Science

Adenovirus expressing modified apoptotic molecule thwarts HCV infection in mice

Last Updated: 2003-05-01 11:29:00 -0400 (Reuters Health)

By Megan Rauscher

NEW YORK (Reuters Health) - In mice with chimeric human livers and hepatitis C virus infection (HCV), an adenovirus vector expressing a genetically engineered apoptosis-inducing molecule called BID targets and kills HCV-infected cells, effectively halting progression of disease.

Dr. Christopher D. Richardson, of the Ontario Cancer Institute in Toronto, and colleagues describe their gene therapy strategy in the May issue of Nature Biotechnology, published online April 21st.

"Originally my postdoctoral fellow, Dr. Eric Hsu, and I were looking for an approach to target the protease of HCV using gene therapy," Dr. Richardson told Reuters Health. "We felt that this viral molecule could be the 'Achilles heel' of the virus since its function is essential for viral replication."

They engineered a proteolytic cleavage site into a number of apoptotic precursor molecules including procaspase 3 and BH3-interacting death domain death agonist (BID), "both of which are normally activated by host cellular proteases in the cascade leading to programmed cell death," Dr. Richardson said.

BID, modified to contain the NS5A/NS5B cleavage site, proved "most efficacious," Dr. Richardson said, effectively activating apoptosis when HCV NS3/NS4A protease resides in the cell.

In culture, modified BID rapidly killed cells containing HCV or its protease, but was nontoxic to healthy neighboring cells. "In a sense, the modified BID was a 'smart bomb' which targeted the infected cell for destruction," Dr. Richardson said.

Modified BID also prevented infection in a Sindbis virus model of HCV. And, in HCV-infected SCID mice transplanted with human liver xenografts, intrajugular injection of the modified BID therapeutic adenovirus vector targeted the liver efficiently, activated apoptosis, and cleared viral infection.

"Although the initial HCV titers varied mouse to mouse, depending on how well the transplanted human liver was infected with the pathogenic virus, adenovirus containing the modified BID gene cleared HCV completely from the liver, and at least decreased the serum levels of the mouse by 2-3 logs," Dr. Richardson told Reuters Health.

Further experiments are underway to see how long the treatment effects last and whether HCV levels rebound. In the current experiments, there did not appear to be viral rebound up to 28 days following treatment.

"I believe that these experiments attest to the power of gene therapy in treating human disease," Dr. Richardson said.

A targeted therapeutic approach using modified BID "may be useful as a prophylactic against accidental virus exposure, in the early stages of hepatitis, during limited infection of the liver, or for ex vivo therapy of hepatocytes," the investigators write in the journal. "It may also reduce virus loads in chronically infected patients, and in conjunction with interferon and ribavirin therapy, might eradicate HCV from the infected host."

Nat Biotechnol 2003.

DOI:10.1038/nbt818 www.nature.com/naturebiotechnology