Modified Lymphocytes for Non-Cytotoxic Therapeutic Protein Delivery
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Solution Overview
Problem
Current biological delivery systems are inadequate for introducing therapeutic agents into the cytoplasm or nucleus of target cells, limiting the effectiveness of gene therapy and gene-editing technologies due to immunogenicity, specificity issues, and the lack of efficient and precise delivery mechanisms.
Innovation Solution
Modified lymphocytes or myeloid cells are engineered to carry non-lytic therapeutic proteinaceous agents, such as chimeric polypeptides comprising a lymphocyte lytic granule-secreted protein and a protein of interest, which can deliver therapeutic agents, including genome-editing proteins like CRISPR-associated protein 9 (Cas9), into target cells without inducing cytotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If viral delivery systems are used for gene therapy, then delivery efficiency is improved, but immunogenicity increases causing acute inflammatory response
Solution Approach 1:
The patent uses modified lymphocytes as intermediary carriers to deliver therapeutic agents into target cells. These engineered lymphocytes naturally interact with target cells through immune synapse formation, providing a biologically compatible delivery mechanism that avoids the immunogenicity of viral vectors while maintaining high delivery efficiency through natural cellular recognition and uptake mechanisms.
Solution Approach 2:
The invention replaces the mechanical/viral delivery system with a biological cellular delivery system. Instead of using viral particles that force entry into cells, the patent employs living lymphocytes that naturally engage target cells through immunological recognition, substituting a harsh mechanical insertion process with a gentle biological interaction that reduces immunogenicity while maintaining delivery effectiveness.
2Adaptability or versatility
If non-specific delivery systems are used, then distribution is improved, but target specificity decreases leading to off-target effects
Solution Approach 1:
The patent applies local quality by engineering lymphocytes with specific surface markers and activation mechanisms that recognize and bind only to target cells expressing specific antigens. This localized recognition capability ensures that therapeutic agents are delivered precisely to intended targets while leaving other cells unaffected, achieving both distribution to relevant cell types and high target specificity simultaneously.
Solution Approach 2:
The invention incorporates feedback mechanisms where modified lymphocytes respond to specific target cell markers through immune synapse formation and activation signals. This feedback loop ensures that delivery only occurs when the correct target is recognized, preventing off-target effects while maintaining the ability to distribute therapy throughout the body to all cells expressing the target marker.
3Productivity
If lymphocytes are used for delivery, then cellular uptake is improved, but cytotoxicity increases causing target cell death
Solution Approach 1:
The patent extracts and removes the cytotoxic granzyme B component from the lymphocyte, retaining only the cellular uptake and delivery mechanisms. By eliminating the harmful cytotoxic payload while preserving the natural immune synapse formation and cellular entry capabilities, the invention achieves high cellular uptake efficiency without the detrimental effect of target cell death.
Solution Approach 2:
The invention converts the natural cytotoxic mechanism of lymphocytes into a beneficial delivery system. By hijacking the immune synapse formation and cellular entry pathways that lymphocytes use for killing, but removing the killing function itself, the patent transforms a harmful cytotoxic process into a beneficial non-cytotoxic delivery mechanism that exploits the same efficient cellular uptake pathways for therapeutic purposes.
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 enables precise and efficient delivery of therapeutic agents into the cytoplasm or nucleus of target cells, overcoming the limitations of existing delivery systems by utilizing the natural lytic pathway of lymphocytes to achieve non-cytotoxic protein transfer and genome editing, thereby enhancing the efficacy of gene therapies.
Implementation Method 1
A non-cytotoxic method of protein transfer, that highjacks lymphocytes' natural lytic pathway to deliver therapeutic agents
Implementation Method 2
Non-lytic chimeric polypeptides comprising a lymphocyte lytic granule-secreted protein, or a functional fragment thereof, and a protein of interest
Data Source
AI summary
Modified cells comprising an exogenous non-cytotoxic therapeutic proteinaceous agent are provided. Non-cytotoxic chimeric polypeptides comprising a lymphocyte lytic granule-secreted protein or a functional fragment thereof and a protein of interest are also provided. Therapeutic compositions, nucleic acid molecules and methods of use related to the modified lymphocytes and chimeric polypeptides of the invention are also provided.