New Enzyme For Treating Rare Genetic Disorder Fabry Disease Shows Promise In Lab

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Main Category: Genetics
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Article Date: 23 Oct 2009 - 2:00 PDT

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Using a new modelling strategy, researchers in Japan have designed a new enzyme that shows significant promise compared with current therapeutic proteins used to treat patients with Fabry disease, a rare genetic disorder that affects about 1 in 40,000 people and often results in cardiac and renal failure.

The researchers, led by senior author Dr Hitoshi Sakuraba from the Department of Clinical Genetics at Meiji Pharmaceutical University in Tokyo, wrote about their work in a study published online on 22 October in the Cell Press journal The American Journal of Human Genetics.

The study describes how Sakuraba and colleagues used a creative structure-based remodeling strategy to design a new therapeutic protein that shows significant advantages over current proteins used in enzyme replacement therapy (ERT) for Fabry disease.

Fabry disease is a rare genetic disorder that occurs when people don't have enough alpha-galactosidase-A (GLA), an enzyme that breaks down fatty substances called glycolipids.

Without enough GLA, a glycopid called globotriaosylceramide (Gb3) accumulates to harmful levels inside lysosomes, small digestion sacs inside cells, resulting in damage to the skin, nerves, eyes, kidneys and cardiovascular system.

Current ERT treatments use manufactured GLA, but there are problems, as Sakuraba explained to the press:

"Many patients have been successfully treated with these manufactured GLA proteins, but there are still problems to be resolved."

"For example, these enzymes are unstable in the blood, do not effectively reach the kidneys and heart and frequently cause an allergic reaction in Fabry patients."

For the study, Sakuraba and colleagues decided to try a different approach to making GLA. Instead of making recombinant GLA they tried to modify a an enzyme called [alpha]-N-Acetylgalactosaminidase (NAGA) so it could work like GLA.

Normally NAGA ignores substrates targeted by GLA and triggers the hydrolisis of a different type of substrate. However, an important feature is that although NAGA is similar to GLA, it does not react with the immune system in the same way as GLA.

After comparing the molecular structures of GLA and NAGA, Sakuraba and colleagues worked out how they could alter NAGA so it might recognize substrates. They found a way to do it without changing the overall molecular structure of NAGA, an important point since that way it would be unlikely to cause an allergic reaction in Fabry patients.

They found that the modified NAGA was more stable than recombinant GLA and demonstrated the features necessary for efficient incorporation into cells.

Sakuraba described what they did:

"Following confirmation of the effect of modified NAGA on cultured Fabry cells, we injected it into Fabry mice, and examined the incorporation of the enzyme into organs and its Gb3-degrading activity."

They managed successfully to insert the altered NAGA into the liver, kidneys and the heart and observed that this was followed by a decrease in Gb3 accumulation in these organs.

Sakuraba said they concluded that:

"The enzyme has many advantages because of its high stability and the low possibility of the occurrence of an allergic reaction, although these characteristics should be confirmed in clinical studies in the future."

"The modified NAGA is highly promising as a new enzyme for ERT for Fabry disease, and such structure-based designing of modified enzymes should be useful for the development of ERT for lysosomal storage diseases," said Sakuraba.

"Use of a Modified [alpha]-N-Acetylgalactosaminidase in the Development of Enzyme Replacement Therapy for Fabry Disease."
Youichi Tajima, Ikuo Kawashima, Takahiro Tsukimura, Kanako Sugawara, Mayuko Kuroda, Toshihiro Suzuki, Tadayasu Togawa, Yasunori Chiba, Yoshifumi Jigami, Kazuki Ohno, Tomoko Fukushige, Takuro Kanekura, Kohji Itoh, Toya Ohashi and Hitoshi Sakuraba.
The American Journal of Human Genetics, Published onlin 22 October 2009.
DOI:10.1016/j.ajhg.2009.09.016

Source: Cell Press, NINDS, Fabry Support & Information Group.

Written by: Catharine Paddock, PhD
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

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