Inventive approach may improve enzyme replacement therapy for Fabry disease

October 22, 2009

A new study uses a creative structure-based remodeling strategy to design a therapeutic protein that exhibits significant advantages over currently available treatments for a rare disease that often leads to cardiac and renal failure. The research, published by Cell Press on October 22nd in the American Journal of Human Genetics, describes a new and highly promising candidate for enzyme replacement therapy (ERT) for Fabry disease.

Fabry disease is a rare genetic disorder caused by a deficiency in alpha-galactosidase-A (GLA), an enzyme that breaks down fatty substances called glycolipids. Without the proper level of enzyme activity, a glycolipid called globotriaosylceramide (Gb3) accumulates to harmful levels inside cellular structures called lysosomes and damages the skin, nerves, eyes, kidneys and cardiovascular system. Although scientists have generated GLA for ERT, thus far this approach has proved challenging.

"Many patients have been successfully treated with these manufactured GLA proteins, but there are still problems to be resolved," explains senior study author Dr. Hitoshi Sakuraba from Meiji Pharmaceutical University in Tokyo. "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."

Dr. Sakuraba and colleagues took a different approach and, instead of making recombinant GLA, attempted to alter a different enzyme, called ?-N-acetylgalactosaminidase (NAGA), so that it could function like GLA. Normally, NAGA catalyses the hydrolysis of a different type of substrate and does not recognize the same substrates as GLA. Importantly, although NAGA is structurally similar to GLA, it does not react with the immune system in the same way.

The researchers examined the structures of GLA and NAGA and predicted how to alter NAGA so that it would recognize GLA substrates. Because the overall structure of NAGA was not changed, it was not expected to cause an allergic reaction in Fabry patients. The modified NAGA was found to be more stable than recombinant GLA and exhibited characteristics necessary for efficient incorporation into cells.

"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," explains Dr. Sakuraba. The modified NAGA was successfully incorporated into the liver, kidneys and the heart and there was a decrease in Gb3 accumulation in these organs.

"The enzyme has many advantages because of it 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," concludes Dr. Sakuraba. "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."
-end-
The researchers include Youichi Tajima, Meiji Pharmaceutical University, Tokyo, Japan, The Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, Tokyo, Japan; Ikuo Kawashima, Meiji Pharmaceutical University, Tokyo, Japan, The Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, Tokyo, Japan; Takahiro Tsukimura, Meiji Pharmaceutical University, Tokyo, Japan, The Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, Tokyo, Japan; Kanako Sugawara, Meiji Pharmaceutical University, Tokyo, Japan; Mayuko Kuroda, Meiji Pharmaceutical University, Tokyo, Japan; Toshihiro Suzuki, Meiji Pharmaceutical University, Tokyo, Japan; Tadayasu Togawa, Meiji Pharmaceutical University, Tokyo, Japan; Yasunori Chiba, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan; Yoshifumi Jigami, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan; Kazuki Ohno, NPO for the Promotion of Research on Intellectual Property Tokyo, Tokyo, Japan; Tomoko Fukushige, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan; Takuro Kanekura, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan; Kohji Itoh, The University of Tokushima, Tokushima, Japan; Toya Ohashi, Institute of DNA Medicine, The Jikei University School of Medicine, Tokyo, Japan; and Hitoshi Sakuraba1, Meiji Pharmaceutical University, Tokyo, Japan.

Cell Press

Related Enzyme Articles from Brightsurf:

Repairing the photosynthetic enzyme Rubisco
Researchers at the Max Planck Institute of Biochemistry decipher the molecular mechanism of Rubisco Activase

Oldest enzyme in cellular respiration isolated
Researchers from Goethe University have found what is perhaps the oldest enzyme in cellular respiration.

UQ researchers solve a 50-year-old enzyme mystery
Advanced herbicides and treatments for infection may result from the unravelling of a 50-year-old mystery by University of Queensland researchers.

Overactive enzyme causes hereditary hypertension
After more than 40 years, several teams at the MDC and ECRC have now made a breakthrough discovery with the help of two animal models: they have proven that an altered gene encoding the enzyme PDE3A causes an inherited form of high blood pressure.

Triggered by light, a novel way to switch on an enzyme
In living cells, enzymes drive biochemical metabolic processes. It is this very ability which allows them to be used as catalysts in biotechnology, for example to create chemical products such as pharmaceutics.

A 'corset' for the enzyme structure
The structure of enzymes determines how they control vital processes such as digestion or immune response.

Could inhibiting the DPP4 enzyme help treat coronavirus?
Researchers and clinicians are scrambling to find ways to combat COVID-19, including new therapeutics and eventually a vaccine.

Bacterial enzyme could become a new target for antibiotics
Scientists discover the structure of an enzyme, found in the human gut, that breaks down a component of collagen.

Chemists create new artificial enzyme
Rajeev Prabhakar, a computational chemist at the University of Miami, and his collaborators at the University of Michigan have created a novel, synthetic, three-stranded molecule that functions just like a natural metalloenzyme, or an enzyme that contains metal ions.

First artificial enzyme created with two non-biological groups
Scientists at the University of Groningen turned a non-enzymatic protein into a new, artificial enzyme by adding two abiological catalytic components: an unnatural amino acid and a catalytic copper complex.

Read More: Enzyme News and Enzyme Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.