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)
Lech P, Somia NV (2008) Retrovirus vectors. Contrib Nephrol. 2008;159:30-46
Agarwal, S, Nikolai, B, Yamaguchi T, Lech, P and Somia, NV (2006) Construction and use of retroviral vectors encoding the toxic gene Barnase. Mol Ther 14(4):555-63
Agarwal S, Harada J, Schreifels J, Lech P, Nikolai B, Yamaguchi T, Chanda SK and Somia NV, (2006). Isolation, characterization and genetic complementation of a cellular mutant resistant to retroviral infection. PNAS 103(43):15933-8
Score PR, Belur LR, Frandsen JL, Guerts JL, Yamaguchi T, Somia NV, Hackett PB, Largaespada DA, McIvor RS. (2006) Sleeping Beauty-Mediated Transposition and Long-Term Expresssion in Vivo: Use of the LoxP/Cre Recmbinase System to Distinguish Transposition-Specific Expression Mol.ther. 13(3):617-24.
Somia N. (2004) Gene delivery to cells in culture using retroviruses. Methods Mol Biol. 246:491-8.
Somia N. (2004) Gene transfer by retroviral vectors: an overview. Methods Mol Biol. 246:463-90.
Somia N.V. and Verma I.M., (2000) Gene therapy: Trials and tribulations. Nature Reviews Genetics 1 (2) 91-99
Somia N.V, Miyoshi H, Schmitt M.J, Verma I.M. ., (2000) Retroviral vector targeting to human immunodeficiency virus type 1-infected cells by receptor pseudotyping. J.Virol. 74 (9) 4420-4424.