Progranulin Variants with Modified C-Termini for Neurodegenerative Therapy
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Solution Overview
Problem
Current therapies fail to effectively address disorders associated with reduced progranulin levels or function, such as frontotemporal dementia, Alzheimer's Disease, and other neurodegenerative conditions, due to challenges in maintaining progranulin stability and delivery across the blood-brain barrier.
Innovation Solution
Development of progranulin variants with modified C-termini and fusion proteins linked to Fc polypeptides, which are less susceptible to cleavage and can maintain sortilin binding, facilitating increased progranulin levels and improved delivery across the blood-brain barrier.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type progranulin is used for therapy, then it can bind to sortilin, but it is susceptible to C-terminal cleavage which reduces its stability and effectiveness
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence at the C-terminus of progranulin (specifically residues 574-576). The wild-type QLL sequence is replaced with alternative sequences such as QAL, QGL, QSL, QTL, QVL, QYL, or QRL. This sequence modification changes the chemical and structural parameters of the progranulin molecule, making it resistant to cleavage by proteases while preserving its ability to bind sortilin and exert therapeutic effects.
2Quantity of substance
If progranulin levels are increased to treat neurodegenerative diseases, then therapeutic benefit is achieved, but delivery across the blood-brain barrier remains challenging
Solution Approach 1:
The patent employs fusion proteins that combine the modified progranulin with carrier molecules or peptides designed to facilitate blood-brain barrier penetration. These intermediary structures act as mediators that enable the progranulin to cross the blood-brain barrier while maintaining its therapeutic function. The fusion construct serves as a vehicle that overcomes the physiological barrier without altering the core progranulin sequence.
3Ease of manufacture
If current therapies are used for progranulin-related disorders, then treatment is provided, but they fail to effectively address the underlying cause due to progranulin instability
Solution Approach 1:
The patent segments the progranulin molecule by identifying and modifying specific regions (the C-terminal residues 574-576) that are responsible for instability. By focusing modifications on this specific segment rather than the entire molecule, the patent maintains the functional integrity of progranulin while eliminating the vulnerable cleavage site. This targeted segmentation approach allows for effective therapy development.
Data Source
AI summary
Provided herein are progranulin variants and fusion proteins that comprise a progranulin variant and an Fc polypeptide. Methods of using such proteins to treat progranulin-associated disorders (e.g., a neurodegenerative disease, such as frontotemporal dementia (FTD)) are also provided herein.