CURRENT CLINICAL
INTERESTS
General hematology/oncology, gene therapy, osteogenesis imperfecta,
stem cell transplantation, regenerative medicine
CURRENT RESEARCH INTERESTS
Stem cells, viral vectors, gene therapy, genetic recombination
RESEARCH DESCRIPTION
Principal Investigator: Dr. Russell is a Professor in the
Department of Medicine (Division of Hematology), Adjunct in the
Department of Biochemistry, and an Investigator of the Markey
Molecular Medicine Center at the University of Washington in Seattle.
Dr. Russell’s research program focuses on the development of
improved methods for manipulating mammalian genomes in living cells.
The technologies being developed have applications in stem cell
biology, gene therapy, and somatic cell genetics.
Adeno-Associated Virus (AAV) vectors are under investigation,
including research on
transduction mechanisms, chromosomal integration, and the development
of gene targeting vectors that introduce precise sequence changes at
homologous chromosomal loci.
One goal of these studies is to carry out therapeutic gene
targeting in human cells to treat genetic diseases.
This approach is being applied towards the treatment of
osteogenisis imperfecta (brittle bone disease) by targeting mutant
collagen genes in bone-forming mesenchymal stem cells. AAV-mediated
gene targeting is also being used to engineer human pluripotent stem
cells with improved engraftment potential.
Vectors based on Foamy Viruses (a type of retrovirus) are
another research interest. These
vectors offer many advantages, such as a lack of pathogenicity,
efficient transduction of stem cells, wide host range, large packaging
capacity, and a reduced likelihood of activating neighboring oncogens
after integration. Ongoing
projects include the development of improved vector production
methods, analyzing the effects of vector integration, and testing in
pre-clinical animal disease models.
Recent work has shown that Foamy Virus vectors can cure a
canine form of leukocyte adhesion deficiency (LAD) by stem cell gene
therapy and a human clinical trial for LAD is currently planned.
A particular focus of the laboratory is the genetic
manipulation of stem cells. Experiments
are underway with hematopoietic stem cells, mesenchymal stem cells,
hepatic stem cells, and pluripotent stem cells.
We are designing new vectors and transducing a variety of cell
types to generate induced plutipotent stem cells. By efficiently
introducing genetic changes into stem cells, basic aspects of stem
cell biology are being addressed, including studies on developmental
potential, transplantation, recombination, and nuclear reprogramming.
rincipal Investigator: Dr. Russell is a Professor in
the Department of Medicine (Division of Hematology), Adjunct in the
Department of Biochemistry, and an Investigator of the Markey
Molecular Medicine Center at the University of Washington in Seattle.
Adeno-associated virus (AAV) vectors are under investigation, including research on transduction mechanisms, chromosomal integration, and the development of gene targeting vectors that introduce precise sequence changes at homologous chromosomal loci. One goal of these studies is to carry out therapeutic gene targeting in human cells to treat genetic diseases. This approach is being applied towards the treatment of osteogenesis imperfecta (brittle bone disease) by targeting mutant collagen genes in bone-forming mesenchymal stem cells.
Vectors based on foamy viruses (an alternative retroviral vector system) are also a research interest. These vectors offer many advantages, such as improved transduction of stem cells, wide host range, and large packaging capacity, making them a promising vector for gene therapy. Ongoing projects include the development of improved vector production methods, mapping and analysis of vector integration sites, and the testing of vectors in pre-clinical animal disease models. Recent work has shown that
foamy virus vectors can efficiently transduce hematopoietic stem cells from mice, dogs, and humans.
A particular focus of the laboratory is the genetic manipulation of stem cells. Experiments are underway with hematopoietic stem cells, mesenchymal stem cells, hepatic stem cells, and embryonic stem cells. The genetic manipulation of cells used for cloning by nuclear transfer is a related research interest. By efficiently introducing genetic changes into stem cells, basic aspects of stem cell biology are being addressed, including studies on developmental potential, transplantation, cell fusion, and nuclear reprogramming.
SELECTED PUBLICATIONS
Russell DW and Hirata RK: Human gene targeting by viral vectors.
Nat. Genet. 18:325-330, 1998.
Hirata RK, Chamberlain JC, Dong R, and Russell
DW. Targeted transgene insertion into human chromosomes by adeno-associated virus vectors.
Nat. Biotechnol.
20:735-738, 2002.
Vassilopoulos G, Wang P, and Russell DW.
Transplanted bone marrow regenerates liver by cell fusion. Nature 422:901-904, 2003.
Chamberlain JR, Schwarze U, Wang P, Hirata RK, Hankenson KD, Pace JM, Underwood RA, Song KM, Sussman M, Byers PH, and
Russell DW. Gene targeting in stem cells from individuals with osteogenesis imperfecta.
Science 303:1198-1201, 2004.
Miller DG, Petek L, and Russell DW.
Adeno-associated virus vectors integrate at chromosome breakage sites.
Nat. Genet. 36:767-773, 2004.
Miller DG, Wang P, Petek LM, Hirata RK, Sands MS, and
Russell DW. Gene targeting in vivo by adeno-associated virus vectors.
Nat. Biotechnol. 24:1022-1026, 2006.
Bauer TR, Allen JM,
Hai M, Tuschong LM, Khan IF, Olson EM, Adler RL, Burkholder TH, Gu Y, Russell
DW, and Hickstein DD. Successful treatment of canine
leukocyte adhesion deficiency by foamy virus vectors. Nat. Med.
14:93-7, 2008.
Khan IF, Hirata RK, Wang P, Li Y, Kho J, Nelson
A, Huo Y, Zavajlevski M, Ware C, and Russell DW. Engineering
of human pluripotent stem cells by AAV-mediated gene targeting. Mol.
Ther. 18:1192-1199, 2010.
Deyle, DR, Li, Y, Olson, EM, and Russell,
DW. Non-integrating foamy virus vectors. J. Virol.
84:9341-9349, 2010.
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