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Polish Drug for Sanfilippo Syndrome
June 2, 2010   
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A team of researchers led by Prof. Grzegorz Węgrzyn at the University of Gdańsk’s Department of Molecular Biology have developed the world’s first drug to treat Sanfilippo syndrome, a genetic disease that was incurable until now.

Sanfilippo syndrome usually affects children, who most often die before they reach adulthood. Although research on a cure for the disease has been conducted in several countries, all attempts at slowing down—not to mention curing—the disease failed.

The new drug developed by the Gdańsk researchers not only arrests the progress of the syndrome, but reverses some of the damage. The results of pilot clinical trials are extremely promising, according to the researchers, because children who for years had no contact with the world around them are now able to move again and walk and eat without help. The final phase of the clinical trials has begun and if the results are satisfactory, the drug may be submitted for government approval, says Węgrzyn.

Genetic disease

Sanfilippo syndrome is a rare genetic disorder that is classified into the mucopolysaccharidosis group of diseases (MPS). It is named after American physician Sylvester Sanfilippo, who first described it in 1963. All types of MPS are caused by mutations that cause the absence or radical deficiency of enzymes which break down the class of polysaccharides known as mucopolysaccharides, or glycosaminoglycans (GAG), the latter being a more frequent term recently. GAG should be normally broken down in cell organelles called lysosomes, but the process does not occur in Sanfilippo patients. As a result, GAG builds up in cells and the extracellular matrix in the form of a deposit. Since GAG is produced in practically all body tissues, the deposits gradually damage all organs.

Depending on which enzyme is missing, a total of 11 types and subtypes of MPS are distinguished. All are chronic and progressive conditions that in most cases attack many tissues and organs at the same time, including the heart, the respiratory system, bones and joints. Sanfilippo syndrome, or MPS type III, mainly affects the central nervous system, that is the brain and its functions. Infants born with the condition do not exhibit any symptoms and they develop normally at first. At some point, however, their mental development starts slowing down and then mental regression sets in along with hyperactivity. The children forget what they have learned. They can hardly sleep and keep running around. When signals from the brain become weaker, the children stop talking and responding to stimuli. Eventually, brain impulses stop reaching organs altogether and the body ceases to perform such basic functions as breathing and swallowing. Most patients die before they reach adulthood.

Breaking through the “blood-brain” barrier

Prior to the discovery made by the Polish researchers, medicine had nothing to offer to Sanfilippo patients other than palliative care. Until not so long ago, no treatment was available for any type of MPS. At present, it is possible to help people who suffer from MPS type I and VI and, since very recently, MPS type II using enzyme replacement therapy whereby patients obtain intravenous infusions containing the enzyme missing from their system. The enzyme is made of recombinant human protein obtained through genetic engineering and biotechnological processes. However, this method does not work in Sanfilippo patients, because enzymes injected intravenously are incapable of crossing what is known as the “blood-brain” barrier.

“The brain has a natural protective barrier to separate it from all kinds of infections,” says Węgrzyn. “It is impenetrable to microbes and harmful substances, but also to some drugs. Sanfilippo syndrome is a neurodegenerative disease with pathological changes taking place primarily in the brain. We thus had to consider a different approach. If you can’t cause GAG deposits to disintegrate, then perhaps the solution could be to restrain the rate at which they grow.”

In their method, the Gdańsk researchers tried to use therapy targeted at the expression of genes. Children with MPS III lack one of four specific enzymes that are necessary to break down a GAG compound called heparan sulfate. When not broken down, the compound is stored inside cells and causes progressive damage. The researchers from Węgrzyn’s team resolved to find a way to inhibit the efficiency of heparan sulfate synthesis to make cells produce it at a much slower rate so that it would not build up in such large quantities.

“We set out to find a substance to curb GAG synthesis and thus balance the decomposition of GAG compounds in patients’ bodies,” said Węgrzyn. “We wanted to obtain a state similar to what happened in healthy systems where the levels of GAG synthesis are high, yet counterbalanced by fast degradation. We thus focused on regulating the expression of genes which encoded enzymes necessary to synthesize GAG. We started the research in 2004 and after many trials, in the following year we found a substance that inhibited the expression of genes responsible for GAG production.”

The substance in question is genistein, found in, for example, soybeans. It can also be produced synthetically. When genistein was introduced into cell cultures, the amount of GAG decreased following incubation and the cells started recovering. Biochemical and cytological evidence in the form of electron microscope images confirmed that genistein, a compound capable of crossing the “blood-brain” barrier, could decrease the efficiency of GAG synthesis in fibroblast cell cultures.

First patients, first success

There is a long way from successful laboratory tests to the day when a drug is put on the market, Węgrzyn says. First, the new drug has to be tested on animals and then undergo several phases of clinical trials. The process usually takes several years, but that is usually far too long for a child suffering from MPS III. The order was consequently reversed for genistein.

“We started tests on children long before we launched experiments on animals, mice in this case,” Węgrzyn says. “We were able do so after the bioethics commission gave us the go-ahead in 2006 to experimentally administer the medication during clinical trials. What helped us get the permission was that genistein was obtained from soybeans and those had been repeatedly tested before and were thus considered safe.”

In this way, only a few months passed between the time the genistein preparation was developed in 2006 and the day the first patients received it. The first pilot clinical trials were conducted back in 2006 on a group of 10 children with Sanfilippo syndrome. In all, there are 50 or so such children in Poland. The tests were coordinated by Prof. Anna Tylki-Szymańska from the Children’s Health Center in Warsaw, who worked with Dr. Anna Liberek from the Medical University of Gdańsk. The trials showed the medication was indeed working. Not only did it arrest the progress of MPS in many cases, but it even caused some health parameters to improve.

