Secreted splicing variant of mammal klotho as a medicament for cognition and behaviour impairments

A mammalian, secreted technology for cognitive and behavioral disorders

Active Publication Date: 2018-07-17
UNIV AUTONOMA DE BARCELONA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The presence of circulating klotho species that do correspond to peptides produced by alternatively spliced ​​mRNA has not been reported in serum or CSF (Forster et al., ""Vitamin D Receptor Controls Expression of the Anti-aging Klotho Gene in Mouse and Human Renal Cells" Biochem Biophys ResCommun.201 1October 28;414(3):557-562)

Method used

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  • Secreted splicing variant of mammal klotho as a medicament for cognition and behaviour impairments
  • Secreted splicing variant of mammal klotho as a medicament for cognition and behaviour impairments
  • Secreted splicing variant of mammal klotho as a medicament for cognition and behaviour impairments

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Example 1. Generation of plasmid vectors encoding secreted Klotho proteins. Preparation of AAV viral vectors for transduction.

[0084] Production of viral vectors for gene therapy is performed from synthetic constructs. Gene construct (plasmid) pCR-KL-TOPO-KL (ImaGenes TM , Germany) full-length cDNA encoding the transmembrane protein isoform of Klotho (m-KL). The Klotho sequence was then cloned by restriction enzyme ligation into the pGG2 plasmid (SEQ ID NO: 12, provided by Genethon) carrying the inverted terminal repeat (ITR) sequence of the adeno-associated virus serotype 2 (AAV2) genome and a multiple cloning site (MCS), where the gene of interest is cloned under the control of the cytomegalovirus immediate early promoter (CMV IE). To this end, the cDNA of m-KL was extracted from pCR-KL-TOPO-KL with XbaI / EcoRI restriction enzymes, and the same enzymes were used to clone this fragment into vector p123T, which contains the CMV IE promoter sequence (MoBiTec, Alem...

Embodiment 2

[0090] Example 2. In vivo administration of AAV s-KL vectors in aged mice

Embodiment 2A

[0091] Example 2A: Administration of AAV Vectors

[0092] The long-term effects of klotho overexpression in the aging CNS were assessed in C57BL / 6 mice injected at 12 months of age (middle-aged, N=10) and aged 6 months later when they Pass a battery of behavioral assessments and functional analysis tests at old age (18 months) ( figure 2 and image 3 ) for detection. The control group was injected with an AAVrh10 vector encoding an unrelated DNA sequence, and the treatment group was injected with an AAVrh10 vector encoding a secreted (s-KL) Klotho isoform. AAV vectors were injected intracerebroventricularly (icv) to mimic the endogenous production system where Klotho produced in the CNS is released into the CSF and distributed throughout the brain.

[0093] For in vivo assays, Harlan Laboratories BV C57B16 mice (wild type males) were used. All animal and necropsy experiments were performed at the Universitat Autonoma de Barcelona (Spain) in accordance with applicable Sp...

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Abstract

The invention discloses using secreted splicing variant of mammal Klotho (s- KL) as an agent for the prevention and / or treatment of cognitive and / or behaviour impairments. It also refers to gene constructs and expression vectors useful in gene therapy for the delivery of said s-KL variant to the central nervous system of a mammal, in particular a rodent or a human. Pharmaceutical compositions comprising either the protein s-KL or any gene construct for expressing the protein in the CNS are also disclosed.

Description

technical field [0001] The present invention relates to the field of medical methods for the prevention and / or treatment of cognitive and behavioral disorders in patients suffering from diseases associated with memory loss and learning difficulties and / or neurodegenerative and / or neuropathological diseases. Background technique [0002] It is well known that memories are often lost over time and that certain aspects may change resulting in a loss of memory efficiency. Examples of these include: difficulty maintaining attention on more than one thing at a time; difficulty learning new things that require effort; and slow retrieval of old information. Verbal ability, information processing, problem solving, working memory, long-term memory, spatial memory, and abilities decrease with age, while specialized knowledge and cognitive abilities such as semantic memory (vocabulary), world knowledge, and implicit memory are lost in the absence of Stable or even better with age in th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/47C12N9/24A61P25/28A61K9/00
CPCA61K9/0085C12Y302/01031C12N9/2402C12N2710/10043C07K16/40A61K38/47A61P25/28A61K45/06A61K48/00
Inventor M·夏兰·罗德里格斯A·马索·查康A·博施·梅里诺
Owner UNIV AUTONOMA DE BARCELONA
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