Liver-directed gene therapy of chronic hepadnavirus infection using interferon alpha tethered to apolipoprotein A-I

Abstract

Background & Aims Current HBV management is challenging as treatment with nucleos(t)ide analogs needs to be maintained indefinitely and because IFNα therapy is associated with considerable toxicity. Previously we showed that linking IFNα to apolipoprotein A-I generates a molecule (IA) with distinct antiviral and immunostimulatory activities which lacks the hematological toxicity of IFNα. Methods Here, we analyze the antiviral potential of an adeno-associated vector encoding interferon alpha fused to apolipoprotein A-I (AAV-IA) in comparison to a vector encoding only IFNα (AAV-IFN) in two animal models of chronic hepadnavirus infection. Results In HBV transgenic mice, we found that both vectors induced marked reductions in serum and liver HBV DNA and in hepatic HBV RNA but AAV-IFN caused lethal pancytopenia. Woodchucks with chronic WHV infection that were treated by intrahepatic injection of vectors encoding the woodchuck sequences (AAV-wIFN or AAV-wIA) experienced only a slight reduction of viremia which was associated with hematological toxicity and high mortality when using AAV-wIFN while AAV-wIA was well tolerated. However, when we tested AAV-wIA or a control vector encoding woodchuck apolipoprotein A-I (AAV-wApo) in combination with entecavir, we found that AAV-wApo-treated animals exhibited an immediate rebound of viral load upon entecavir withdrawal while, in AAV-wIA-treated woodchuks, viremia and antigenemia remained at low levels for several weeks following entecavir interruption. Conclusions Treatment with AAV-IA is safe and elicits antiviral effects in animal models with difficult-to-treat chronic hepadnavirus infection. AAV-IA in combination with nucleos(t)ide analogs represents a promising approach for the treatment of HBV infection in highly viremic patients.

Antiviral Efficacy and Host Immune Response Induction during Sequential Treatment with SB 9200 Followed by Entecavir in Woodchucks

“…Since recrudescence of viral replication following cessation of prolonged monotherapy with ETV can be variable in individual woodchucks [32, 33], it could be argued that viral relapse from ETV treatment is itself slow, or slower than relapse from SB 9200 treatment, thereby causing the delayed rebound that was observed in Group 2. While the inclusion of control groups receiving ETV and SB 9200 alone in the present study was not possible for addressing this question, a comparison of viral rebound kinetics following 4 weeks of monotherapy with ETV [18, 33] or 12 weeks of monotherapy with SB 9200 [12] using the same doses as applied in the present study indicates that viral relapse occurs rather rapidly with either drug and that rebound from ETV treatment is not markedly slower than from SB 9200 treatment.…”

“…ETV at the selected dose was used for achieving rapid and potent suppression of WHV DNA in serum within a 4-week treatment period as also done previously in another woodchuck study [18]. Group 1 (n = 5) received ETV for 4 weeks followed by SB 9200 for 12 weeks while Group 2 (n = 5) received SB 9200 for 12 weeks followed by ETV for 4 weeks (Fig 1).…”

The role of innate immunity in the immunopathology and treatment of HBV infection

“…Pegylated interferon-alpha (Peg-IFN) is still one of the mainstays of treatment of CHB because it can achieve functional cure in a proportion of patients; a better understanding of its modes of action could allow it to be modified to enhance its therapeutic efficacy and reduce toxicity. For example, targeting IFN directly to hepatocytes can be achieved by coupling it to TCR-like antibodies that only bind MHC/peptide complexes of infected hepatocytes (102), or by tethering IFN to apoplipoprotein A1 (103). Such targeting should reduce unwanted haematological side effects and maximize direct antiviral effects of IFNsuch as its recently elucidated capacity to induce the antiviral protein tetherin, that can inhibit HBV virion secretion (104).…”

Efficient in vivo editing of OTC-deficient patient-derived primary human hepatocytes

“…The demonstrated therapeutic efficacy of recombinant adenoassociated virus (rAAV) vectors in the treatment of haemophilia B 1 has intensified interest in exploiting this vector system to treat more demanding genetic/metabolic liver disease phenotypes 2 and other hepatic pathologies caused by viral infection, 3 hepatotoxin exposure 4 and neoplasia. 5 Challenges include the need to efficiently target a greater proportion of the hepatic cell mass, 6 overcome the limitations imposed by the loss of rAAV episomes that occurs in concert with hepatocellular replication 7,8 and develop preclinical models that better predict the performance of AAV-based gene addition and editing technologies in the human liver.…”