Viral Capsid Tolerance Induction for Repeat rAAV Gene Therapy
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Solution Overview
Problem
Immune responses to viral vectors, such as therapeutic recombinant adeno-associated virus (rAAV), limit the repeated administration of gene therapy due to the development of immune reactions in patients.
Innovation Solution
Administering a tolerance-inducing gene therapy vector that encodes a portion of the capsid protein of the therapeutic rAAV, targeting either the liver or hematopoietic stem cells, to induce specific immune tolerance, using vectors like lentiviral or lipid nanoparticles, and employing liver-specific or HSC-specific promoters to express the capsid protein.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic rAAV is administered repeatedly to treat disease, then therapeutic efficacy is improved, but immune response against the viral vector increases
Solution Approach 1:
The patent applies preliminary action by administering a tolerance-inducing vector before repeat administrations of therapeutic rAAV. This pre-treatment expresses capsid proteins to induce immune tolerance in advance, creating a permissive immune environment that allows subsequent therapeutic vectors to be administered repeatedly without eliciting harmful immune responses.
Solution Approach 2:
The patent uses an intermediary approach by introducing a tolerance-inducing vector as a mediator between the immune system and the therapeutic rAAV. This intermediary vector expresses capsid proteins that act as a bridge, training the immune system to tolerate the therapeutic vector without attacking it, thereby enabling repeat administrations.
2Object-affected harmful factors
If immune tolerance is induced by expressing capsid protein, then immune response is reduced, but additional vector administration is required
Solution Approach 1:
The patent applies universality by designing a tolerance-inducing vector that can target multiple cell types (liver cells, hematopoietic stem cells, dendritic cells) through selective promoters. This multi-functional approach allows a single vector administration to induce immune tolerance through multiple pathways, reducing the need for complex multi-step protocols.
Solution Approach 2:
The patent uses local quality by employing tissue-specific promoters (liver-specific promoters, HSC-specific promoters) to direct capsid protein expression to specific cell types. This localized expression strategy enables targeted induction of immune tolerance in specific immune compartments, optimizing the tolerance-inducing effect while simplifying the overall approach.
Data Source
AI summary
Described are viral vectors, compositions, kits, and methods or using the vectors, compositions, kits to modulate immune response in a subject. The viral vectors include therapeutic recombinant adeno-associated viruses (rAAVs) and tolerance inducing gene therapy vectors. The therapeutic rAAVs and tolerance inducing gene therapy vectors can be used to deliver one or more therapeutic nucleic acids to the subject. The tolerance inducing gene therapy vectors induce immune-specific tolerance to the therapeutic rAAVs to improve efficacy of the therapeutic rAAVs and allow for multiple administrations of the therapeutic rAAVs with little or no associated immune response to the therapeutic rAAVs. The therapeutic rAAVs can be used to administer a therapeutic effect to the subject.