Benitec to collaborate in AIDS therapy trial

Australian gene therapy company Benitec (ASX:BLT) is taking its novel AIDS therapy into a Phase I clinical trial in volunteers with AIDS-related lymphoma at the City of Hope Hospital in Duarte, California.

Researchers at Benitec's research laboratories in Mountain View, California, have been collaborating with City of Hope scientists to develop an RNA-interference (RNAi) gene package targeting several genes crucial to the AIDS virus' ability to infect and replicate in T-cells and macrophages.

Benitec's acting CEO, Sarah Cunningham, credited Benitec's Australian chief scientific officer, Ken Reed, with setting up the City of Hope collaboration. City of Hope lead researcher Prof Jonathan Rossi heads Benitec's scientific advisory board.

Cunningham said the collaboration had evolved into two complementary projects, both of which will use a non-pathogenic lentivirus as a vector to integrate an RNAi-gene package into the patient's own white cells, to make them resistant to HIV infection.

The first project, which is backed by a $7.5 million grant from the National Institute of Allergy and Infectious Diseases (NIAID) in Maryland, is a Phase I trial in five AIDS patients with lymphoma, who no longer respond to the drugs used in highly active anti-retroviral therapy (HAART).

The principal investigator named on the NIAID grant, Dr John Zaia, of the Beckman Research Institute, said T-cell immunotherapy was a potentially valuable therapeutic for AIDS patients who have lost T-cells, which normally mediate the immune system's response to HIV.

"Our early results are highly promising, and a T-cell approach will allow us to treat patients earlier in the disease progression of AIDS," Zaia said.

Cunningham said gene therapy could not be tested in healthy volunteers, so volunteers are recruited from patients who are already receiving T-cell therapy for AIDS-related lymphoma. The therapy involves a morbidity risk that volunteers are willing to accept because of their poor prognosis.

The technique, known as autologous ('self') grafting, involves purifying healthy T-cells from the patient's own blood, infecting them with the modified lentivirus, and re-infusing them to boost the patient's immune function. The loss of CD4 lymphocytes -- so called helper-inducer T-cells that play a key role in activating the adaptive immune response -- leads to the collapse of the immune system.

The lentivirus-delivered RNAi transgene contains a three-in-one gene-silencing package, directed at both the host cell and the virus.

One RNAi element will delete the CCR5 co-receptor from the surface of the T-cells. Before it can infect T-cells, the virus requires them to express two receptors -- CD4 and an accessory receptor, CCR5.

Many individuals of European descent are naturally resistant to HIV because they have inherited a mutation that deletes the CCR5 co-receptor from their T-cells and macrophages. The RNAi package will have the same effect.

Cunningham said the RNAi package also targets a region of the virus' genome where the tat and rev genes overlap. The genes, which are essential to the virus' ability to replicate in T-cells, should be rendered inoperable - the RNAi package has already been shown to suppress HIV replication in pre-clinical, in vitro trials.

In the T-cell therapy trial, because the re-infused, HIV-resistant T-cells are fully differentiated and relatively short-lived, the benefits will be transient, so repeated infusions will be required.

The gene-transplant will confer resistance to a common lymphoma drug that is normally toxic to T-cells, applying positive selection pressure for the healthy engineered cells while destroying the lymphoma cells.

Cunningham said the T-cell trial aims to provide quantitative data on the safety and tolerability of the therapy that will support a subsequent Phase Ib trial with bone marrow stem cells engineered for HIV resistance.

The advantage of stem-cell therapy is that when the transformed cells are reinfused back into the patient, they should migrate back into the bone marrow, where they will establish a self-renewing source of HIV-resistant T-cells and macrophages.

Cunningham said Benitec was involved in the stem-cell trial, but was not driving it. However, the company will have first option to commercialise the RNAi therapy if it proves successful.

The T-cell trial, involving five patients, is likely to begin in the first half of 2006; the stem-cell trial may run in tandem. The patients will separately started over a 12-month period, providing maximum opportunity to detect any adverse side-effects.

CombiMatrix deal

Meanwhile, Benitec has announced that it has signed a broad cross-licensing agreement with the CombiMatrix Group of Acacia Research Corp.

Under their agreement, Benitec has given CombiMatrix a non-exclusive license to its portfolio of 10 issued and 60 pending patents, to develop RNAi therapeutics for treating or preventing injuries and diseases resulting from exposure to biological, chemical, radioactive and other weapons of mass destruction.

Cunningham said the deal with CombiMatrix was attractive because the company has received large grants from the US Department of Defence in the past two years to develop bio-threat and bio-detection technologies.

In return, CombiMatrix has given a non-exclusive license to Benitec for IP related to the use of cocktails of short interfering RNA (siRNA) molecules as therapeutic agents against viral diseases. Benitec has also been given a co-exclusive sub-licence to two specific sequences targeting key genes in HIV.

The companies will collaborate in a number of other areas including the use of CombiMatrix CustomArrays to study possible off-target effects of RNAi therapeutics. They may also seek joint funding from sources such as the Department of Defence for collaborative research projects.

"We'll do it if the money is there, and is substantial enough," Cunningham said. "CombiMatrix is a really interesting company, with some very interesting approaches to commercialisation.

"They also have a drug-discovery platform that makes them a good supporting company to work with."