The Niche

Gene therapy combined with reprogramming makes disease-free cells

Cells containing mutations for Fanconi’s anemia can be repaired and reprogrammed

Human cells carrying mutations for a complex genetic disease can be repaired and reprogrammed so that they appear indistinguishable from cells taken from healthy individuals. Juan Carlos Izpisúa Belmonte at the Center for Regenerative Medicine in Barcelona and colleagues have generated 19 lines of so-called induced pluripotent stem (iPS) cells from patients carrying a variety of mutations that give rise to Fanconi’s anemia, a rare and often fatal disease. “We show that genetic correction, combined with iPS cell technology, can be used to produce disease-free cells with potential value for cell therapy applications,” explains Belmonte.

Though the cells have not yet been tested in patients or even animal models, it is an important proof of principle for both cell and gene therapy, says John Wagner, clinical director of the Stem Cell Institute at the University of Minnesota. “The problem with gene therapy wasn’t with the gene but the fact that [the gene] wasn’t getting to the right cell. This is a new strategy that says now we can get many cells,” he says. “It’s very much boosted my enthusiasm for gene therapy, at least for this horrendous disease.”

Both Belmonte and Wagner cite several factors that must be overcome before the procedure is ready to move into patients. First come better procedures for making the necessary cells. Cells from Fanconi’s patients typically do not proliferate well, and Belmonte found that the cells’ genetic defects had to be repaired before they could be reprogrammed and differentiate.

In order to get enough cells to make gene therapy feasible, Belmonte estimates that the reprogramming efficiency needs to be about 0.1%, the rate seen with the original ‘Yamanaka technique’ of using viruses to insert copies of four pluripotency genes into the cells. However, `cleaner’ techniques that transform cells without viral integration and with less risk of tumour formation are much less efficient. Furthermore, current techniques to differentiate hematopoietic progenitors from embryonic stem cells and iPS cells produce cells that seem unable to sustain long-term blood formation.

The biggest concern is making sure the transformed cells don’t lead to malignant growth. Tumours are a concern for any cell products derived from pluripotent cells, but since Fanconi patients are especially susceptible to leukemias and skin cancers, their cells may have already accumulated mutations making them prone to malignant growth.

Despite the risks, this strategy should be actively pursued therapeutically, says Wagner. Though bone marrow transplants can often treat Fanconi’s anemia successfully, he says, the treatments can be painful, debilitating, and emotionally draining for patients and their families. He adds that there are adult patients for whom bone-marrow transplants are not an option, providing a ready population of candidates for a clinical trial.

Establishing techniques to make the cells and to test them for efficacy and tumorigenicity in appropriate animal models will take “very, very optimistically” five years, says Wagner, but he thinks the strategy is likely to work, eventually. “For moving this into a treatment, all the issues are likely to be addressable.”

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A podcast of Nature editor Natalie DeWitt discussing this paper will be available on June 4.

Genetically corrected stem cells treat anaemia in mice


Reya, A. et al. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature advance online publication, doi: 10.1038/nature08129 31 May 2009


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