Responsable : Jamila FAIVRE, MCU-PH
Marion DARNAUD, Ingénieur de Recherche
François FAITOT, Etudiant en Master
Fataneh FATEMI, Etudiante en Master
Michèle GIGOU, Assistant-Ingénieur
Claire LACOSTE, Ingénieur de recherche, Doctorante
Nicolas MONIAUX, Chargé de recherche Inserm
Haiyan SONG, Post-doctorante
Eric VIBERT, Chirurgien, Doctorant
From a therapeutic standpoint, extensive preclinical studies performed by our group have shown the potential of patented drugs, namely, a recombinant protein HIP/PAP for the stimulation liver regeneration, and a recombinant viral vector AdHIP-NIS against HCC. A partnership between U785 and the Biotech company ALFACT Innovation has been established for the R&D of these drugs. Phase I and phase II clinical trials will be led in 2009-2010 in partnership with ALFACT, INSERM, University Paris XI, and AP-HP.
The goal of this project is to develop clinical programs for acute liver failure based on the proofs-of-concept of the curative potential of a manufactured recombinant HIP/PAP protein that we have established during the last few years. We showed that the manufactured HIP/PAP protein caused a clear protective effect against experimental severe hepatitis. A clear correlation was found between enhancement of BrdU incorporation rate and inhibition of apoptosis in the liver, and the strength of the protective effect of the manufactured protein confirming that this drug efficiently enhances liver regeneration.
These results establish that ALF-5755 is a promising candidate for the pharmacological treatment of acute and fulminant hepatitis. A phase-I trial in healthy volunteers and phase II trial in patients with fulminant hepatitis should take place in 2009-2010.
Because no curative therapy for primary liver cancer exists, novel therapeutic strategies are urgently needed. Transfer of therapeutic genes to the tumor tissue has been actively investigated as a new approach for cancer therapy. It has long been known that thyroid cancers can be effectively managed, even in advanced metastatic cases, thanks to the ability of thyroid cells to trap and concentrate iodine, making therapy with radioactive iodine possible and highly effective. Recently, radioiodine therapy after Sodium Iodide Symporter (NIS) gene delivery has been proposed as a treatment of some non-thyroid cancers.
We demonstrated the feasibility of such an approach in an in vivo experimental HCC model, namely, diethylnitrosamine (DEN)-treated rats. 131I therapy after infection by a recombinant CMV-NIS adenovirus vector led to an almost complete destruction of the tumor nodules, and a marked increase of the survival rate (Faivre et al., Cancer Res 2004). However, the CMV promoter could raise problems in clinical studies of NIS-mediated radiotherapy since the targeted volume would be the whole liver, so that only a fraction of the injected 131I dose would reach the tumors. Therefore, we seeked to replace CMV with a liver tumor-specific promoter in order to increase the 131I tumor targeting index, and thus the efficacy of NIS-mediated 131I therapy at a fixed administrated dose. The available tumor-specific promoters, which were few in number and exhibited weak transcriptional activity in vivo. We have therefore sought to determine a new tumor-specific promoter capable of strong transcriptional activity in liver tumors. We demonstrated that HIP/PAP meets these requirements. The HIP/PAP regulatory sequence is activated specifically and strongly in HCC tumors, thus ensuring the efficacy of AdrHIP-NIS-mediated 131I therapy for HCC. The safety of this approach should be greatly improved by restricting 131I uptake to liver tumor cells obtained in vivo with this new AdrHIP-NIS vector (Herve J, Hum Gene Therapy, 2008). A partnership between U785 and the Biotech company ALFACT Innovation has been established for the valorisation and development of the AdrHIP-NIS vector. A phase-I/IIa clinical trial in patients with HCC is envisaged within two years.