12:49pm Wednesday 16 October 2019

Successful correction of a patient’s genetic mutation

Researchers led by the Wellcome Trust Sanger Institute and the University of Cambridge targeted a gene mutation responsible for both cirrhotic liver disease and lung emphysema. The condition is the commonest known inherited lung and liver disorder, occurring in about one in 2,000 North Europeans.

Using cutting-edge methods, scientists were able to correct the sequence of a patient’s genome, remove all exogenous DNA and show that the corrected gene worked normally.

Dr Ludovic Vallier, principal investigator at the University of Cambridge’s MRC Centre for Stem Cell Biology and Regenerative Medicine and Department of Surgery, said:

“This study represents a first step toward personalised cell therapy for genetic disorders of the liver. We still have major challenges to overcome before any clinical applications but we have now the tools necessary to advance toward this essential objective.”

The researchers used human induced pluripotent stem cells (hIPSCs) which, once reprogrammed in the Petri dish, can be converted into a wide range of tissues. If stem cells from a patient with a gene defect can be corrected, scientists believe that they could treat the effects of the mutation when reintroduced into the patient.

The team looked a condition caused by a mutation in the alpha1-antitrypsin gene, which is responsible for making a protein in the liver that protects against excessive inflammation. People with mutant alpha1-antitrypsin cannot release the protein properly and it becomes trapped in the liver, eventually leading to cirrhosis and lung emphysema.

The team successfully and accurately corrected an alpha1-antitrypsin gene in an established cell line containing the mutation. Using ‘molecular scissors’ to snip the genome at precisely the right place, they then inserted a correct version of the gene using a DNA transporter called piggyBac.

The piggyBac sequences were subsequently removed from the cells, allowing them to be converted into liver cells without any trace of residual DNA damage at the site of correction.

The scientists then proved that the accurate copy of the gene was active in the liver cells they had produced by demonstrating the presence of normal alpha1-antitrypsin protein in both test tube and mouse experiments.

Professor Allan Bradley, Director Emeritus of the Wellcome Trust Sanger Institute, said:

“We have developed new systems to target genes and integrated all the components to correct, efficiently, defects in patient cells. Our systems leave behind no trace of the genetic manipulation, save for the gene correction. These are early steps but, if this technology can be taken into treatment, it will offer great possible benefits for patients.”

Professor David Lomas, Professor of Respiratory Biology at the University of Cambridge and Consultant Physician at Addenbrooke’s and Papworth Hospitals (who has worked on the mechanism of alpha1-antitrypsin deficiency for 20 years and looks after patients with this condition), said:

“As there is currently no cure for this disease other than liver transplantation, and given the increasing strains being placed on the national liver transplant programme as a result of the sharp increase in the frequency of liver disease, alternative therapies for genetic and other liver diseases are urgently being sought.

“Our research is a critical step to developing enhancing or life-saving treatments these individuals. It is a quite remarkable series of results, founded on strong research and the generous participation of our patients. One of the next steps will be exploring the use of this technique in human trials.”

Professor Roger Pedersen, Director of MRC Cambridge Centre for Stem Cell Biology and Regenerative Medicine, said:

“This is an important step forward in the Medical Research Council’s drive to translate fundamental stem cell research into new treatment strategies for this and other genetic and degenerative diseases. It deftly solves two major obstacles to successful therapy, first by fixing the mutation that causes the disease, and second, by doing this with the patient’s own cells, thereby avoiding immune rejection.”


Notes to Editors


Yusa K, Rashid T et al. (2011) Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells. Nature, published online on Wednesday 12 October 2011

doi: 10.1038/nature10424.

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