Jolla, CA (1/28/99)- Some of the most valuable medical treatments, like
the vaccines for small pox and rabies, are based on weakened version of pathogenic
organisms. Researchers from the Salk Institute now report that one of the
deadliest pathogens known to man, HIV, may, with careful modification, prove
to be an optimal vector for gene therapy.
Can HIV Redeem
Itself as a Vector for Gene Therapy?
Hiroyuki Miyoshi and colleagues created a modified version of HIV (human
immunodeficiency virus, the cause of AIDS) and then spliced in genes from
human hematopoietic stem cells (HSCs). When they injected the cocktail into
mice, they saw signs of HSC expression in the animals' bloodstream and bone
marrow. The transferred cells survived and differentiated in the mice for
at least five months.
Hematopoietic stem cells residing in bone marrow are the progenitors of all
the different types of components of the bloodstream. Researchers have long
sought a method to introduce healthy stem cells into the bloodstream of patients
with inherited blood disorders such as sickle cell anemia, as well as certain
cancers including leukemia. The hope is that the fresh stem cells would transfer
genes to the faulty stem cells of the patients, allowing regeneration of healthy
"This will open the door to many applications, including thalassemias, sickle-cell
anemias, hemophilias and certain cancers. Stem cells are capable of becoming
any type of cell in the blood, from immune system cells to oxygen-ferrying
red blood cells," said Inder Verma, a professor at the Salk institute.
Verma was part of the team that developed the attenuated version of HIV used
as the vector. Retroviruses (like HIV) enter their host's cells and copy their
own genetic material into the cell's nucleus. Thus, the same thing that makes
them so destructive as pathogens, also makes them potentially very good vectors,
or delivery vehicles, for gene therapy.
Scientists have already had some success with retroviral vectors. While
researchers have been able to deliver genes via this method to mouse hematopoetic
stem cells, the Salk team is the first to report the delivery of stem cells
from humans into mice.
"This is probably because the human stem cells are at rest; that is, they're
not actively dividing," according to Hiroyuki Miyoshi. "There is often a problem
in scaling up gene therapy procedures from mice to large animals."
"The HIV-based vector is unique in its ability to penetrate the nucleus of
non-dividing cells," said Verma, adding that this ability makes the vector
will allow investigators to "add genes to virtually any cell type in the body."
Genes have been successfully inserted into stem cell precursors, but only
in the presence of cytokines, hormone-like substances, that can interfere
with the developmental program of the stem cells. In this case, cytokines
were not used to stimulate cell production. The current study represents a
"major advance" in the manipulating the genetic content of blood
cells, said Verma.
Before human trials can begin, safety concerns about using any kind of HIV
for therapy will have to be addressed. In this study, the researchers knocked
out the the pathogenic genes of the virus. The viral vectors are designed
to deliver their cargo and then deactivate.
"We expect that these vectors will be safe. In fact, we have recently developed
even more seriously crippled versions of the vector. It's possible that clinical
trials may begin for some applications within a year," Varma added.
The study appears in the January 29,1999 issue of Science.