Preliminary success in blood stem cell gene therapy

Author: David Kent, 08/12/13

Last month, two studies were published in Science from Luigi Naldini’s group on correcting disease-associated mutations in patient’s stem cells. The two diseases, Wiskott-Aldrich Syndrome (WAS) and Metachromatic Leukodystrophy, are sometimes treated with bone marrow transplantation, which relies on identification of matched donors and risks severe complications through graft vs. host disease and lifelong immunosuppression. Using a patient’s own stem cells and correcting the mutation — known as gene therapy — avoids both of these problems and sounds like an ideal solution, but the technology did not get off to a wonderful start.

In the late 1990s, gene therapy trials for diseases with known genetic causes were undertaken with great fervour.  The most famous trials were those in children with severe combined immunodeficiency (SCID)a condition most commonly caused by mutations in the IL2 receptor gamma gene. While the children were effectively cured by the introduction of a non-mutated copy of the gene, a significant proportion (4 of 10 in the famous French trial) developed leukemia. An excellent scientific summary is located here which details the main issues, and the United Kingdom’s National Health Service has published a good lay summary of the current state of affairs.

The first trials used retroviral vectors to deliver the corrected gene and, as noted, some patients developed leukemia — caused when the corrected gene was inserted into a cancer causing gene, now a known risk when using this mode of gene delivery. It has subsequently been shown that lentiviruses (a subclass of retroviruses) more commonly insert into areas of the genome that do not cause cancer. Therefore, the next generation of delivery systems for gene therapy have been using lentiviral vectors in the hopes of avoiding the development of cancer.

This is what makes the pair of studies from the Naldini group so exciting — they show two important proofs of principle. The first is that so far, the therapies appear safe (7-21 months follow up in 3 patients with metachromatic leukodystrophy and 20-32 months in patients with WAS) and the second is that the gene correction appears to have been beneficial to patients. Notably in WAS patients, platelet numbers and immune cell function were much improved and metachromatic leukodystroppy patients had restored arylsulfatase A enzyme expression.

While all of this news is very exciting, these timelines are still quite short as cancer sometimes evolves slowly and it would be dangerous to roll out this therapy without waiting to see how things progress. We will therefore need to watch these first few patients very carefully to see if longterm function is restored in the absence of cancer development.

I for one will be looking forward with cautious optimism to the day when gene therapy can be a viable technology benefitting the tens of thousands of patients with known genetic mutations without needing to resort to bone marrow donors and the complications of heterologous transplantations.

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David Kent

David Kent

Principal Investigator at University of Cambridge
Dr. David Kent is a Principal Investigator at the University of Cambridge in the Cambridge Stem Cell Institute ( His laboratory's research focuses on fate choice in single blood stem cells and how changes in their regulation lead to cancers. David is currently the Stem Cell Institute’s Public Engagement Champion and has a long history of public engagement and outreach including the creation of The Black Hole in 2009. He has been writing for Signals since 2010.
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