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The discovery in 1998 of a way to extract and grow human embryonic stem cells (hESCs) was hailed as the dawn of an era of “regenerative medicine”, in which new cells could be implanted into patients to replace diseased or missing tissues.
Diabetes was immediately seen as one of the top prospects for regenerative treatment, if new insulin-producing beta cells could be produced to replace the ones that disappear in type 1 (and some type 2) patients.
The research required to make this possible turned out to be more difficult than some optimists had expected, but reliable cell therapy for diabetes is in prospect at last.
The past month has seen two crucial developments. ViaCyte, a privately owned biotechnology company based in San Diego, started the world’s first clinical trial of a diabetes treatment based on hESCs.An academic research team at Harvard University published the first evidence that hESCs can generate fully functional beta cells in the huge quantities required for such treatment to reach the medical mainstream.
Richard Insel, chief scientist of the Juvenile Diabetes Research Foundation, which helps fund both projects, says that together they represent a historic advance toward cell therapy for type 1 diabetes, an autoimmune disease caused by the patient’s immune system destroying his or her own beta cells.
Such therapy could also help the 10 per cent or so of people suffering from type 2 diabetes who are dependent on insulin injections.
The two projects are running separately and have slightly different approaches to stem cell technology, though they might come together in a joint effort that combines their best features.
The lead product of ViaCyte’s programme, called VC-01, consists of “pancreatic precursor cells” – essentially immature beta cells – being implanted under the skin. They are encapsulated in a semi-permeable membrane designed to protect them from immune attack and prevent vascularisation (the growth of unwanted blood vessels through the implanted cells).
If VC-01 works in humans as well as it has in animal tests, the pancreatic precursor cells will differentiate and mature after implantation. After a few months they will be fully functioning beta cells, producing not only insulin but also other hormones that are important for healthy metabolism and regulation of blood sugar levels.
ViaCyte expects to enrol 40 patients for the study, who will live with the implanted product for up to two years. As with any Phase I trial, the primary aim is to assess safety but clinicians will also evaluate the effectiveness of VC-01 in replacing the lost insulin-production function central to type 1 diabetes.
The second project, led by Doug Melton at Harvard University, is not ready for the clinic but is carrying out trials on animals, including monkeys. In contrast to the immature pancreatic cells produced by ViaCyte, which need to develop further inside the patient before they are fully active, the Harvard team has discovered how to convert hESCs into potentially unlimited numbers of fully mature beta cells – which might make a more effective treatment.
Commenting on the research, Chris Mason, professor of regenerative medicine at University College, London, says: “A scientific breakthrough is to make functional cells that cure a diabetic mouse, but a major medical breakthrough is to be able to manufacture at large enough scale the functional cells to treat all diabetics . . . If this scalable technology is proven to work in both the clinic and in the manufacturing facility, the impact on the treatment of diabetes will be a medical game-changer on a par with the effect of antibiotics on bacterial infections.”
Professor Melton is working with colleagues at the Massachusetts Institute of Technology on an implantation device that, like the ViaCyte system, protects the implanted cells from the recipient’s immune system. The cells are potentially subject to two types of attack: the immune system is likely to target any tissue transplanted from a genetically different donor – and there is the added problem with an autoimmune disorder such as diabetes that genetically identical beta cells are attacked too.
The first immune attack problem, recognition of the implanted cells as foreign material, could be overcome by using the more recent “induced pluripotent stem cell” (iPSC) technique rather than hESCs – making the beta cells from stem cells that originate from the patient. But that leaves the risk of autoimmune attack.
One possibility is simply to replace the implanted cells when they are no longer working. Without clinical data, it is hard to estimate how long they would last inside the patient but replacement every year or so might be necessary.