The procedure will have to undergo several years of trials before it can be used in humans, but if approved, it could launch a new era of personalised therapies for serious genetic disorders.
In Britain 30,000 people carry a genetic defect that causes antitrypsin deficiency, a disease that can only be cured by a liver transplant. The operation requires a suitable donor organ and costs around £500,000, with drugs to prevent rejection by the immune system adding more than £20,000 a year to medical costs.
Treating a patient with their own cells removes the need for anti-rejection drugs, reduces the burden on strained transplant services and is likely to be cheaper, the scientists behind the technique believe.
The scientists now hope to partner with a major pharmaceutical firm and work towards trials in people. Rather than injecting the cells directly into patients, the cells will probably be encapsulated in a porous bag. This will ensure that patients are not put at risk if some of the cells turn out to be faulty and develop into tumour cells.
Scientists elsewhere are now expected to develop the procedure to treat other genetic conditions, including those that require the correction of several mutations at once.
Nature - Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells
Human induced pluripotent stem cells (iPSCs) represent a unique opportunity for regenerative medicine because they offer the prospect of generating unlimited quantities of cells for autologous transplantation, with potential application in treatments for a broad range of disorders. However, the use of human iPSCs in the context of genetically inherited human disease will require the correction of disease-causing mutations in a manner that is fully compatible with clinical applications. The methods currently available, such as homologous recombination, lack the necessary efficiency and also leave residual sequences in the targeted genome. Therefore, the development of new approaches to edit the mammalian genome is a prerequisite to delivering the clinical promise of human iPSCs. Here we show that a combination of zinc finger nucleases (ZFNs) and piggyBac technology in human iPSCs can achieve biallelic correction of a point mutation (Glu342Lys) in the α1-antitrypsin (A1AT, also known as SERPINA1) gene that is responsible for α1-antitrypsin deficiency. Genetic correction of human iPSCs restored the structure and function of A1AT in subsequently derived liver cells in vitro and in vivo. This approach is significantly more efficient than any other gene-targeting technology that is currently available and crucially prevents contamination of the host genome with residual non-human sequences. Our results provide the first proof of principle, to our knowledge, for the potential of combining human iPSCs with genetic correction to generate clinically relevant cells for autologous cell-based therapies.
16 pages of supplemental information
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