Immune-orthogonal orthologues of AAV capsids and of Cas9 circumvent the immune response to the administration of gene therapy
| Autor: | Andrew Pla, Prashant Mali, Nathan Palmer, Ning Jiang, Mansun Law, Wei Leong Chew, Fernando Alemán, Ana M. Moreno, Genghao Chen |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male viruses Genetic enhancement 1.1 Normal biological development and functioning Genetic Vectors Biomedical Engineering Medicine (miscellaneous) Bioengineering Adaptive Immunity Major histocompatibility complex Inbred C57BL Protein Engineering Article 03 medical and health sciences Mice 0302 clinical medicine Immune system Capsid Immunity Underpinning research Genetics CRISPR Cytotoxic T cell Animals Inbred BALB C Gene Editing Mice Inbred BALB C biology 5.2 Cellular and gene therapies Inflammatory and immune system Genetic Therapy Gene Therapy biochemical phenomena metabolism and nutrition Dependovirus Acquired immune system Computer Science Applications Cell biology Mice Inbred C57BL 030104 developmental biology biology.protein Antibody CRISPR-Cas Systems Development of treatments and therapeutic interventions 030217 neurology & neurosurgery Biotechnology |
| Zdroj: | Nature biomedical engineering, vol 3, iss 10 Nature biomedical engineering |
| Popis: | Protein-based therapeutics can activate the adaptive immune system, leading to the production of neutralizing antibodies and the clearance of the treated cells mediated by cytotoxic T cells. Here, we show that the sequential use of immune-orthogonal orthologues of CRISPR-associated protein 9 (Cas9) and adeno-associated viruses (AAVs) evades adaptive immune responses and enables effective gene editing using repeated dosing. We compared total sequence similarities and predicted binding strengths to class-I and class-II major histocompatibility complex (MHC) proteins for 284 DNA-targeting and 84 RNA-targeting CRISPR effectors and 167 AAV VP1-capsid-protein orthologues. We predict the absence of cross-reactive immune responses for 79% of the DNA-targeting Cas orthologues-which we validated for three Cas9 orthologues in mice-yet we anticipate broad immune cross-reactivity among the AAV serotypes. We also show that efficacious in vivo gene editing is uncompromised when using multiple dosing with orthologues of AAVs and Cas9 in mice that were previously immunized against the AAV vector and the Cas9 cargo. Multiple dosing with protein orthologues may allow for sequential regimens of protein therapeutics that circumvent pre-existing immunity or induced immunity. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|