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发表于 2001-11-24 03:39
Ribozymes: An Emerging Therapy for Chronic Viral Hepatitis?
By Brian Boyle, MD
Ribozymes are an emerging technology that in preliminary studies appear capable of disrupting the viral lifecycle of hepatitis B virus (HBV) and hepatitis C virus (HCV) by cleaving RNA transcripts and pregenomic RNA. Several studies evaluating the use of ribozymes in the treatment of chronic viral hepatitis B and C were presented at the 52nd AASLD meeting in Dallas, Texas.
One study explored the use of ribozymes targeting the highly conserved regions of HBV RNA (HepBzyme) in the treatment of chronic HBV infection. In a prior study, one of these ribozymes was shown in a HBV transgenic mouse to significantly reduce viremia compared to saline-treated animals and appeared to be as effective as treatment with Epivir-HBV (lamivudine).
To assess the potential of combination therapy, HepG2 cells transfected with a replication competent HBV cDNA, were treated with HepBzyme, Infergen (interferon), and Epivir-HBV either alone or in combination. Initial results indicate that combination treatment with either HepBzyme plus Infergen or HepBzyme plus lamivudine resulted in additive down regulation of HBsAg expression (P<0.001).
The authors concluded, "These preliminary results suggest the potential for combination therapy of HepBzyme plus currently available therapies for the treatment of chronic Hepatitis B."
Another study presented evaluated the use of nuclease-resistant ribozymes targeting the minus strand complement of the highly conserved 5' untranslated region (UTR) of HCV RNA in the treatment of chronic HCV infection. In prior studies, the investigators have found that an HCV-poliovirus (HCV-PV) chimera, which requires the 5' HCV UTR for translation and replication could be inhibited in a dose-dependent manner, up to 90%, by the use of ribozymes targeting two sites in the minus strand.
In a study reported at the 52nd AASLD, these researchers investigated the potential advantage of targeting the plus and minus strands in combination, using HEPTAZYME™ (the ribozyme targeting site 195 of the plus strand) together with a ribozyme targeting site 152 in the minus strand. They found that the level of inhibition in cells co-treated with both ribozymes was not improved compared to cells treated with HEPTAZYME™ alone at the same total dose; however, they theorized that multi-site combination treatment may negate any possibility of the generation of ribozyme-resistant virus.
The authors concluded, "These studies indicate that synthetic stabilized ribozymes directed against the HCV minus strand RNA demonstrate potent antiviral activity and have the potential to be effective therapeutic agents for the treatment of chronic Hepatitis C infection, alone or possibly in combination with HEPTAZYME™. "
In another study, the safety of 28 days of HEPTAZYME™ treatment was evaluated in patients with chronic HCV infection. Twenty-four patients were enrolled in this multiple-dose, open-label, study. The researchers found that all HEPTAZYME™ doses were well tolerated. Further, there were no serious adverse events and no patients discontinued due to an adverse event.
The most frequently reported events were an unexpected benefit (either "increased energy" (21%) or "thinking was clearer" (4%)), abdominal pain (17%) and asthenia (17%). All other events assessed as possibly or probably related to Heptazyme occurred in 2 patients (8%). The majority of adverse events were assessed as mild and transient in nature. There were no clinically relevant changes in serum chemistries or blood counts, and HEPTAZYME™ did not appear to have any appreciable effect on electrocardiographic intervals.
Based upon these data, the authors concluded that HEPTAZYME™ was relatively well-tolerated over the dose range evaluated. A Phase II study in chronic Hepatitis C patients is being initiated to evaluate the use of HEPTAZYME™ alone or in combination with interferon.
11/16/01
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