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Inducible Caspase9-mediated suicide gene for MSC-based cancer gene therapy

Filippo Rossignoli1, Giulia Grisendi2,3, Carlotta Spano2,3

  • 1Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy. filippo.rossignoli@unimore.it.

Cancer Gene Therapy
|June 30, 2018
PubMed

Insights

Engineered mesenchymal stromal/stem cells (MSC) with a novel suicide gene (iCasp9) offer enhanced safety for cancer therapy. These modified MSCs, co-expressing anti-cancer TRAIL, effectively target tumors without compromising efficacy.

Area of Science:

  • Cellular and Molecular Oncology
  • Regenerative Medicine
  • Gene Therapy

Background:

  • Mesenchymal stromal/stem cells (MSC) show therapeutic promise in regenerative medicine and oncology.
  • Concerns exist regarding MSC safety in cancer patients, necessitating methods to control infused cell fate.
  • Existing suicide gene strategies (HSV-TK, Cytosine Deaminase) have limitations.

Purpose of the Study:

  • To evaluate the suitability of the inducible Caspase 9 (iCasp9) suicide gene system for enhancing MSC safety.
  • To develop and test adipose-derived MSCs engineered to co-express iCasp9 and TNF-Related Apoptosis-Inducing Ligand (TRAIL) for combined anti-cancer therapy.

Main Methods:

  • MSC transfection using a lentiviral vector encoding the iCasp9 suicide gene.
  • Assessment of iCasp9-expressing MSC viability upon treatment with the small molecule inducer AP20187.
  • Generation of adipose MSCs co-expressing iCasp9 and TRAIL for targeting aggressive sarcoma models.

Main Results:

  • iCasp9 effectively induced cell death in transfected MSCs upon AP20187 administration, confirming its function as a suicide gene.
  • Co-expression of iCasp9 and TRAIL in MSCs did not impair their anti-cancer activity against sarcoma.
  • The combined approach demonstrated that safety mechanisms (iCasp9) and therapeutic functions (TRAIL) can coexist in engineered MSCs.

Conclusions:

  • The iCasp9 suicide gene system is a suitable and effective strategy for enhancing the safety of MSC-based cancer therapies.
  • Combining iCasp9 with MSC-mediated anti-cancer gene delivery, such as TRAIL, offers a potent and controllable therapeutic approach.
  • This study validates the dual functionality of engineered MSCs for both safety and targeted tumoricidal activity.

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