and body composition was analyzed by CT scan (Dynamic 60). A standard 24 scans are used to reveal the solid portion of the cervical region of the spine. All animal manipulations were performed according to protocols approved by the Institutional Animal Care and Use Committee of Regeneron Pharmaceuticals.

[0230] Global motor function was assessed using a subjective blind scoring test. Sports impairment anal...

Embodiment 3

[0247] Example 3. Immunophenotyping of Non-Human Animals with Disruption of the C9orf72 Locus

[0248] This example demonstrates that non-human animals prepared according to Example 1 exhibit an immunological phenotype characterized in some examples by splenomegaly and lymphadenopathy caused by infiltration of various immune cell populations. Furthermore, this example specifically demonstrates that such non-human animals suffer from glomerulonephritis, which is characterized by infiltration of the kidneys by populations of immune cells. Wishing not to be bound by any particular theory, the inventors propose that the product of the C9ORF72 locus plays a key role in immune function, and that loss of the C9ORF72 polypeptide in the non-human animals described herein is not the primary mechanism for developing ALS and / or FTD. from C9orf72 - / - Various tissues were obtained for analysis from wild type mice (n=4-6 animals / genotype, 8, 18 and 37 weeks (female), 9-10, 18 and 57-60 week...

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Abstract

A non-human animal model for neurodegenerative and / or inflammatory diseases is provided. The non-human animals comprise a disruption in a C9ORF72 locus. In particular, the non-human animals describedherein comprise a deletion of an entire coding sequence of a C9ORF72 locus. Methods of identifying therapeutic candidates that may be used to prevent, delay or treat one or more neurodegenerative (e.g., amyotrophic lateral sclerosis (ALS, also referred to as Lou Gehrig's disease) and frontotemporal dementia (FTD)), autoimmune and / or inflammatory diseases (e.g., SLE, glomerulonephritis) are also provided.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 62 / 168,171, filed May 29, 2015, U.S. Provisional Application No. 62 / 232,658, filed September 25, 2015, and U.S. Provisional Application No. 62 / 245,382, filed October 23, 2015 The entire content of said application is incorporated herein by reference. [0003] References to Sequence Listings [0004] This Sequence Listing is an ASCII text file named 32698_10152US01_SequenceListing, 56kb in size, created on May 19, 2016, and submitted to the US Patent and Trademark Office via EFS-Web, which is incorporated herein by reference. Background technique [0005] Neurodegenerative diseases are an important cause of disability and disease. In particular, amyotrophic lateral sclerosis (ALS, also known as Guerrake's disease) and frontotemporal dementia (FTD) are rare neurological disorders characterized by progressive neuronal loss and / or death. Although aging is conside...

Claims

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Application Information

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IPC IPC(8): A01K67/027C12N5/10C12N15/85C12N15/90A61K49/00A61P25/28A61P29/00A61P37/00
CPCA01K67/0276A61K49/0008C12N15/8509C12N15/907A01K2217/072A01K2217/075A01K2227/105A01K2267/0381A01K2267/0393A01K2267/0318A01K67/02A61P25/28A61P29/00A61P37/00
Inventor 阿曼达·阿塔纳西奥布尔钦·艾克兹国春·龚迈克尔·L.·拉克鲁瓦-法利什卡曼·维纳斯·莱大卫·M.·瓦伦苏埃拉
Owner REGENERON PHARM INC
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