Taken statistically, the patients’ condition improved considerably. Węgrzyn tells about a 13-year-old girl who for many years just lay in bed unable to make any movement and had no contact with the world around her. After two years of genistein therapy, the girl can smile at her parents, eat meals without help, and do exercises with her mother, Węgrzyn says. “This is a tremendous success, because until now nobody managed to undo the damage Sanfilippo syndrome does to the brain,” he adds.

Rare disorder, expensive medication

The international research community learned about the success of the Węgrzyn team from Węgrzyn’s speeches at scientific conferences and from publications. The first one was printed in the European Journal of Human Genetics in 2006. The discovery met with huge interest, but in order to prove the therapy was indeed efficient, further clinical trials were necessary, including so-called double-blind trials.

This was when the researchers encountered an entirely new non-medical problem, that of funding. While basic research on cell cultures can be co-financed from government grants, for instance, or with money from foundations, clinical trials cannot. The laboratory tests of genistein were financed by the Polish Ministry of Science and Higher Education, the British Society for Mucopolysaccharide Diseases, Daniel’s Sanfilippo Fund of Switzerland, the Polish Association of People with Mucopolysaccharide and Rare Diseases, and the Foundation for Polish Science.

The clinical trials were financed using funds from the University of Gdańsk. The university could afford that because the group of patients covered by the tests was small and the company which produced the genistein preparation for the tests provided it free of charge.

Generally, experts say, it is common practice around the world for pharmaceutical companies to sponsor clinical trials because pharmaceutical companies derive profits from marketing a drug after it is officially registered for use. So far, however, for economic reasons, no pharmaceutical company in Poland or abroad has done anything to have the Sanfilippo syndrome drug registered. This is because Sanfilippo syndrome is a rare disease that affects no more than 3,000 to 4,000 people worldwide. Consequently, a drug for MPS III would have to be extremely expensive to make sure the high costs of clinical trials pay back for the producer. What is more, genistein is naturally found in some plants and so it cannot be patented, experts says. Patent protection can only apply to the utilization of genistein in the treatment of MPS III, which consequently cannot prevent other producers from obtaining the substance as well. That could lead to a situation where one pharmaceutical company puts in a lot of effort and money for research and trials and develops an expensive drug, and then other companies are free to produce genistein fast and cheaply without incurring any costs, Węgrzyn says. Of course, other companies would not officially call it a “cure for Sanfilippo syndrome,” but it would be clear that it is the same substance.

Trials in the Netherlands

In the absence of a pharmaceutical company willing to finance the trials, the researchers had to find another way around the problem. Thanks to contacts abroad, they managed to launch the final clinical trial phase together with an academic center in the Netherlands that raised the necessary funds. In June 2009, the University Hospital in Amsterdam started double-blind and placebo-controlled trials that are scheduled to last 13 months. The subsequent data analysis will take several more months. The Gdańsk researchers helped plan the tests and will analyze some of the samples.

If the results of the trials are satisfactory, Polish company Biofarm in Poznań will be able to register the medication as a Sanfilippo syndrome drug. Biofarm produced the medication for the pilot trials at the Children’s Health Center and has also provided it, along with the placebo, for the trials in the Netherlands. If things go according to plan, the Polish remedy for MPS III could be out on the market by the end of this year, experts say.

New research, new hope

Meanwhile, Węgrzyn and his team are working to improve the drug and the treatment method. “We are testing genistein derivatives that could prove to be even more efficient,” Węgrzyn says. “We are trying different doses and different compounds to curb GAG synthesis. Besides, treatment methods have yet to be developed for other types of MPS and other neurodegenerative diseases that could be treated in a similar way. We recently obtained a research grant to finance the project, which is scheduled to continue until 2013. We hope to be able to arrest the progress of at least some neurodegenerative disorders.”
Ewa Dereń

Factfile
Prof. Grzegorz Węgrzyn aged 47, is one of Poland’s leading molecular biologists. Most of his research concerns the replication of genetic material, regulation of gene expression, human genetics and the mechanisms of genetic diseases. Węgrzyn has also detected a mechanism for the inheritance of the replication complex, or a complex of proteins that replicate DNA helixes in cells.

Węgrzyn graduated from the Faculty of Biology, Geography and Marine Science at the University of Gdańsk. At the university, he obtained his doctoral (1991) and post-doctoral degrees (1995) and became a professor in 1998 at the age of 35. In 1996, he took over as head of the Department of Molecular Biology and subsequently became dean of the Faculty of Biology, Geography and Marine Science (2002-2008). Since 2008, he has been vice-president for research at the University of Gdańsk.

Węgrzyn served two long-term secondments at the Department of Biochemistry of the University of Nottingham Medical School in Britain and at the University of California’s Center for Molecular Genetics in San Diego. He works with scientists from many research centers, including the Max Planck Institute for Molecular Genetics (Germany), the University of Sheffield (UK), the University of California, San Diego (USA), the State University New York in Buffalo (USA), the University of Michigan, Ann Arbor (USA), the Stockholm University of Technology (Sweden), the University in Oulu (Finland), the E.-M.-Arndt University of Greifswald (Germany), and the Royal Manchester Children’s Hospital (Britain).

Węgrzyn has written and co-written 246 research papers, most of which have been printed in international, peer-reviewed science journals. He has also authored a textbook and contributed to an international patent. He works as an editor with international science journals including FEMS Microbiology Reviews, Plasmid, and Microbial Cell Factories.
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