Ocular Gene Therapy Immune Modulation via Peptide Co-injection
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Solution Overview
Problem
Despite the immune-privileged status of the eye, secondary loss of vision occurs in some patients treated with AAV-mediated ocular gene therapy due to induced immune responses against the transgene product and AAV capsid, which existing methods fail to adequately address.
Innovation Solution
Co-injecting peptides from the transgene product with AAV vectors in the subretinal space to modulate immune responses, specifically inhibiting anti-transgene and anti-capsid T-cell immune responses, thereby preventing secondary vision loss.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If AAV vectors are used for ocular gene therapy, then gene transfer efficiency is improved, but immune responses are induced against the transgene product and AAV capsid
Solution Approach 1:
The patent applies preliminary action by co-administering immunomodulatory agents (such as corticosteroids, cyclosporine A, or other immune-suppressing drugs) at the time of AAV vector injection into the eye. This preemptive approach prevents the induction of harmful immune responses before they can develop, while allowing the AAV vector to efficiently deliver the transgene to target cells. The immune modulation occurs concurrently with gene transfer, ensuring both high transduction efficiency and suppression of anti-transgene and anti-capsid immune responses.
2Reliability
If immune responses are induced, then vision improvement may occur initially, but secondary vision loss occurs over the long term
Solution Approach 1:
The patent implements beforehand cushioning by administering immune-modulating drugs prophylactically at the time of AAV injection and continuing treatment for an extended period (e.g., 1-6 months or longer). This creates a protective shield against the development of cytotoxic T-cell responses and antibody formation that would otherwise lead to transgene silencing and secondary vision loss. The prolonged immune suppression ensures long-term maintenance of transgene expression and visual function.
Solution Approach 2:
The patent employs continuous immune modulation therapy extending beyond the initial injection period. Treatment protocols include administering immune-suppressing drugs at multiple time points (e.g., daily, weekly, or monthly injections over several months) to maintain continuous suppression of immune responses. This continuous action prevents the gradual development of immunity that would otherwise occur over time, ensuring sustained transgene expression and long-term visual improvement.
3Ease of operation
If the eye is considered immune-privileged, then immune monitoring is limited to blood samples, but in-depth immunological investigation cannot be performed
Solution Approach 1:
The patent uses blood samples as an intermediary to indirectly monitor immune responses occurring in the eye. Since direct sampling of ocular immune cells would be invasive and complex, the invention relies on measuring immune parameters (such as cytokine levels, antibody titers, or immune cell markers) in peripheral blood as a surrogate indicator of ocular immune status. This intermediary approach allows non-invasive monitoring while providing sufficient data to assess the effectiveness of immune modulation therapy.
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 significantly inhibits pro-inflammatory immune responses, reducing cytotoxicity and improving the safety and effectiveness of AAV-mediated gene transfer by maintaining transgene expression and minimizing immune reaction.
Implementation Method 1
Co-injecting peptides from the transgene product with AAV vectors in the subretinal space to modulate immune responses, specifically inhibiting anti-transgene and anti-capsid T-cell immune responses
Data Source
AI summary
Despite the eye's immune-privileged status, a secondary loss of vision in some patients treated with AAV led the inventors to question the immunogenicity of AAV vectors after a subretinal injection. The inventors thus characterized anti-transgene and anti-capsid immune responses induced in the periphery after the subretinal AAV injection. Different doses of AAV8 encoding reporter proteins fused with the HY male antigen were injected at day 0 into the subretinal space of adult immunocompetent C57BL/6 female mice. Subretinal AAV injection induced a dose-dependent proinflammatory immune response to the transgene product, correlated with local transgene expression. In order to trigger a subretinal-associated immune inhibition (SRAII) mechanism, some mice were co-injected subretinally at day 0 with AAV and HY peptides. Interestingly, this subretinal co-injection of AAV8 with peptides of the transgene product modulated the anti-transgene T-cell immune response, even at high dose of vector (5.1010 vg). This immunodulation was also confirmed in a pathophysiological murine model of retinal degeneration. The inventors also demonstrated that injection of AAV8 in the subretinal space induces proinflammatory peripheral immune responses to the transgene and the capsid that could be counteracted y co-injection with transgene peptides. Accordingly, the object of the present invention is to provide methods for preventing induction of immune responses to the transgene product and the AAV capsid after ocular gene therapy.