Behind the scenes of the world's first commercial stem-cell therapy

Contrasto/eyevine

Biologist Graziella Pellegrini has worked on stem-cell therapy at four different Italian institutions, including a hospital run by priests.

Last month saw a major landmark for regenerative medicine: the first time that a stem-cell therapy beside the use of cells extracted from umbilical cords had been cleared for sale by any regulatory agency in the world. The European Commission approved Holoclar for use in cases of blindness caused by burning. The achievement is all the more remarkable because Holoclar was developed by a small laboratory in Italy, a country better known for its lack of support for life sciences and for its recent tolerance of an unproven stem-cell concoction, marketed by the Stamina Foundation, that claimed to be a panacea for many diseases. Nature talked to Graziella Pellegrini from the University of Modena about how she and her colleagues overcame the many obstacles to take the therapy from bench to bedside.

The surface of the cornea the transparent tissue that sits in front of the iris is constantly renewed in a healthy eye, to keep it smooth and clear. New corneal cells are generated from a niche of stem cells in the limbus, an area between the cornea and the white of the eye. But if the limbus is destroyed by burning, then the white of the eye grows over the cornea and becomes criss-crossed with blood vessels. This causes chronic pain and inflammation, as well as blindness.

I had seen patients who had starting seeing again after 20 years of blindness: how could I stop?

Holoclar treatment can help to reverse these symptoms by adding new stem cells to seed the regrowth of a transparent cornea. But there must be enough surviving limbus in one eye to allow 1 or 2 square millimetres of tissue to be extracted. This tissue is then cultivated on a support made from modified human fibrin (a biodegradable blood protein) under stringent clinical conditions until at least 3,000 stem cells have been generated. The culture, still on its fibrin scaffold, is transplanted into the injured eye, which has been scraped clear of the invading white, and from there stem cells seed the regrowth of a transparent cornea, free of blood vessels, within a year.

Only around 1,000 people annually in the whole of Europe will be eligible: burns victims who have become blind but whose eyes have not been too extensively destroyed.

It is always very hard to find research money in Italy. We had to uproot many times. I first started working on the concept of the therapy, with my colleague Michele De Luca, in 1990 when we were post-docs at the University of Genova studying the fundamental biology of epithelial cells the cells that form the sheets lining organs, and also the skin. In 1996, we moved to Rome to the Institute Dermopatico Immaculate, a hospital run by priests who were highly committed to research and who offered us wonderful facilities and access to patients. But in the end they did not want to support our eye work through to the clinic. So in 2002, we moved to the Veneto Eye Bank Foundation in Venice, which had an epithelial stem-cell laboratory. Then in 2008 we moved again, to the Centre for Regenerative Medicine Stefano Ferrari, which had been newly created at the University of Modena specifically to incubate such types of advanced therapy.

Italy is not supportive of biomedical research. Things might have been easier if we had not had to struggle so much. But I am Italian, and the best way to stimulate me to find a solution is to tell me I cant do something. And despite the problems, research into advanced therapies does have a history here. One of the worlds first gene-therapy trials on children with an immunodeficiency disorder was carried out in Milan.

We published the results of our first two patients both successes in 19971. That was proof of principle that the therapy could work. Our major clinical paper, on 112 patients, was published in 20102. Around 77% of the transplants were fully successful, and a further 13% partially successful.

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Behind the scenes of the world's first commercial stem-cell therapy