FailSafe (TM)

The advent of human embryonic stem (hES) cells and induced pluripotent stem (iPS) cells had a paradigm-shifting effect on regenerative medicine – a powerful new treatment against diseases underlined by cell loss, tissue degeneration and aging.

With these applications came critical and important challenges:

  • uncontrolled proliferation;
  • genetic mutations; and,
  • other safety risks for patients

panCELLa developed a solution:  the solution to safe cell therapies

Quantifying & Mitigating the Risk

Engineering cells to give us total control over their fate:

FailSafe (TM) and induced Allogeneic Cell Tolerance (iACT Stealth Cells (TM))

The FailSafe Cell System

FailSafe(TM) uses cell division loci to control cell proliferation

Cell-based therapies are associated with risks that need to be understood and quantified in order to develop treatments with an acceptable level of safety.

panCELLa offers a solution: FailSafe (TM)

One of the biggest concerns with cell-based therapies is safety, in particular the concern of inducing malignant growth originating from the graft. In vitro cell expansion is open to the generation of abnormal cells; a cell culture is a competitive environment, in which the better surviving and faster dividing cells can take over the culture very rapidly. Increased growth rate in cell culture is frequently the consequence of the same genetic or epigenetic changes also associated with cancer. Stem cells could remain among the therapeutic cells, which could also develop into tumours, called teratomas. Therefore, the safety of iPS and hES cell-based therapies is complex and a huge concern. panCELLa’s FailSafe(TM) addresses these concerns.

Previous attempts to address safety issues have employed suicide genes that are used to kill the cells with a specific drug. The suicide gene has to be reliably expressed or problems can develop:

  • cells can shut down the expression of transgenes, even if inserted in “permissive” locations
  • OR
  • in the event of a deletion or mutation the suicide gene can be lost

In order to obtain a reliable expression of the suicide gene, panCELLa links its expression to a cell division essential locus (CDEL), in this way, if the cell is proliferating, it will be forced to express the suicide gene as well, making it more susceptible and allowing the clinician greater control. FailSafe(TM) is even more unescapable, as a homozygous link is created, with both alleles of the CDEL carrying the safety switch.

panCELLa’s exclusive FailSafe (TM) uses a suicide gene (HSV-TK) and an FDA-approved prodrug (Gancivlovir).

An example of CDEL is the CDK1 locus. CDK1 (cyclin-dependent kinase 1) is a critical element of the cell cycle, unlike other members of the CDKs family, its function cannot be replaced by any other protein, and without CDK1 cells are unable to divide. 

Through precise genetic engineering, HSV-TK is inserted in the 3’-end of the CDK1 coding sequence, the two genes are transcribed as a single mRNA and two separate proteins are produced due to a 2A linking sequence. In this configuration, the expression of HSV- TK is linked to cell division, and administration of GCV kills all the proliferating cells, leaving non-dividing cells intact. This has proven to be effective both in-vitro and in-vivo.

Pluripotent stem cells engineered with FailSafe(TM) are still capable of differentiation in a multitude of potential therapeutic cell types, showing that FailSafe(TM) does not interfere with their properties.

With a suicide gene placed in a locus essential for cell-life, all the transplanted cells can be eliminated regardless of their proliferative status.  FailSafe(TM) ensures that cell-based therapies are safe for patients and enables practitioners to control the persistence of cells after transplantation

A therapeutic batch of cells are considered FailSafe(TM) if all of the cells have a functional safety switch. 

The FailSafe Level (FSL) is the odds of receiving a non- FailSafe Cell batch. For example, one out of one thousand (FSL=1,000) or one out of one million (FSL=1,000,000).

panCELLa technology allows one to provide a precise definition of safety and to quantify the safety level of a prospective cell therapy.

The integration of FailSafe(TM) in cell therapies will be critical for regulators, clinicians and patients to make informed decisions.