Research Profile:

One of the major problems in developing therapeutic approaches for inherited genetic diseases is the lack of efficient vectors for targeted gene delivery in vivo. In recent years, viral vectors have been extensively studied for delivery of therapeutic genes to correct many inherited diseases. However, clinical studies have shown that poor understanding of viral vector interactions with host cells in vivo impedes the successful application of gene therapy approaches in clinical practice. Therefore, safety and efficacy are currently major areas of concern.

One of the main projects in our laboratory involves the analysis of molecular mechanisms responsible for the initiation of immediate innate immune and inflammatory responses toward systemically applied adenovirus vectors.

The second area of our research involves an analysis of initial adenovirus-host interactions and the modification of virus tropism to allow for efficient and targeted gene delivery into cell types which are naturally resistant to adenovirus infection (specifically human hematopoietic stem cells, human dendritic cells, and tumor cells in vivo). We found that, following systemic application, adenovirus capsid proteins interact with blood factors including coagulation factors IX and FX, and complement component C4 binding protein, which target virus to hepatic cells in vivo. We are now utilizing mass spectrometry, surface plasmon resonance, and cryo-electron microscopy to analyze the structural basis for adenovirus-blood factor interactions.

The third area of our research activity deals with the analysis of DNA double strand break repair and homologous recombination in primary human hematopoietic stem cells. The project is a result of our collaboration with Sangamo Corp., who provided the unique engineered DNA-sequence-specific Zinc-finger nuclease proteins, capable of recognizing and introducing DSBs within mutated genes in the human genome. By utilizing helper-dependent, capsid-modified adenovirus vectors targeted to human hematopoietic cells, the basic biology of DSB-repair in these cells can be analyzed. Once sufficient understanding of these processes is obtained, viral vectors can be designed for therapeutic gene correction in human hematopoietic stem cells.

Selected publications:

Shayakhmetov D.M., Papayannopoulou T, Stamatoyannopoulos G., and Lieber A. (2000) Efficient gene transfer into human CD34+ cells by a retargeted adenovirus vector. Journal of Virology, v. 74, No 6: 2567-2583.

Shayakhmetov D.M., Carlson C.A., Stecher H., Li Q., Stamatoyannopoulos G., and Lieber A. (2002) A high-capacity, capsid-modified hybrid adeno-AAV vector for stable transduction of human hematopoietic cells. Journal of Virology, v. 76, No. 3: 1135-1143.

Shayakhmetov D.M., Li, Z.-Y., Ni S., Lieber A. (2002) Targeting of adenovirus vectors to tumor cells does not enable efficient transduction of breast cancer metastases.Cancer Research, v. 62: 1063-1068.

Gaggar A, Shayakhmetov D.M., Lieber A. (2003) CD46 is a cellular receptor for group B adenoviruses. Nature Medicine, v. 9(11):1408-12.

Shayakhmetov D.M., Z.-Y. Li, S. Ni, and A. Lieber (2004) Analysis of liver sequestration, transduction of hepatic cells, and innate toxicity after injection of fiber-modified adenovirus vectors. Journal of Virology, V. 78(10): 5368-81.

Shayakhmetov D.M., Li Z.-Y., Gaggar A, Gharwan H, Ternovoi V, Sandig V, and Lieber A. (2004) Genome size determines efficiencies of post-attachment steps and gene transfer of capsid-modified adenovirus vectors in a cell type specific manner. Journal of Virology, V. 78(18):10009-22.

Shayakhmetov D.M., Gaggar A., Ni S., Li Z.-Y., Lieber A. (2005) Adenovirus binding to blood factors results in liver cell infection and hepatotoxicity. Journal of Virology, V. 79(12):7478-7491.

Shayakhmetov D.M., Z.-Y. Li, S. Ni, and A. Lieber (2005) Interference with IL-1 signaling pathway improves the toxicity profile of systemically applied adenovirus vectors. Journal of Immunology, V. 175(11): 7310-7319.

Baker A.H., Waddington S.N, Di Paolo N.C., and Shayakhmetov D.M. (2007) The Influence of Blood on In Vivo Adenovirus Bio-distribution and Transduction. Molecular Therapy, 15(8):1410-6.

Di Paolo N.C., Kalyuzhniy O., and Shayakhmetov D.M. (2007) The fiber shaft-chimeric adenovirus vectors lacking the KKTK-motif efficiently infect liver cells in vivo. Journal of Virology, 81(22):12249-59.

Junt T, Moseman EA, Boes M, Fink K, Di Paolo N, Shayakhmetov DM, Mampel T, Whelan SP, von Andrian UH. (2007) Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells. Nature, 450(7166):110-114.

Kalyuzhniy O, Di Paolo NC, Silvestry M, Hofherr SE, Barry MA, Stewart PL, Shayakhmetov DM (2008) Adenovirus serotype 5 hexon is critical for virus infection of hepatocytes in vivo. Proc. Natl. Acad. Sci, USA, in press.

Investigator:  Dr. Shayakhmetov is a Research Assistant Professor of Medicine (Medical Genetics).

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Last updated: April 19, 2004