Fail Safe Cell Therapy

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Suicidal cells — Are they the key to safe cell therapy?

Like nuclear power plants, stem cells can be created with a “Fail-Safe” system to minimize damage in the event of an unwanted event. Photo: Tobin via Flickr

Dr. Andras Nagy, a stem cell researcher at the Lunenfeld-Tanenbaum Research Institute in Toronto has been thinking a lot about risk. In his talk at the 2016 Till and McCulloch Meetings held in Whistler, BC last month, he explained the unique and innovative approach that his lab has developed to keep the risk associated with stem cell-based therapies in check.

It has to do with encoding the cells with a suicide option.

While suicidal cells might seem counter-intuitive — after all, the idea behind cell therapy is to introduce or modulate cells to promote healing — it does have a practical and important purpose. Dr. Nagy works with induced pluripotent stem cells (iPSCs) generated from adult cell types through a process known as reprogramming. Despite their therapeutic potential, there is a risk with iPSCs, based on concerns that the reprogramming process will introduce genetic changes that might give the cells the capacity to grow out of control, and potentially become cancerous.

Despite this potential danger, stem cells are entering clinical trials for a variety of different diseases. No one wants to miss the boat on the therapeutic potential of stem cells — but scientists in the field are still debating the best way to deal with the risks.

Dr. Nagy’s answer is the Fail-Safe cell system. In this system, the stem cells are genetically modified with a “kill switch” that triggers the destruction of out-of-control cells that undergo unwanted cell divisions.

The kill switch is the enzyme thymidine kinase (TK) — normally produced by the herpes virus. When TK is exposed to the drug ganciclovir, it produces a byproduct that is toxic to dividing cells.

Generating populations of fail-safe cells that reliably express the kill switch gene is no easy task. As Dr. Nagy explains, “cells are smart,” and will find ways to escape engineered controls on their behaviour. To outsmart cells, and make sure TK is expressed in the extreme majority of dividing cells, Dr. Nagy had to take into consideration all the ways a cell can lose genes.

He concluded that best way to prevent this was to ensure that each cell has two copies of the kill switch gene. Further, this gene is placed in a location that is hard for the cell to delete, for example near a gene that is absolutely essential for cell growth and division in both homologous chromosomes at the same position. Dr. Nagy calls these locations in the genome Cell Division Essential Loci (CDELs).

The result is kill switch — or TK — expression in cells that are actively dividing.

While the work I’ve just described is truly on the cutting edge of stem cell science, it is worth noting that the fail-safe cell system is still in experimental stages, and has not yet been used in humans.

What might be the impacts of this work outside of the lab? And most importantly, what could it mean for patients?

The term Fail-Safe is borrowed from the nuclear power industry. Dr. Nagy explained in his talk that nuclear power plants are built with systems in place to minimize damage in case of an accident. He pointed out that even with these systems in place, there have been some rare nuclear reactor melt-downs. Despite this reality, we take the calculated risk of using nuclear power.

Dr. Nagy used the analogy of the nuclear power station to illustrate that nothing in life is absolutely safe. The aim of the fail-safe system is to reduce the risk so that we no longer consider adverse events a deterrent to using cell-based therapies.

Dr. Nagy’s aim is to use hard numbers to explain risk level to doctors and patients. To accomplish this he has developed the concept of “Fail-Safe Level” — a number that indicates the odds of picking a non-fail safe population of cells for treatment. For example, if the fail-safe level is one million, the odds of getting a non-fail-safe, or potentially dangerous population of cells are one in a million. To date, the fail-safe level has been estimated using mathematical modelling in a variety of different cell types. More work in cells and animals is required to confirm predictions about fail-safe level.

Despite being at an early stage of development, the concept of fail-safe level could prove to be a game-changer in the field of regenerative medicine. It is a rare example of a technology that has been designed with patient perspectives in mind. This type of thinking could help change the perception that regenerative medicine is science fiction, and make it into something that will slowly start becoming a real option to patients.

–Source: https://oirmexpression.ca/suicidal-cells-are-they-the-key-to-safe-cell-therapy-63022b7fd7b9

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