Secreted Klotho Variant for Targeted CNS Cognitive Therapy
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Solution Overview
Problem
Current treatments for cognitive and behavioral impairments associated with aging and neurodegenerative diseases, such as Alzheimer's, are inadequate in effectively addressing memory loss and cognitive decline, with existing approaches often having side effects or not specifically targeting the central nervous system.
Innovation Solution
The development of a method involving the administration of the secreted splicing variant of the Klotho protein (s-KL) directly to the central nervous system using AAVrh10 vectors, which enhances cognitive performance and memory capabilities without affecting body weight or sensorimotor skills, and specifically targets areas involved in cognition and behavior.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If full-length transmembrane Klotho protein is administered systemically, then cognitive functions are improved, but side effects occur and the treatment does not specifically target the central nervous system
Solution Approach 1:
The patent extracts and utilizes only the secreted splicing variant (s-KL) of the Klotho protein, which is specifically detected in the central nervous system, rather than administering the full-length transmembrane form systemically. This extraction of the specific active variant enables targeted cognitive enhancement while avoiding the side effects associated with non-specific systemic administration.
Solution Approach 2:
The invention applies local quality by directing the therapeutic effect specifically to the central nervous system where s-KL is naturally expressed. The treatment locally enhances cognitive functions in the brain and spinal cord without affecting other body systems, thereby improving reliability of cognitive improvement while minimizing harmful side effects in other tissues.
2Reliability
If full-length transmembrane Klotho protein is administered, then cognitive performance is enhanced, but the treatment affects body weight and sensorimotor skills
Solution Approach 1:
The patent extracts the specific secreted splicing variant (s-KL) that is responsible for cognitive enhancement, separating this function from the full-length transmembrane protein that causes unwanted effects on body weight and sensorimotor skills. This extraction allows selective improvement of cognitive performance without the harmful side effects.
Solution Approach 2:
The invention segments the Klotho protein into different functional variants: the secreted splicing variant (s-KL) that provides cognitive benefits, and the full-length transmembrane form that provides structural and metabolic functions. By administering only the segmented s-KL variant, the patent achieves cognitive enhancement without interfering with body weight regulation and sensorimotor functions.
3Reliability
If existing treatments for cognitive impairment are used, then memory loss is addressed, but the treatments are not specifically targeting the central nervous system
Solution Approach 1:
The patent applies local quality by using the secreted splicing variant (s-KL) that is specifically detected and expressed in the central nervous system. This ensures the treatment is naturally targeted to the brain and spinal cord, providing specific therapy for cognitive impairment without requiring complex delivery systems to reach the CNS.
Solution Approach 2:
The invention utilizes the self-service principle by employing a treatment agent (s-KL) that is naturally produced and detected in the central nervous system. The protein's inherent presence and specificity in the CNS allow it to serve as both the therapeutic agent and the targeting mechanism, eliminating the need for external targeting devices or complex administration protocols.
Data Source
AI summary
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.