The Effect of Rapamycin and Ibrutinib on Antibody Responses to Adeno-Associated Virus Vector-Mediated Gene Transfer

Xiang, Zhiquan; Kuranda, Klaudia; Quinn, William J.; Chekaoui, Arezki; Ambrose, Robert; Hasanpourghadi, Mohadeseh; Novikov, Mikhail; Newman, Dakota; Cole, Christina; Zhou, Xiangyang; Mingozzi, Federico; Ertl, Hildegund C. J.

doi:10.1089/hum.2021.258

Cited by 20 publications

(13 citation statements)

References 60 publications

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“…124 Rapamycin (Sirolimus), a macrolide immunosuppressant, alone or in combination with ibrutinib, inhibits immune responses stimulated by either the capsid or the transgene. 109,125,126 Intravenous co-administration of AAV vectors with rapamycin prevented the induction of anti-AAV antibodies. [127][128][129] The protective effects of rapamycin have also been confirmed in clinical trials for Pompe's disease.…”

Section: Safety Considerations and Methods To Reduce Gene Therapy Tox...mentioning

confidence: 99%

“…Corticosteroids reduce the levels of pro‐inflammatory cytokines and chemokines produced by T‐ and B‐cells 124 . Rapamycin (Sirolimus), a macrolide immunosuppressant, alone or in combination with ibrutinib, inhibits immune responses stimulated by either the capsid or the transgene 109,125,126 . Intravenous co‐administration of AAV vectors with rapamycin prevented the induction of anti‐AAV antibodies 127–129 .…”

Section: General Aspects Of Gene Therapies For Cmt Neuropathiesmentioning

confidence: 99%

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Charcot–Marie–Toothneuropathies: Current gene therapy advances and the route toward translation

Stavrou

Kagiava

Sargiannidou

et al. 2023

J Peripheral Nervous Sys

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Charcot–Marie–Tooth (CMT) neuropathies are a group of genetically and phenotypically heterogeneous disorders that predominantly affect the peripheral nervous system. Unraveling the genetic and molecular mechanisms, as well as the cellular effects of CMT mutations, has facilitated the development of promising gene therapy approaches. Proposed gene therapy treatments for CMTs include virally or non‐virally mediated gene replacement, addition, silencing, modification, and editing of genetic material. For most CMT neuropathies, gene‐ and disease‐ and even mutation‐specific therapy approaches targeting the neuronal axon or myelinating Schwann cells may be needed, due to the diversity of underlying cellular and molecular‐genetic mechanisms. The efficiency of gene therapies to improve the disease phenotype has been tested mostly in vitro and in vivo rodent models that reproduce different molecular and pathological aspects of CMT neuropathies. In the next stage, bigger animal models, in particular non‐human primates, provide important insights into the translatability of the proposed administration and dosing, demonstrating scale‐up potential and safety. The path toward clinical trials is faced with further challenges but is becoming increasingly feasible owing to the progress and knowledge gained from clinical applications of gene therapies for other neurological disorders, as well as the emergence of sensitive outcome measures and biomarkers in patients with CMT neuropathies.

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Section: Safety Considerations and Methods To Reduce Gene Therapy Tox...mentioning

confidence: 99%

Section: General Aspects Of Gene Therapies For Cmt Neuropathiesmentioning

confidence: 99%

Charcot–Marie–Toothneuropathies: Current gene therapy advances and the route toward translation

Stavrou

Kagiava

Sargiannidou

et al. 2023

J Peripheral Nervous Sys

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“…Belimumab, an anti-B-cell-activating factor (BAFF), is another B-cell-depleting antibody that has shown promising results in controlling autoimmune diseases [ 171 , 172 ]. Furthermore, utilizing ibrutinib, a B-cell inhibitor, reduced primary antibody responses against AAV in a murine model [ 173 ]. However, systemic IS may increase the risk of infection and is not effective in complete remission of high titer NAbs [ 107 , 169 ].…”

Section: Strategies To Mitigate Immune Responses In Aav Gene Therapymentioning

confidence: 99%

Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer

et al. 2023

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Recombinant adeno-associated viruses (AAVs) have emerged as promising gene delivery vehicles resulting in three US Food and Drug Administration (FDA) and one European Medicines Agency (EMA)-approved AAV-based gene therapies. Despite being a leading platform for therapeutic gene transfer in several clinical trials, host immune responses against the AAV vector and transgene have hampered their widespread application. Multiple factors, including vector design, dose, and route of administration, contribute to the overall immunogenicity of AAVs. The immune responses against the AAV capsid and transgene involve an initial innate sensing. The innate immune response subsequently triggers an adaptive immune response to elicit a robust and specific response against the AAV vector. AAV gene therapy clinical trials and preclinical studies provide important information about the immune-mediated toxicities associated with AAV, yet studies suggest preclinical models fail to precisely predict the outcome of gene delivery in humans. This review discusses the contribution of the innate and adaptive immune response against AAVs, highlighting the challenges and potential strategies to mitigate these responses, thereby enhancing the therapeutic potential of AAV gene therapy.

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“…Thus, immunosuppressants that inhibit T cell responses may represent attractive approaches for use with CRISPR gene editing, at least transiently. Different combinations of immunosuppressants can also be considered ( Xiang et al, 2022 ). Recently, biodegradable nanoparticles encapsulating rapamycin (ImmTOR) were shown to mitigate the immunogenicity of biologics both in preclinical ( Kishimoto, 2020 ; Ilyinskii et al, 2021 ) and clinical ( Sands et al, 2022 ) trials, while free rapamycin was only partially effective ( Shi et al, 2021 ).…”

Section: Considerations To Mitigate Immunogenicity For Clinical Trans...mentioning

confidence: 99%

Immunogenicity of CRISPR therapeutics—Critical considerations for clinical translation

Ewaisha

Anderson

2023

Front. Bioeng. Biotechnol.

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CRISPR offers new hope for many patients and promises to transform the way we think of future therapies. Ensuring safety of CRISPR therapeutics is a top priority for clinical translation and specific recommendations have been recently released by the FDA. Rapid progress in the preclinical and clinical development of CRISPR therapeutics leverages years of experience with gene therapy successes and failures. Adverse events due to immunogenicity have been a major setback that has impacted the field of gene therapy. As several in vivo CRISPR clinical trials make progress, the challenge of immunogenicity remains a significant roadblock to the clinical availability and utility of CRISPR therapeutics. In this review, we examine what is currently known about the immunogenicity of CRISPR therapeutics and discuss several considerations to mitigate immunogenicity for the design of safe and clinically translatable CRISPR therapeutics.

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The Effect of Rapamycin and Ibrutinib on Antibody Responses to Adeno-Associated Virus Vector-Mediated Gene Transfer

Cited by 20 publications

References 60 publications

Charcot–Marie–Toothneuropathies: Current gene therapy advances and the route toward translation

Charcot–Marie–Toothneuropathies: Current gene therapy advances and the route toward translation

Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer

Immunogenicity of CRISPR therapeutics—Critical considerations for clinical translation

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