UCLA researchers in the Department of Neurology have produced novel AAV serotypes for a wide range of tissue and cell specific gene delivery.
BACKGROUND: Gene therapies are the forefront of therapeutic advancements for debilitating diseases. However, delivery and insertion of the therapeutic transgene are major hurdles that must be solved to effectively implement this technology. Adeno-associated viruses (AAVs) have been widely adopted as a tool for gene therapy due to their non-pathogenicity and ability to cross the blood brain barrier. Genetic therapy is a promising approach for many severe diseases including muscular dystrophy. However, clinical efficacy is variable due to limited viral transduction efficiency for particular cell populations, such as muscle stem cells (MuSCs), with conventional AAV tools. Therefore, there is a strong need for new AAV serotypes with the capacity to target MuSCs and other cells/tissues of the body for more efficient gene therapies.
INNOVATION: Researchers at UCLA sought to identify novel AAV serotypes–distinct types of viral capsids used to package with an AAV vector–that could offer greater cell-type specificity. Serotype selection controls viral infection preference, which is mediated by interactions between variable regions of the capsid proteins and cell surface receptors. Researchers found that the variable regions of the AAV capsid exhibit significant sequence variation and are responsible for the diversity of receptor binding domains. Using this knowledge, researchers were able to generate new AAV serotypes with the ability to specifically target various tissues including muscle stem cells (MuSCs), brain, bone marrow, and more. Additionally, they are screening AAV variants that target both MuSCs and skeletal muscle fibers to improve delivery of CRISPR editing components for degenerative muscular diseases. Furthermore, they observed improved transduction of MuSCs and other tissue stem cells using their novel serotypes. By directing CRISPR-based gene editing to stem cells, the therapy will offer long-term stability given that the corrected stem cells can propagate and replenish the tissue. Thus, the novel AAV serotypes provide precise tissue and cell specific targeting, reducing the risk of off-target toxicity and improving the safety and efficacy of gene therapies.
POTENTIAL APPLICATIONS:
- AAV serotypes for delivery of gene editing platforms to multiple different cell and tissue types
ADVANTAGES:
- Unique tissue and cell specific tropism for decreased off-target effects
- Improved viral transduction to stem cells compared to previous AAV serotypes
- Identification of one AAV variant that targets both MuSCs and skeletal muscle fibers may optimize delivery of gene editing components
DEVELOPMENT-TO-DATE: Library screen of AAV variants was produced and used to detect AAV tissue specific serotypes after injection in mice.
KEYWORDS: AAV, gene therapy, gene editing, musculoskeletal disorders, genetic disorders, gene delivery, cell-specificity, tropism, stem cells