Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
1998-11-25
2003-01-07
Guzo, David (Department: 1636)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C514S04400A, C536S023100, C536S024500, C435S455000, C435S458000, C435S325000, C435S370000
Reexamination Certificate
active
06503533
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention was made utilizing funds from contracts NO1-AI-72623 and NO1-AI-45179 between the National Institute for Allergy and Infectious Diseases and Georgetown University.
The present invention relates to compositions for the treatment of Hepatitis B virus (HBV) infection. In particular, the invention relates to antisense oligonucleotides and their use to inhibit HBV replication.
Hepatitis B virus, a member of the Hepadnaviridae family, is a blood-borne, hepatotropic pathogen which infects large numbers of people annually. In 1987 there were approximately 25,000 newly reported cases of disease attributable to HBV infection in the US. It is estimated that 60-70% of HBV infections lead to subclinical (asymptomatic) disease, and it is therefore probable that the actual number of new HBV infections each year is much higher. Of those infected with HBV, 90% make a full recovery, but 2-10% of infected patients develop chronic, persistent HBV infection. It is estimated that 1 million people in the US and 300 million people worldwide are chronically infected with HBV. In parts of Asia and Africa it is thought that between 5 and 20% of the population are chronically infected with HBV.
There is strong evidence linking chronic HBV infection to the incidence of primary hepatocellular carcinoma (HCC). Epidemiological studies demonstrate a much higher rate of HCC in regions of the world where HBV infection is endemic than in regions where infection is relatively low. A study in Taiwan demonstrated that HBV carriers (those chronically infected with the virus) were over two hundred times more likely to develop HCC as non-carriers. At the molecular level HBV DNA integration into the host genome has been demonstrated in nearly all hepatocellular carcinomas where HBV infection was present. This integration closely resembles that undergone by other tumor-causing viruses prior to malignant transformation. Over 500,000 deaths per year worldwide have been attributed to HCC, and hence a means of reducing the incidence of this cancer caused by HBV would be highly desirable.
Prior art has demonstrated that the course and outcome of HBV infections relates largely to the interaction of the duration and level of HBV replication and the degree of the host immune response. The severity of HBV-induced disease is, therefore, directly linked to HBV replication. See, for example, Purcell et al. “Hepatitis Viruses” In: DIAGNOSTIC PROCEDURES FOR VIRAL, RICKETTSIAL AND CHLAMYDIAL INFECTIONS. N. Schmidt et al., Ed. 6th Edition, pp 957-1065 (1989).
The only treatment for HBV currently licensed in the United States is alpha interferon. However this drug is not an effective treatment for all HBV chronic carriers and produces substantial side effects in some individuals during prolonged treatment. See, for example, Hoofnagle, “Current Status and Future Directions in the Treatment of Chronic Viral Hepatitis” In: VIRAL HEPATITIS AND LIVER DISEASE, Hollinger F. B. et al. (Eds.), pages 632-3. The majority of new approaches to the development of new antiviral agents against HBV have focused on the use of nucleoside analogues to inhibit the activity of viral polymerases. See Hoofnagle, supra. The limited success of this strategy against other viruses, together with the appearance of drug-resistant viral strains, indicates that this approach is unlikely to be a panacea.
A more recent approach to treatment of chronic HBV infection is the use of antisense oligonucleotides to inhibit viral gene expression. Goodarzi et al.,
J. Gen. Virol
. 71: 3021 (1990); Wu et al.,
J. Biol. Chem
. 267: 12436 (1992). The use of antisense oligonucleotides is known in the art. For a review, see Stein et al.,
Cancer Research
48: 2659 (1988). The method presents many technical hurdles however, and requires extensive experimentation if a successful outcome is to be achieved. See Stein and Chang,
Science
261: 1004 (1993). Use of the antisense method to inhibit replication of HBV requires knowledge of both the sequence of the HBV genome (to design suitable complementary oligonucleotides) and of the viral replication cycle (to target those regions of the genome critical to replication). Both the structure of the hepatitis B virus particle, known as a virion, and the viral replication cycle are well understood. See, for example, Tiollais et al.,
Nature
317: 489 (1985), Wang and Seeger,
J. Virol
. 67: 6507 (1993).
Goodarzi et al. prepared six antisense oligonucleotides against the S gene region of the HBV RNA pregenome, and measured their effects on HBsAg production in PLC/PRF/5 cells, which carry an unknown number of chromosomally integrated copies of HBV. Five of the six oligonucleotides proved effective at inhibiting production of HBsAg by the cells. The cell line used was not an ideal model for HBV replication in vivo however, since the HBV in this cell line is integrated as fragmented and rearranged pieces which cannot support HBV replication. Effects on HBV DNA and RNA were not measured.
Wu et al. described the use of a single antisense oligonucleotide targeted at the HBV polyadenylation signal/sequence, linked to a carrier intended to bind specifically to asialoglycoprotein receptors, which are abundant in the liver. The complex showed inhibition of HBsAg production, but the uncomplexed oligonucleotide was much less active. Again, effects on HBV DNA and RNA were not measured.
It is apparent therefore that new treatments for chronic HBV infection are greatly to be desired. In particular, it is greatly desirable to provide compositions and methods for treatment which are highly effective, but have a much lower incidence of side effects than those currently available.
SUMMARY OF THE INVENTION
It is therefore an object of this invention to provide compositions which provide a therapy for chronic hepatitis B virus infection by providing compositions that inhibit the replication of hepatitis B virus.
It is a further object of this invention to provide antisense oligonucleotides which inhibit hepatitis B virus replication by controlling at least one of the steps of virus transcription, translation, encapsidation, and virus release from a host cell.
It is a further object of this invention to provide antisense oligonucleotides which inhibit hepatitis B virus replication by controlling the synthesis of at least one member of the hepatitis B antigen group consisting of HBsAg, HBcAg, HBeAg, pres1 and Pol.
In accomplishing the foregoing objects of the invention, there has been provided, in accordance with one aspect of the current invention, a composition containing at least one antisense oligonucleotide capable of hybridizing specifically to segments of HBV RNA controlling the synthesis of at least one member of the hepatitis B antigen group consisting of HBsAg, HBcAg, HBeAg, pres1 and Pol.
In accordance with another aspect of the current invention, a composition has been provided that contains at least one antisense oligonucleotide capable of hybridizing specifically to HBV messenger RNA encoding regions of at least one HBV gene selected from the group of pres1, S, C, e, pol, and the e encapsidation signal sequence.
There has been provided, in accordance with yet another aspect of the current invention, pharmaceutical compositions comprising an effective amount of at least one of the antisense oligonucleotides of the invention in combination with a pharmaceutically acceptable, sterile vehicle.
In accordance with yet another aspect of the current invention a method has been provided for treating chronic HBV infections in a patient by administering to the patient at least one antisense oligonucleotide which inhibits HBV replication.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of
Gerin John L.
Korba Brent E.
Bennett-Paris Joseph M.
Georgetown University
Guzo David
King & Spalding
Knowles Sherry M.
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