Chen Yuan-tsong--Developing a Treatment for Pompe Disease

Once Myozyme was approved for sale, more than 100 related news reports appeared in the US and European media. In early May, after the Academia Sinica held a press conference to announce this notable achievement, Taiwan's local media also provided widespread coverage, turning Chen Yuan-tsong into a household name overnight.

In fact, it was not the first time that Chen had attracted notice in Taiwan. Last year, the research team he leads located a genetic marker and thus the means to screen for Stevens-Johnson Syndrome (SJS), a severe allergic reaction to anti-epilepsy drugs that is also the most common type of acute allergic reaction to medication in Taiwan, accounting for 20-25% of the total. SJS leads to ulceration of the skin and mucous membrane, and sometimes even death. This breakthrough gained considerable coverage in the local media.

Chen's outstanding accomplishments in saving patients' lives also led to his receiving an Outstanding Pharmaceutical Science and Technology Award in the Lee Tian-De Medical and Pharmaceutical Science and Technology Awards sponsored by Yung Shin Pharmaceutical (YSP), Taiwan's largest drug company.

"Last month YSP's founder Lee Tian-de died suddenly of a heart attack," laments Chen, pointing to the medal Lee presented him, which he keeps in his office. That prize further impressed upon Chen the great responsibility that he shoulders.

Chen Yuan-tsong and the first child with Pompe disease to participate in human trials of the treatment. This young American boy is now attending kindergarten.

A love of research

Lanky, soft-spoken and slightly shy in manner, Chen was born to a family of doctors. His father is well-known National Taiwan University Hospital pediatrician Chen Chiung-lin.

After graduating from National Taiwan University's College of Medicine, Chen pursued advanced studies at Columbia University in the US, doing research in human genetics. After completing his studies, he became an assistant professor at Duke University, as well as practising as a physician at a medical center. At the same time, he began research on Pompe disease, an ailment whose effective treatment had long eluded medical science.

"I never imagined I would be doing this research for so long," relates Chen. He admits that while he understood the etiology of Pompe disease, which is caused by a defect in a single gene, he believed it would take only seven or eight years to find an effective treatment. Unexpectedly, the struggle extended over 15 years before he finally discovered a drug that could save the lives of the childhood victims of Pompe disease.

Pompe disease is caused by a defect in a gene on chromosome 17. Because of this defect, victims lack an enzyme for metabolizing glycogen, resulting in its accumulation in the skeletal muscles and heart. The muscle fibers are replaced by glycogen, resulting in a loss of muscular function and swelling of the heart. In addition, symptoms such as loss of muscle strength and breathing difficulties gradually appear. Ninety percent of afflicted infants do not survive to their first birthday, dying from respiratory failure or infection.

A rare ailment, Pompe disease afflicts about one out of every 40,000 infants. With 200,000 babies born last year in Taiwan, it is estimated that five or so had Pompe disease. Prior to the discovery of a treatment, once the disease was diagnosed, there was nothing anyone could do but watch the child move day by day toward death.

For Chen Yuan-tsong, the inventor of the first drug for treating Pompe disease, the 15 years of its development were long and arduous.

The key to a cell

More than 30 years ago, attempts were made to compensate for the body's lack of the critical enzyme by injecting it. However, after being introduced into the body, the enzyme only remained in the bloodstream, unable to penetrate into cells, and consequently the therapeutic effect was negligible.

From the 1970s through the 1980s, advances were made in medical technology that enabled the enzyme to penetrate into cells. However, because each type of cell had its own specific "key" for allowing entry, only liver and spleen cells could be effectively penetrated, while the main therapeutic targets--muscle and heart tissue cells--remained impervious.

Chen was the first person to successfully deliver the enzyme into skeletal muscle and heart tissue cells. The key to his success was his discovery of the "key" for entering the cells of these tissues.

The so-called "key" refers to a carbohydrate that binds to the protein, and unlocks a figurative "door" that allows entry into the muscle cells. The peculiar thing was that this carbohydrate would disappear as soon as it entered the cell along with the enzyme. For a long time, researchers were thus unable to locate this chemical key.

After three years of observation and tests, Chen's research team at Duke finally found the chemical key for entering muscle cells. Even after finding it however, the problem of how to produce the substance remained. After various experiments on E. coli, yeast, and fruit fly cells, they still could not produce the enzyme with the carbohydrate attached. Finally, they succeeded in isolating enzyme with the bound carbohydrate from a nutrient medium in which hamster cells had been cultivated. After purification, the enzyme could be injected into the body and penetrate skeletal muscle and heart tissue cells, enabling the breakdown of glycogen in infants with Pompe disease.

Hamsters cells in a nutrient medium secrete enzyme with the special marker.

A sick bird takes flight

Hamsters played a pivotal role in Chen's development of an enzyme with the carbohydrate key bound to it, while quails were crucial to verifying that the enzyme was indeed effective.

Chen explains that cows, quails and humans are all afflicted by Pompe disease. However, with the amount of medication available for testing quite limited, he selected quails for use in animal experiments because of their small body size and the lower dosages they would need for testing.

Quite fortuitously, Chen then learned that a quail with Pompe disease had been discovered in Japan. He immediately sent the enzyme his team had just developed from the US to Japan for testing.

Not long thereafter, Chen received a call from a Japanese colleague, who said there was one piece of bad news and one of good, asking which he wanted to hear first.

