Gene therapy for Fabry disease shows promise in mouse model

Further research is needed to optimize administration, researchers say

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A hand holds a mouse with three vials of blood in a stand next to it.

A gene therapy treatment increased levels of the deficient alpha-glactosidase A (Gal A) enzyme in the organs of mice in a model of Fabry disease, according to a new study.

Results showed the gene therapy approach reduced the toxic buildup of fatty molecules in most organs assessed, but not in the brains of the mice. Researchers said further studies are needed to optimize how gene therapies are administered in order to get the maximum possible benefit in Fabry disease.

The study, “Therapeutic strategy for Fabry disease by intravenous administration of adeno-associated virus 2 or 9 in α-galactosidase A-deficient mice,” was published in The Journal of Gene Medicine.

Fabry disease is caused by mutations that interfere with the production of the Gal A enzyme. This enzyme normally is needed to break down certain fatty molecules, particularly globotriaosylceramide (Gb3); without a working version of the enzyme, Gb3 builds up to toxic levels in the body’s tissues, causing damage that drives the symptoms of the disease.

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Gene therapy is a treatment strategy that aims to deliver a working copy of the mutated gene to the body’s cells, allowing the production of a functional Gal A enzyme to reduce toxic Gb3 buildup. Most gene therapies use a modified harmless virus to deliver their genetic payload; a particular type of virus called adeno-associated virus (AAV) is commonly used for this purpose because it doesn’t cause disease in people and is easy to manipulate in a lab.

AAV-based gene therapies for other genetic diseases have shown promise, but in other cases, the gene therapy is usually targeted at just one specific type of cell in a particular organ. In Fabry disease, where many organs throughout the body can be affected, an ideal gene therapy would be able to deliver a working gene to cells throughout the body — but it has proven challenging to create a gene therapy that can do this effectively.

Scientists created novel gene therapies for testing Gal A, Gb3 levels in tissues

Here scientists in Japan created two novel gene therapies for Fabry disease using two different versions of AAV, called AAV2 and AAV9. The researchers injected the gene therapies into the bloodstreams of mice with Fabry disease, then analyzed Gal A and Gb3 levels in various tissues.

Results showed the AAV9-based gene therapy generally led to higher Gal A levels, accompanied by lower Gb3 buildup, compared to the therapy using the AAV2 vector.

With the highest tested dose of the AAV9 therapy, Gal A levels in the blood were more than three times higher than levels seen in mice without Fabry disease. Levels of Gal A in the mice’s hearts and livers also were higher in treated mice than in mice without Fabry. However, levels of the enzyme in the mice’s kidneys were only about 40% of normal, and levels in the brain were only about 10% of normal.

The AAV9-based gene therapy also led to marked reductions in Gb3 levels in the heart, liver, and kidneys. However, levels of this fatty molecule in the brain were not significantly altered by the gene therapy.

“Even the [highest dose] AAV9 administration was not sufficient to reduce the accumulation of Gb3 in the brain, whereas it significantly reduced Gb3 in the heart, liver and kidney,” the researchers wrote.

The team speculated that, in order to achieve optimal effects in the brain, it may be necessary to use higher doses of gene therapy, or to deliver the therapy directly into the fluid that surrounds the brain and spinal cord. They called for further studies to help optimize this approach.

Analyses of the mice’s tissues showed no obvious signs of damage related to the gene therapy treatment. After receiving the gene therapy, all of the mice developed antibodies against the AAV viral vectors used, but the presence of these antibodies didn’t seem to affect Gal A activity. These data support the safety and feasibility of the AAV gene therapy approach, the researchers said.

“The result suggested that AAV vectors will be useful in gene therapy for” Fabry disease, the scientists concluded.