PSEN1 Gene Therapy Delivery to Restore γ-Secretase Activity
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Solution Overview
Problem
Current treatments for Alzheimer's disease are ineffective, and there is no cure for this neurodegenerative condition, which is characterized by progressive cognitive decline and neurodegeneration.
Innovation Solution
A codon-optimized polynucleotide encoding human presenilin 1 (PS1) protein is delivered using exosomes or lipid-based nanoparticles, expressed via viral vectors like AAV or lentiviral vectors, to rescue impaired γ-secretase activity in cells with dominant negative PSEN1 mutations, thereby addressing the underlying cause of Alzheimer's disease.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for Alzheimer's disease, then treatment is provided, but the treatments are ineffective and there is no cure
Solution Approach 1:
The patent extracts and replaces the defective PSEN1 gene with a functional copy delivered via AAV vector, removing the harmful genetic defect and restoring normal γ-secretase function to prevent amyloid plaque formation
Solution Approach 2:
The AAV vector serves as an intermediary carrier to deliver the functional PSEN1 gene into neuronal cells, enabling gene therapy without direct genetic manipulation and achieving sustained therapeutic expression
2Reliability
If gene therapy is implemented to rescue impaired γ-secretase activity, then PS1 expression is increased and disease progression is slowed, but the complexity of delivery systems increases
Solution Approach 1:
The AAV vector acts as a biological intermediary that simplifies delivery by utilizing its natural ability to infect neuronal cells and provide long-term transgene expression, avoiding complex chemical or physical delivery methods
Solution Approach 2:
The patent optimizes the PSEN1 coding sequence through codon optimization and adds specific regulatory elements to the vector construct, changing molecular parameters to enhance expression levels and therapeutic efficacy
Data Source
AI summary
The present disclosure provides, among other things, human codon-optimized sequences encoding presenilin 1, and methods for using the sequences in gene therapy to treat neurodegenerative diseases including, but not limited to Alzheimer's disease, frontotemporal dementia, frontotemporal lobar degeneration, Pick's disease, Lewy body dementia, memory loss, and cognitive impairment including mild cognitive impairment (MCI).