Multi-Serotype AAV Gene Delivery for Aging Research Translation
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Solution Overview
Problem
Current gene delivery technologies are limited in effectively translating aging research into clinical applications due to lack of translatability and high costs, and there is a need for efficient methods to deliver geroprotective genes to treat aging-related diseases.
Innovation Solution
A high-efficiency adeno-associated virus (AAV)-based gene therapy system, known as DAEUS, which uses multiple viral serotypes to achieve uniform systemic expression of geroprotective genes, such as Cisd2, Atg5, and PTEN, across various tissues in animals, including aged mice.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional gene delivery methods are used, then research can be conducted, but translatability to clinic is poor and costs are high
Solution Approach 1:
The patent segments the gene delivery approach by using multiple AAV serotypes (AAV9, AAVrh10, AAV-DJ, AAV-PHP.B, AAV-PHP.eB) with different tissue tropisms to target specific organs systematically. This segmentation allows optimized delivery to heart, liver, muscle, brain, and other tissues, improving translatability while maintaining research efficiency through modular vector design
Solution Approach 2:
The patent changes key parameters of the gene delivery system by using self-complementary AAV genomes that bypass the need for cellular DNA replication, achieving immediate and sustained transgene expression. This parameter change from conventional single-stranded AAV to self-complementary AAV improves both clinical translatability and research productivity
2Adaptability or versatility
If transgenic animals are generated and bred for aging research, then genetic studies can be performed, but time and cost increase significantly
Solution Approach 1:
The patent applies preliminary action by pre-engineering self-complementary AAV vectors containing geroprotective genes (e.g., Cisd2, Atg5, PTEN) that can be rapidly administered to aged animals without requiring generation and breeding of transgenic lines. This preliminary preparation of delivery vectors eliminates the time-consuming process of creating transgenic cohorts while maintaining genetic study capability
Solution Approach 2:
The patent uses copying by delivering functional gene copies via AAV vectors to aged animals, bypassing the need to create heritable transgenic modifications. This approach copies the desired genetic function temporarily and reversibly, enabling genetic studies without the time and cost of breeding transgenic animals
3Ease of operation
If single AAV serotype is used for gene delivery, then vector design is simple, but tissue-specific expression is limited
Solution Approach 1:
The patent merges multiple AAV serotypes (AAV9, AAVrh10, AAV-DJ, AAV-PHP.B, AAV-PHP.eB) into a coordinated delivery system, each targeting different tissues. This merging maintains relative vector design simplicity while achieving comprehensive tissue coverage including heart, liver, muscle, brain, and other organs through the combined tropisms of the serotypes
4Reliability
If geroprotective genes are overexpressed in aged animals, then healthspan and lifespan can be extended, but delivery efficiency must be high
Solution Approach 1:
The patent changes the genomic parameter by using self-complementary AAV genomes that form double-stranded DNA immediately upon entry into the nucleus, bypassing the need for cellular DNA replication. This parameter change enables immediate and sustained high-level expression of geroprotective genes, achieving both high delivery efficiency and reliable long-term expression in aged animals
Data Source
AI summary
The disclosure provides viral vector delivery systems for use in treating diseases or disorders in a subject to whom the viral vector delivery systems are administered, as well as to methods of making and using the viral vector delivery systems.