Investigators of a new gene therapy approach to HIV
treatment claim that their findings represent “significant progress towards a
`functional cure`”, after results from Sangamo Biosciences phase 1 study of SB-728-T showed no evidence of viral rebound after
treatment interruption in one of six patients treated with the drug.
The findings were presented
on September 17 at the 51st ICAAC in Chicago.
SB-728-T is a one-off
procedure rather than an ongoing medication. It uses a zinc finger nuclease to
`edit` the genetic material of CD4+ T-cells harvested from each individual in
the study. The zinc finger nuclease is designed to bind to a specific position
in the DNA sequence of the target gene, causing a break that is repaired by
normal DNA repair mechanisms.
However, this cleavage edits
out a small portion of the DNA sequence, and this is enough to cripple the
functioning of the gene.
This particular genetic
modification process is designed to reduce the expression of the CCR5 receptor
on the surface of these cells, which would otherwise be used by HIV to gain
entry to these cells. This approach follows the observation that individuals
with a natural mutation that limits expression of CCR5 are resistant to HIV
After the genetic
modification takes place the modified cells are stimulated to copy themselves
in vast numbers in the laboratory, and then reintroduced into the
The aim of the treatment
approach is that the CCR5-deficient CD4 cells will begin to replace the existing
population of CD4 cells. When this is accomplished, the target cells for HIV
infection will be removed, and so viral replication will be impossible even
when antiretroviral therapy is halted.
The findings presented in Chicago come from two
cohorts of patients who took part in the phase 1 dose-ranging and safety study
of SB-728-T. This study was not designed to assess efficacy, so any results are
suggestive, and the soundest conclusions that can be drawn from the study are
that the process of introducing genetically engineered CD4 cells worked to some
extent in all patients, and did not cause any major adverse events.
The first cohort of nine
patients, who had CD4 cell counts between 200 and 500 cells/mm3
after several years of fully suppressive antiretroviral treatment, and were
therefore judged to be immunological non-responders, were divided into three
successive dosing groups, who received infusions of 10, 20 and 30 billion
genetically modified cells. The only adverse events were mild, related to the
infusion, and cleared up quickly.
The researchers observed that
the CCR5-modified CD4 cells were successfully transferred, and then multiplied
and persisted for a median of 337 days. The median CD4 cell increase in those
who had completed more than six months of observation was 163 cells/mm3.
After 28 days genetically
modified cells comprised between 0.2 and 2.8% of cells in peripheral blood
samples, but the proportion of CD4 cells that had been modified reached 6% in
the gut mucosa after 90 days. The gut mucosa is an important reservoir of
HIV-infected cells in people on antiretroviral treatment.
The proportion of
gene-modified cells was 5.5 times higher than predicted and at least 1 log higher
than observed in any previous studies of CD4+ T-cell transfer. This suggests
that expansion of the modified CD4 cells is occurring after infusion, say the
All patients treated
experienced an increase in CD4 cell count, and a normalisation in CD4+: CD8+
ratio occurred in the majority of patients, indicating a return towards normal immunologic
In the second cohort of six
patients, each had fully suppressed viral load on antiretroviral treatment and
a CD4 count above 450 cells/mm3 (median 974). They underwent a
12-week treatment interruption four weeks after receiving an infusion of 10
billion SB-728-T-modified CD4+ cells.
After 12 weeks investigators
noted a statistically significant relationship between the proportion of
circulating CD4 cells with genetically modified CCR5 genes and both viral load
at the end of the treatment interruption (p=0.001) and the total amount of
measurable viral replication during the treatment interruption (expressed as
area under the curve) (p=0.037).
In three of six patients
viral load decreased by at least 0.8 log after an initial rebound during the
treatment interruption. In one case viral load became undetectable, and
remained so for the rest of the 12-week treatment interruption. This patient
had the highest levels of genetically modified CD4 cells.
However, this patient
underscores the challenge involved in attempting to use genetically modified
cells. He entered the study with an advantage: he had inherited one copy of the
delta 32 CCR5 mutation that provides protection against HIV infection. Each of
us inherits two copies of the gene that codes for the CCR5 receptor, one from
Individuals with two copies
are described as homozygous, and are fairly resistant to infection. Individuals
with one copy of the gene are described as heterozygous, and have partial
protection, and also tend to have slower disease progression if they do become
infected. Around 10% of people of northern European descent are heterozygous
for this mutation, but the mutant gene is far less common in other ethnic
Sangamo said that one of the
avenues it will explore in the development of SB-728-T is a larger study that
will recruit people who are naturally heterozygous for the CCR5 delta-32
mutation. Other research will look at how to improve the introduction and
persistence of genetically modified cells.
"The next step is to increase the frequency of the modified cells in HIV-infected patients with the ultimate hope that if we do, we will achieve a `functional cure` and eliminate the need for continued HAART," said Dr Carl June, Director of Translational Research at the Abramson Family Cancer Research Institute at the University of Pennsylvania School of Medicine.
A functional cure for HIV would consist of a treatment intervention that could stop or control HIV replication without the need for lifelong treatment, even though HIV was not eliminated from the body.