Moving gene therapy one step closer to clinical reality

Scientists from the Morgridge Institute for Research, the University of Wisconsin-Madison, the University of California and the WiCell Research Institute moved gene therapy one step closer to clinical reality by determining that the process of correcting a genetic defect does not substantially increase the number of potentially cancer-causing mutations in induced pluripotent stem cells.

Their work, published in the online edition of the journal Proceedings of the National Academy of Sciences and funded by a Wynn-Gund Translational Award from the Foundation Fighting Blindness, suggests that human induced pluripotent stem cells (iPS) altered to correct a genetic defect may be cultured into subsequent generations of cells that remain free of the initial disease.

However, although the gene correction itself does not increase the instability or the number of observed mutations in the cells, the study reinforced other recent findings that induced pluripotent stem cells themselves carry a significant number of genetic mutations.

In brief, scientists produced iPS cells by episomal reprogramming, corrected a disease-causing mutation by homologous recombination and removed the puromycin cassette that was used for gene selection using Cre recombinase.

Results of the study indicate that both homozygous recombination and cassette removal did not increase the iPS mutational load. Nonetheless, the initial induction of primary dermal fibroblasts into iPS cells lead to a fairly substantial mutational load at the time of derivation.

This study is important in that it demonstrated that downstream cloning events do not introduce further mutations into iPS cells which can be a source of tremendous therapeutic value. Nonetheless, it is important for further studies to focus on reducing mutational events caused by iPS induction which may be a serious drawback to introducing iPS therapy into the clinic.

Sources:

Howden S et al, (2011) Genetic correction and analysis of induced pluripotentstem cells from a patient with gyrate atrophy. PNAS

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