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CURATOR

Graduate Student, California Institute of Technology

PINBOARD SUMMARY

Development of novel gene delivery viral vectors to target specific cell type or tissue of interest.

The use of gene delivery vehicles to target a tissue or a cell-type with greater specificity and efficiency is a primary need for any gene therapy or gene perturbation studies. There are a few viral vectors which have been recognized for these purposes. A promising candidate among them is the recombinant adeno-associated virus (rAAV), a non-enveloped, single stranded DNA virus with a capsid protein coat. Their non-pathogenicity and ability to infect a wide range of diving and non-diving cells (nerve cells) makes them appealing for applications in basic science research and in gene therapy trials for genetic diseases. However, there is a need to engineer these vectors for our specific needs. Currently the use of rAAV suffers from low transduction or infection efficiency and broad tropism which makes it difficult to target gene delivery to a specific region. Several groups have tried to design novel rAAVs using rational designs or directed evolution approach. The evolution method is more promising when we have little understanding of how the viral tropism works. We can easily build a large library (several thousand) of novel rAAVs and allow natural selection to help us narrow down on the variants that performed the best. Recently, one such selection method called CREATE was published in Nature Biotechnology 2016 from Dr. Viviana Gradinaru’s laboratory at Caltech. In this paper, we have developed a novel rAAV capsid called AAV-PHP.B that was evolved from a wild-type rAAV9. This variant transduces the central nervous system (CNS) with 40 fold higher efficiency compared to the parent. This was achieved using a “cre recombination-based AAV targeted evolution method” (CREATE) where the variants were selectively recovered from the nerve cell astrocytes of genetically modified mice. In 2017, few more variants were reported in Nature Neuroscience from the same laboratory using the same method. One variant is specific for sensory neurons (AAV-PHP.S) and another has enhanced broad CNS transduction with higher specificity to neurons (AAV-PHP.eB). My work focuses on finding novel variants targeting different nerve cell types that were not studied earlier such as microglia and interneurons. These nerve cell types are hard to target and will be very useful tool for the scientific community. In addition, my work focuses on finding novel variants targeting different organs such as heart, lung, small intestine and muscle which are widely studied for genetic diseases.

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