Targeted gene correction of alpha1-antitrypsin deficiency

For the first time scientists from the Department of Medicine (Professor David Lomas), the Laboratory of Regenerative Medicine (Dr Ludovic Vallier) and the Sanger Institute (Professor Allan Bradley) have cleanly corrected a human gene mutation in a patient’s stem cell. The results were reported in Nature on 20th October brings the possibility of patient specific therapies closer to becoming a reality.

The researchers focused on a genetic condition that results in deficiency of alpha1-antitrypsin. This protein is produced by the liver and serves to protect the tissues against damage. Mutants that cause severe deficiency of alpha1-antitrypsin are found in 1 in 25 of the UK population. They result in mutant alpha1-antitrypsin being trapped within the liver in association with cirrhosis. The lack of an important circulating protein results in emphysema. The current work used a skin biopsy from an individual with alpha1-antitrypsin deficiency. The skin cells were there reprogrammed to produce stem cells. The team corrected both copies of the alpha1-antitrypsin mutation in the stem cell without affecting other base pairs within the genome. The corrected stem cells were then differentiated to liver cells where they function normally in the test tube and when transplanted into mice. This ‘molecular scalpel’ effectively corrects the genetic defect underlying alpha1-antitrypsin deficiency and can be used for genome correction in other genetic diseases.


Figure a. Immunofluorescence showing the absence of polymeric a1-antitrypsin protein in hepatocyte-like cells generated from corrected induced pluripotent stem cells. All forms of a1-antitrypsin (left panels) and misfolded polymeric a1-antitrypsin (middle panels) are shown.

Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells.Yusa K, Rashid ST, Strick-Marchand H, Varela I, Liu PQ, Paschon DE, Miranda E, Ordóñez A, Hannan NR, Rouhani FJ, Darche S, Alexander G, Marciniak SJ, Fusaki N, Hasegawa M, Holmes MC, Di Santo JP, Lomas DA, Bradley A, Vallier L. Nature. 2011 Oct 12;478(7369):391-4. doi: 10.1038/nature10424. PubMed PMID: 21993621; PubMed Central PMCID: PMC3198846.