Delving into the Latest Updates on RR-001 with Synapse

Overview

Basic Info

Drug Type

Gene therapy

Synonyms

AD-PC sTRAIL, RR 001, RR001

Target-

Mechanism

Cell replacements

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease

Active Indication

Pancreatic Carcinoma

Inactive Indication-

Originator Organization

Rigenerand Srl

Active Organization

Rigenerand Srl

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Author: Chiavelli, Chiara ; Melandri, Aurora ; Casari, Giulia ; Dominici, Massimo ; Prapa, Malvina ; Masciale, Valentina ; D'Esposito, Angela ; Murgia, Alba ; Baschieri, Maria Cristina ; Ceccherelli, Giovanni Battista ; Neri, Giovanni ; Spano, Maria Carlotta ; Dall'Ora, Massimiliano ; Grisendi, Giulia

BACKGROUND AIMS:

The proapoptotic protein tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is physiologically expressed by immune cells and performs regulatory functions in infections, autoimmune diseases and cancer, where it acts as a tumor suppressor. Adipose-derived mesenchymal stromal cells (AD-MSCs) also may play immunomodulatory roles in both primary and acquired immune responses. We have previously demonstrated the efficacy of an anticancer gene therapy based on AD-MSC engineered to secrete a soluble TRAIL variant (sTRAIL) against pancreatic cancer. However, the impact of AD-MSC sTRAIL on leukocyte subsets has been not yet considered also to predict a possible immunotoxicity profile in the clinical translation of this cell-based anticancer strategy.

METHODS:

Monocytes, polymorphonuclear cells and T lymphocytes were freshly isolated from the peripheral blood of healthy donors. Immunophenotype and functional (DR4 and DR5) and decoy (DcR1 and DcR2) TRAIL receptors were tested by flow cytometry. The viability of white blood cells treated with sTRAIL released by gene-modified AD-MSC or co-cultured with AD-MSC sTRAIL was then evaluated by both metabolic assays and flow cytometry. In addition, cytokine profile in co-cultures was analyzed by multiplex enzyme-linked immunosorbent assay.

RESULTS:

Monocytes and polymorphonuclear cells showed high positivity for DR5 and DcR2, respectively, whereas T cells revealed negligible expression of all TRAIL receptors. Irrespective of TRAIL receptors' presence on the cell membrane, white blood cells were refractory to the proapoptotic effect displayed by sTRAIL secreted by gene-modified AD-MSC, and direct cell-to-cell contact with AD-MSC sTRAIL had negligible impact on T-cell and monocyte viability. Cytokine crosstalk involving interleukin 10, tumor necrosis factor alpha, and interferon gamma secreted by T lymphocytes and vascular endothelial growth factor A and interleukin 6 released by AD-MSC was highlighted in T-cell and AD-MSC sTRAIL co-cultures.

CONCLUSIONS:

In summary, this study demonstrates the immunological safety and thus the clinical feasibility of an anticancer approach based on AD-MSC expressing the proapoptotic molecule sTRAIL.

01 Aug 2016·Acta pharmacologica SinicaQ1 · MEDICINE

Dendritic cells serve as a “Trojan horse” for oncolytic adenovirus delivery in the treatment of mouse prostate cancer

Q1 · MEDICINE

Article

Author: Li, Zhao-Lun ; Li, He-Cheng ; Wang, Zi-Ming ; Chong, Tie ; Liang, Xuan

AIM:

Adenovirus-mediated gene therapy is a novel therapeutic approach for the treatment of cancer, in which replication of the virus itself is the anticancer method. However, the success of this novel therapy is limited due to inefficient delivery of the virus to the target sites. In this study, we used dendritic cells (DCs) as carriers for conditionally replicating adenoviruses (CRAds) in targeting prostate carcinoma (PCa).

METHODS:

Four types of CRAds, including Ad-PC (without PCa-specific promoter and a recombinant human tumor necrosis factor, rmhTNF, sequence), Ad-PC-rmhTNF (without PCa-specific promoter), Ad-PPC-NCS (without an rmhTNF sequence) and Ad-PPC-rmhTNF, were constructed. The androgen-insensitive mouse PCa RM-1 cells were co-cultured with CRAd-loading DCs, and the viability of RM-1 cells was examined using MTT assay. The in vivo effects of CRAd-loading DCs on PCa were evaluated in RM-1 xenograft mouse model.

RESULTS:

Two PCa-specific CRAds (Ad-PPC-NCS, Ad-PPC-rmhTNF) exhibited more potent suppression on the viability of RM-1 cells in vitro than the PCa-non-specific CRAds (Ad-PC, Ad-PC-rmhTNF). In PCa-bearing mice, intravenous injection of the PCa-specific CRAd-loading DCs significantly inhibited the growth of xenografted tumors, extended the survival time, and induced T-cell activation. Additionally, the rmhTNF-containing CRAds exhibited greater tumor killing ability than CRAds without rmhTNF.

CONCLUSION:

DCs may be an effective vector for the delivery of CRAds in the treatment of PCa.

01 Jun 2014·Artificial cells, nanomedicine, and biotechnologyQ2 · ENGINEERING & TECHNOLOGY

Experiment research on inhibition of glioma with sTRAIL in vitro

Q2 · ENGINEERING & TECHNOLOGY

ArticleOA

Author: Yihe Dou ; Zhaojian Li ; Yangang Wang ; Jian Xu ; Qinghai Meng ; Peng Sun

We report that adenovirus mediated TNF-related apoptosis-inducing ligand (TRAIL) influenced the cell growth and cell cycle in the glioma cells in vitro. After being infected with the Ad-sTRAIL, U251 cell growth was inhibited. The expression of sTRAIL was detected using immunofluorescence. The higher rate of apoptosis was demonstrated using short-term microculture tetrazoliun (MTT) assay and flow cytometry. The rate of Ad-sTRAIL-inducing U251 cell apoptosis was increased depending on the dosage and the time. The apoptosis of G0/G1 and S phase cells was more significant than that of the control groups. The growth and proliferation of U251 cell line was inhibited after the infection of Ad-sTRAIL. It is dose- and time dependent.

100 Deals associated with RR-001

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