Recombinant Viral Vector Transduction via Immunosuppressive Regimens
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current gene therapy using recombinant viral vectors faces limitations in transduction efficiency and transgene expression, primarily due to immune responses, which hinder their therapeutic efficacy in diseases such as cystic fibrosis.
Innovation Solution
Administering a dosing regimen of recombinant viral vectors in combination with an immunosuppressive regimen that includes calcineurin inhibitors, glucocorticoids, antimetabolites, mTOR inhibitors, and other immunomodulatory agents to suppress immune responses, thereby enhancing transduction efficiency and transgene expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If recombinant viral vectors are administered to deliver therapeutic transgenes, then gene therapy treatment is achieved, but transduction efficiency is limited due to immune responses
Solution Approach 1:
The patent applies preliminary action by administering immunosuppressive therapy before viral vector administration to pre-condition the subject's immune system. This prevents the immune system from mounting a neutralizing response against the viral vector, thereby improving transduction efficiency. The immunosuppressive regimen is started prior to vector dosing and continued through the treatment period to maintain suppressed immune activity.
Solution Approach 2:
The patent uses immunosuppressive agents as intermediaries to mediate between the viral vector and the immune system. These agents (such as corticosteroids, calcineurin inhibitors, antimetabolites) act as chemical mediators that suppress immune cell activity and prevent immune recognition of the viral vector, allowing the vector to successfully transduce target cells without being neutralized.
2Reliability
If immunosuppressive regimen is administered to improve transduction efficiency, then transduction efficiency and transgene expression are improved, but treatment complexity increases
Solution Approach 1:
The patent applies parameter changes by modifying the immunological state of the subject through pharmacological intervention. By changing the immune system's parameters (cellular activity, cytokine production, antibody formation) through immunosuppressive drugs, the treatment creates a permissive environment for viral vector transduction. This involves adjusting multiple physiological parameters simultaneously to achieve the desired therapeutic effect.
3Reliability
If multiple doses of viral vector are administered to increase transgene expression, then therapeutic efficacy is improved, but neutralizing antibody titers increase
Solution Approach 1:
The patent applies preliminary action by establishing immunosuppression before the first dose and maintaining it through subsequent doses. This pre-conditioning prevents the formation of neutralizing antibodies that would otherwise accumulate with repeated dosing. The immunosuppressive coverage is timed to precede and accompany each vector dose to prevent immune recognition.
Solution Approach 2:
The patent maintains continuous immunosuppressive therapy throughout the multi-dose treatment regimen. This continuous suppression ensures that the immune system remains inhibited across all dosing intervals, preventing the development of neutralizing antibodies that would occur with intermittent or no immunosuppression. The useful action of immunosuppression continues uninterrupted to protect each subsequent vector dose.
Data Source
AI summary
Provided herein are methods of transducing a recombinant viral, e.g., retroviral, vector, improving the transgene expression from a recombinant viral vector, and reducing titers of neutralizing antibodies that bind a recombinant viral vector. In general, these methods include administering to a subject a recombinant viral vector and an effective amount of an immunosuppressive regimen.