Mitochondria-Replaced T Cells for Reversing Exhaustion
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Solution Overview
Problem
T cell exhaustion, characterized by poor effector function and sustained expression of inhibitory receptors, hinders the optimal control of infections and tumors, particularly in chronic antigen stimulation settings like cancer and chronic viral infections, necessitating a method to reduce or reverse this state.
Innovation Solution
The method involves electroporating exhausted T cells with a nucleic acid sequence encoding XbaIR to reduce endogenous mitochondrial DNA copy number, followed by incubation with isolated exogenous mitochondria, thereby generating mitochondria-replaced T cells with decreased expression of exhaustion markers like PD-1, enhancing their effector function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cells are used to combat cancer and chronic viral infections, then immune response is activated, but T cell exhaustion occurs leading to reduced effector function
Solution Approach 1:
The patent extracts and replaces the dysfunctional endogenous mitochondria with healthy exogenous mitochondria from young donors. This is achieved by depleting endogenous mitochondrial DNA using XbaIR enzyme and then introducing fresh mitochondria, thereby removing the source of exhaustion and restoring T cell function.
Solution Approach 2:
The patent changes the mitochondrial parameter by replacing old, dysfunctional mitochondria with young, functional mitochondria. This is evidenced by the decrease in PD-1 expression (a marker of exhaustion) and restoration of effector functions through mitochondrial replacement therapy.
2Reliability
If mitochondria replacement is performed to restore T cell function, then exhaustion markers decrease, but the process complexity increases
Solution Approach 1:
The patent uses XbaIR enzyme as an intermediary to deplete endogenous mitochondrial DNA before introducing exogenous mitochondria. This intermediary step facilitates the replacement process by clearing the way for new mitochondria to take over, making the complex process more manageable and efficient.
3Reliability
If exogenous mitochondria are introduced to replace endogenous mitochondria, then T cell exhaustion is reduced, but the manufacturing process becomes more complex
Solution Approach 1:
The patent performs preliminary depletion of endogenous mitochondrial DNA using XbaIR before introducing exogenous mitochondria. This preliminary action simplifies the overall manufacturing process by ensuring that the cellular environment is prepared and ready to accept the new mitochondria, reducing potential conflicts and improving efficiency.
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 effectively decreases PD-1 expression by at least 5-60% in mitochondria-replaced T cells, improving their effector functions such as proliferation and cytokine secretion, making them more effective in combating cancer and chronic viral infections.
Implementation Method 1
electroporating exhausted T cells with a nucleic acid sequence encoding XbaIR to reduce endogenous mitochondrial DNA copy number
Implementation Method 2
electroporating exhausted T cells with a nucleic acid sequence comprising a nucleotide sequence encoding XbaIR
Data Source
AI summary
The present disclosure provides methods and compositions for producing mitochondria replaced T cells from exhausted T cells, that involves reducing exhausted T cells mitochondrial DNA (mtDNA) and incubating with isolated exogenous mitochondria for a sufficient period of time to generate mitochondria replaced T cells in which expression of at least one exhaustion marker is altered by at least 5%, at least 10%, 20% (e.g., at least 1.25 fold), at least 30%, at least 40%, at least 50%, at least 60%, or more, wherein the mitochondria replaced T cells have improved effector function relative to the exhausted T cells. In addition, the present disclosure also provides methods of treating or ameliorating an age-related disease (e.g., cancer or an autoimmune disease), as well as methods for ameliorating a symptom of a chronic infection (e.g., a chronic viral infection), that involve administering the mitochondria replaced T cells.