Tolerogenic CRISPR-Cas Compositions for Immune Tolerance Induction
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Solution Overview
Problem
The immune response elicited by CRISPR-Cas effector polypeptides, such as Cas9, in mammalian hosts can neutralize the polypeptides and reduce the efficiency of gene editing, necessitating methods to induce immune tolerance.
Innovation Solution
The use of tolerogenic compositions, including microparticles or dissolvable microneedle arrays, to stimulate regulatory T cells and promote a tolerogenic immune response to CRISPR-Cas effector polypeptides, such as Cas9, by encapsulating Treg stimulating agents and the polypeptides or their immunogenic fragments.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If CRISPR-Cas effector polypeptide is administered for gene editing, then gene editing efficiency is improved, but immune response is elicited leading to neutralization and cell death
Solution Approach 1:
The patent applies preliminary action by administering tolerogenic compositions containing CRISPR-Cas effector polypeptides or their immunogenic fragments before the actual gene editing treatment. This pre-exposure conditions the immune system to recognize the CRISPR-Cas polypeptide as self-tolerant, preventing subsequent immune responses that would otherwise neutralize the editing agent or cause cell death. The tolerogenic composition is given in advance to establish immune tolerance, enabling successful in vivo gene editing without immune-mediated complications.
2Object-affected harmful factors
If immune tolerance is induced using tolerogenic compositions, then immune response is reduced, but device complexity increases due to microparticle or microneedle array formulation
Solution Approach 1:
The patent employs an intermediary approach by using microparticles or microneedle arrays as delivery vehicles that contain both the CRISPR-Cas effector polypeptide and Treg-stimulating agents. These intermediaries facilitate the induction of immune tolerance by delivering the tolerogenic composition in a controlled manner that specifically targets immune cells. The microparticle or microneedle formulation acts as a mediator between the CRISPR-Cas polypeptide and the immune system, enabling tolerance induction while managing the complexity through standardized delivery platform technology.
3Reliability
If standard immunization methods are used, then immune response is enhanced, but this worsens the problem of CRISPR-Cas polypeptide neutralization
Solution Approach 1:
The patent applies inversion by completely reversing the conventional immunization approach. Instead of using adjuvants and formulations designed to enhance immune activation and antibody production, the invention uses tolerogenic compositions that actively suppress immune responses and promote regulatory T cell development. The CRISPR-Cas effector polypeptide or its fragments are delivered in a context that induces tolerance rather than immunity, thereby preventing the harmful neutralization that would result from standard immunization while still achieving reliable delivery and expression of the editing agent.
Data Source
AI summary
Tolerogenic compositions are disclosed that are of use for inducing a tolerogenic immune response to a CRISPR-Cas effector polypeptide in a subject. In some aspects, the tolerogenic composition includes: a) one or more microparticles; b) one or more regulatory T cell (Treg) stimulating agents encapsulated within each microparticle; and c) a CRISPR-Cas effector polypeptide or immunogenic fragment thereof, or a fusion polypeptide comprising a CRISPR-Cas effector polypeptide or immunogenic fragment thereof. In other aspects, the tolerogenic composition includes a) a dissolvable microneedle array; b) one or more agents that promote differentiation of tolerogenic DCs in the dissolvable microneedle array; and c) a CRISPR-Cas effector polypeptide or immunogenic fragment thereof, or a fusion polypeptide comprising a CRISPR-Cas effector polypeptide or immunogenic fragment thereof.