Two successful gene therapy trials block inherited diseases in humans

Gene therapy: not just for mice.

Genetic traits, like a bulbous nose or balding, give some people reasons to moan about what they inherited from their parents. But more serious genetic flaws can cause debilitating disease. Now, Italian researchers have come up with a way of treating one such inherited disease and reversing another using a promising new method of gene therapy.

The idea behind gene therapy is to replace a faulty gene with a shiny new version that works properly. Modified versions of viruses, which have been sculpted by millions of years of evolution, perfectly penetrate human cells. They act as courriers delivering DNA payloads to defective cells and ensure they are stably inherited.

This deceptively simple idea, though, has been challenging to achieve in practice. The first commercial gene therapy product, Glybera, only received regulatory approval in 2012.

Part of the reason for this is the difficulty of successfully clearing three hurdles at once: delivering replacement genetic information to the exact cells that need help, getting this information safely translated in high enough volumes to overcome the defects, and stopping the immune system from reacting to normal genes when it has grown used to only seeing mangled ones.

Now, a team led by Alessandra Biffi at the San Raffaele Scientific Institute in Milan, Italy, reports inScience that they have developed a new approach that navigates each of these hurdles to treat three children with metachromatic leukodystrophy (MLD), a devastating inherited disease that affects around 1 in 40,000 people.

MLD usually manifests in early childhood and kills patients just a few years after the first symptoms appear. It is caused by a defect in a single gene, ARSA. This gene encodes information used by the lysosome, a piece of recycling machinery used by human cells to break down unwanted material. When this recycling process does not work properly in nerve cells, as is the case with MLD patients, they become filled with rubbish and begin to slowly decline, leading to brain and spinal cord degeneration, as well as sensory deprivation.

Supplying a replacement ARSA gene to affected cells in the nervous system is a tricky task, because these areas are heavily protected. To overcome these defenses, the team employed haematopoietic stem cells (HSCs), which can usually be found nestling quietly in the bone marrow, as stealthy genetic courriers. A tiny number of these cells were harvested from each patient, loaded with benign viruses carrying a working copy of ARSA, and put back into the bloodstream.

These engineered cells either lodged in the bone marrow or continued to travel around the body in the blood, where they corrected defective cells in the nervous system by supplying the normal version of ARSA. Because these were stem cells, they also reproduced to form new blood cells that themselves took on the same supportive roles.

Most MLD patients produce a garbled version of ARSA that has a very low level of activity, nowhere near enough to let the lysosome carry out its normal job. Restoring partial activity is not enough to make a clinical impactlevels must be hiked to make an obvious difference.

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Two successful gene therapy trials block inherited diseases in humans