Yuet Wai Kan's team at the Howard Hughes Medical Institute at the University of California, San Francisco, has devised a method for delivering a genetic message to tissues and cells displaying the same molecular "address."
A problem confronting gene therapy researchers is that they cannot deliver enough beneficial genes to the precise location in the body where they are needed. Now, Yuet Wai Kan's team at the Howard Hughes Medical Institute at the University of California, San Francisco, has devised a method for delivering a genetic message to tissues and cells displaying the same molecular "address."
The shuttle that contains the genetic payload is a crippled retrovirus, a virus capable of entering human cells and inserting its genetic material into those cells to be copied. Retroviruses have been used as gene therapy vehicles before, but scientists wishing to hit a precise target with the restorative genes have been confounded by the promiscuity of the viruses; they attach to almost any cell or tissue that crosses their path. "Our work on this started in 1988," Kan said. "We went through a lot of problems. And finally we found a strategy that works."
HHMI investigator Y. W. Kan of the University of California, San Francisco is leading an effort to design gene therapy vectors that can carry beneficial genes to precise cellular targets.
The moloney murine leukemia virus (MoMLV), a retrovirus that infects both human and mouse cells, gains a foothold inside its intended host by attaching itself to receptors that are found on virtually all cells in the body. The virus' genetic instructions are tucked safely inside an envelope protein that interacts with host cell proteins.
Kan's group, using a strain of MoMLV that only infects mouse tissues, inserted a portion of the genetic message for a human hormone into the genetic code for the virus' envelope protein. With this "molecular editing," Kan's team had created a MoMLV whose envelope protein was studded with fragments of the hormone erythropoietin (EPO).
In an article in the November 25, 1994 issue of Science, Kan and his coworkers Nori Kasahara and Andrée Dozy report that the altered MoMLV bound to human cells in culture bearing the same address, the EPO receptor. The retrovirus particles were then able to enter the human cells through the EPO receptors. Human cells that did not display the EPO receptor were not invaded by the modified retrovirus. "The use of EPO in the experiments served primarily as proof that this strategy for targeting a retrovirus works," Kan said. Other hormones or proteins might be engineered into retroviruses in the same way, and used in gene therapy to target only those tissues with receptors for those hormones or proteins, he added.
There are several ways this approach might be used in the clinic. One is to target the delivery of genes to bone marrow stem cells, which are the progenitors of red and white blood cells. Delivery of therapeutic genes into these cells might help correct inherited hemoglobin disorders such as sickle cell anemia or thalassemia.
This technique might prove valuable in fashioning a tumor-specific shuttle for viruses bearing anti-cancer genes. Breast cancer tumors, for example, produce large quantities of proteins not usually found on normal cells. These cancers already may provide an attractive address for the delivery of a destructive genetic message that obliterates the tumor.