Somia's interests are in the development and refinement of retrovirus vectors as tools for gene therapy and gene discovery.
Our ability to transfer genes into cells is at the heart of the concept of gene therapy (Somia and Verma, 2000). The retrovirus life cycle can be subverted so that the virus will ferry therapeutic genes into cells, as opposed to its normal pathogenic cargo. Although the methods already developed are sophisticated and allow high levels of gene transfer, one of the next steps in the development of vectors is to target infections to certain cell types. This will have great utility in organs such as the brain, which is composed of a complex mix of heterogeneous cells, as well as uses in systems where the cells are dispersed through the body - such as blood. Since the present vectors infect most cell types, they also include cells such as dendritic cells - the professional antigen presenting cells of the immune system. This could generate an immune response against the vector, the therapeutic gene product or both. In this regard, targeted vectors are important in the cell types that they don't infect. Presently the Somia lab is developing and refining new envelope proteins, which would mediate binding to the target cell and facilitate entry of the vector RNA in the cell (Somia et al., 1995, and Somia et. al., 2000).
More recently Somia has been interested in developing these high efficiency gene transfer tools towards gene discovery. To this end the lab has generated cDNA libraries in retroviral vectors enabling us to transfer entire complements of coding RNA from one cell type to another. If the lab can devise a suitable screen for the target cell, this technology enables us to discover function for the cDNA encoded by the retroviral vector. In initial screens we focused on programmed cell death, or apoptosis, caused by a molecule called Fas. Somia generated a cDNA library from a cell line that is resistant to Fas mediated cell death, transferred the library into a cell line that was sensitive to Fas mediated cell death, and cloned a novel gene for a protein that confers resistance to Fas (Somia et al., 1999). The Somia lab is currently dissecting this new gene and learning about its function and how it mediates the protection to apoptosis, a process that is important in development, the immune system, and in cancer. The lab wants to expand on this technology and have a number of different screens that will allow us to clone and identify the function of genes in diverse processes such as in stem cells, in transcription and in viral infection - which connects us back to the interest in gene therapy.
Selected Publications: PubMed Search
O'Brien SA, Lee K, Fu HY, Lee Z, Le TS, Stach CS, McCann MG, Zhang AQ, Smanski MJ, Somia NV, Hu WS. (2018) Single Copy Transgene Integration in a Transcriptionally Active Site for Recombinant Protein Synthesis. Biotechnol J 13:e1800226.
Podetz-Pedersen KM, Olson ER, Somia NV, Russell SJ, McIvor RS. (2016) A Broad Range of Dose Optima Achieve High-level, Long-term Gene Expression After Hydrodynamic Delivery of Sleeping Beauty Transposons Using Hyperactive SB100x Transposase. Mol Ther Nucleic Acids 5:e279.
Multhaup MM, Podetz-Pedersen KM, Karlen AD, Olson ER, Gunther R, Somia NV, Blazar BR, Cowan MJ, McIvor RS. (2015) Role of transgene regulation in ex vivo lentiviral correction of artemis deficiency. Hum Gene Ther 26:232-43.
Boso G, Somia NV. (2015) Characterization of resistance to rhabdovirus and retrovirus infection in a human myeloid cell line. PLoS One 10:e0121455.
Boso G, Orvell C, Somia NV. (2015) The nature of the N-terminal amino acid residue of HIV-1 RNase H is critical for the stability of reverse transcriptase in viral particles. J Virol 89:1286-97.
Podetz-Pedersen KM, Vezys V, Somia NV, Russell SJ, McIvor RS. (2014) Cellular immune response against firefly luciferase after sleeping beauty-mediated gene transfer in vivo. Hum Gene Ther 25:955-65.
Hackett PB, Somia NV. (2014) Delivering the second revolution in site-specific nucleases. Elife 3:e02904.
Boso G, Tasaki T, Kwon YT, Somia NV. (2013) The N-end rule and retroviral infection: no effect on integrase. Virol J 10:233.
Zu T, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A, Stone MD, Margolis J, Peterson M, Markowski TW, Ingram MA, Nan Z, Forster C, Low WC, Schoser B, Somia NV, Clark HB, Schmechel S, Bitterman PB, Gourdon G, Swanson MS, Moseley M, Ranum LP. (2011) Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A 108:260-5.
Multhaup MM, Gurram S, Podetz-Pedersen KM, Karlen AD, Swanson DL, Somia NV, Hackett PB, Cowan MJ, McIvor RS. (2011) Characterization of the human artemis promoter by heterologous gene expression in vitro and in vivo. DNA Cell Biol 30:751-61.
Cermak T, Doyle EL, Christian M, Wang L, Zhang Y, Schmidt C, Baller JA, Somia NV, Bogdanove AJ, Voytas DF. (2011) Efficient design and assembly of custom TALEN and other TAL effector-based constructs for DNA targeting. Nucleic Acids Res 39:e82.
Multhaup M, Karlen AD, Swanson DL, Wilber A, Somia NV, Cowan MJ, McIvor RS. (2010) Cytotoxicity associated with artemis overexpression after lentiviral vector-mediated gene transfer. Hum Gene Ther 21:865-75.
Iizuka YM, Somia NV, Iizuka K. (2010) Identification of NK cell receptor ligands using a signaling reporter system. Methods Mol Biol 612:285-97.