Precision Gene Therapy Targeting APOE e4 Allele
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Solution Overview
Problem
Current therapies for Alzheimer's disease, particularly late-onset Alzheimer's disease (LOAD), are ineffective due to the disease's heterogeneity and lack of understanding of its underlying pathophysiologic processes, leading to no disease-modifying treatments and significant economic burden.
Innovation Solution
Development of a precision gene therapy using a viral vector carrying a nucleic acid sequence encoding a Cas endonuclease, a polypeptide with enzymatic activity, and a guide RNA to target and downregulate the APOE gene, specifically the APOE e4 allele, through CRISPR/Cas9 gene editing technology.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used for Alzheimer's disease, then treatment is provided, but the therapies are ineffective due to disease heterogeneity and do not modify disease progression
Solution Approach 1:
The patent applies local quality by developing personalized gene therapy approaches that target specific genetic variants (such as APOE e4 carriers) rather than treating all Alzheimer's patients uniformly. This involves identifying patients with specific genetic profiles and administering tailored CRISPR/Cas9-based therapies that address their particular molecular mechanisms, thereby improving therapeutic effectiveness while accounting for disease heterogeneity
Solution Approach 2:
The patent segments the Alzheimer's disease population into distinct subgroups based on genetic risk factors and molecular profiles. By dividing patients into categories such as APOE e4 carriers versus non-carriers, and further stratifying by other genetic variants, the therapy can be customized for each segment, addressing the specific pathophysiologic processes relevant to each subgroup rather than applying a one-size-fits-all approach
2Measurement precision
If gene therapy approaches are developed to address specific genetic targets, then therapeutic precision is improved, but treatment complexity and development challenges increase
Solution Approach 1:
The patent employs the CRISPR/Cas9 platform as a universal tool that can be adapted to target multiple different genetic variants and molecular mechanisms underlying Alzheimer's disease. The same basic CRISPR system can be reprogrammed with different guide RNAs to target APOE, TOMM40, or other risk genes, providing a multi-functional approach that maintains precision while leveraging a standardized platform to reduce overall development complexity
Solution Approach 2:
The patent uses guide RNA molecules as intermediaries that bridge the connection between the CRISPR/Cas9 system and specific target genes. These guide RNAs serve as programmable mediators that direct the Cas9 enzyme to precise genomic locations, enabling high genetic targeting precision while simplifying the design process through modular RNA sequences that can be easily synthesized and exchanged to target different genetic variants
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach potentially reduces APOE expression, thereby addressing the pathological phenotype associated with Alzheimer's disease, offering a novel method for treating and preventing disease progression.
Implementation Method 1
through CRISPR/Cas9 gene editing technology
Data Source
AI summary
Disclosed herein are methods of administering precision gene therapy, treating and/or preventing Alzheimer' disease progression, and reducing expression of APOE and APOE e4. Disclosed herein are isolated nucleic acid molecules, viral vectors, lentiviral vectors, pharmaceutical formulations, host cells, guide RNAs and plasmids for use in the disclosed methods.