"I was thinking that it's better to deal with problems sooner than later, so I asked to hear the bad news first," says Chen. Such a choice fits in rather well with Chen's usual cautious approach.

The colleague informed Chen that the bad news was that the quail under testing had disappeared. The good news was that after treatment with the enzyme, the ailing bird, which had previously been unable to stand and was struggling to breathe, had unexpectedly gotten up and flown off!

Only after testing in quails had shown that the enzyme Chen developed was indeed effective and did not cause adverse side effects could the final challenge of human testing begin.

Pompe disease is a rare ailment, and large pharmaceutical companies have little interest in developing so-called "orphan drugs" for what would be a small market. It was not until 1997 that Chen, with the help of Andrew Huang, currently president of the Koo Foundation Sun Yat-Sen Cancer Center, obtained grants from Synpac, a UK pharmaceutical company in which the Koos Group had invested, to perform the first phase of human trials.

However, the initial human trials did not go smoothly. Because the infants in the trials were extremely weak, a minor cold or damage to esophageal muscle leading to difficulty in swallowing could cause the child to choke on milk, leading to pneumonia or even death. In some cases, treatment proved futile because the medication was administered too late, and the body's muscular tissue had already been irreversibly damaged.

Additionally, Synpac, the drug company supporting the trials, was geared toward small experimental production volumes, with quite limited production capacity. When the time came to expand clinical trials and begin mass production, it had a hard time meeting requirements.

In 2000, Synpac transferred its license to the large American pharmaceutical firm Genzyme. In September 2001, at the urging of Academia Sinica president Lee Yuan-tseh, Chen, who was at the time chief of the Division of Medical Genetics in the Department of Pediatrics at the Duke University Medical Center, returned to Taiwan to take the position of director of the Institute of Biomedical Sciences at Academia Sinica.

Not long after Chen returned to Taiwan, the second phase of clinical trials for Myozyme began. He invited the medical team of Hu Wu-liang, a physician in the pediatrics and genetic medicine departments at National Taiwan University, to join international clinical trials that included participation by nine medical centers in the US and Europe.

Chen received the conclusion from the second-phase trials: "Early diagnosis and treatment are the keys to success." He points out that if treatment is begun in within three months of a baby's birth, and medication is administered twice a month, most of the children can reach adulthood normally.

An unbearable risk

Now that the new medication has arrived, in the midst of the congratulations he has received, Chen cannot conceal his regrets. "It's really a pity for Taiwan," he says, explaining that Myozyme was originally licensed to Synpac of the UK. However, after the first phase of human trials, Synpac decided not to continue making investments, and transferred its license to Genzyme, relinquishing the opportunity to make a name for itself and win markets just when these achievements were within reach.

Examining the reasons, it is apparent that developing and manufacturing a new drug requires substantial investment. There is no assurance of success during the human trials phase. In addition, because Taiwan's drug companies are small, they are much less willing to risk large investments than are big multinational pharmaceutical firms.

Although The Wall Street Journal estimated that there was a global market worth US$1 billion for Myozyme, Chen believes that in the short term such a market scale is unlikely. That is because "a vast majority of affected children have already died." Looking to the future, the number of surviving patients with Pompe disease will continously increase, and they will require medication throughout their lives. Gaucher disease, a condition that also results from a genetic mutation, and that like Pompe disease compels a lifetime of enzyme supplements, can serve as an example of what Pompe disease patients will face. People with Gaucher disease require more than NT$6 million for medication annually, allowing pharmaceutical firms to recover their initial outlays within a few years without difficulty.

While it's unfortunate that Taiwan yielded manufacturing rights, even more worthy of attention is the state of Taiwan's biomedical R&D capabilities. If he had been in Taiwan, would Chen have had the chance to develop a treatment for Pompe disease? In other words, does Taiwan provide an adequate environment for developing new drugs?

The muscles of quails with Pompe disease are flaccid and weak (left), but after receiving treatment with Myozyme, vigor is clearly restored.

An impossible mission

On this question of concern to people in Taiwan, Chen says that while 15 years ago it might have been impossible, Taiwan now possesses sufficient sophistication in the biomedical field to develop new drugs. However, the key is that there is a long road that must be traversed from successful development to introduction on the mass market. So unless a total commitment exists, the effort is wasted.

The main obstacles are the numerous restrictions on human trials that currently exist in the laws governing medicines. Human trials are an unavoidable step in the process of bringing a new drug to market. After a drug has passed animal trials, but before human trials commence, an application must be made to the Center for Drug Evaluation (CDE). However, there is an unwritten rule in Taiwan that drugs that have been certified for use in humans by the US Food and Drug Administration will be quickly approved by the CDE, upon which the Department of Health's Bureau of Pharmaceutical Affairs will grant approval for human trials. If such an "endorsement" does not exist, the CDE will examine the effectiveness, risks, ethics and other factors of human trials, expending much time in the process.

At a press conference launching Myozyme in early May, Academia Sinica president Lee Yuan-tseh stated that while in the past Taiwan lacked the ability to develop new drugs, dictating that it rely on foreign certification, the capabilities of the country's academic institutions and industry have already improved to the point that the government's regulatory system needs to be adjusted.

In addition, current medical laws specify that as well as civil liability, doctors face the possibility of criminal prosecution in cases of dispute over medical treatment. For human trials of new drugs, whose results are difficult to predict, such laws undoubtedly present a formidable risk to the physician. If the treatment should happen to fail, the patient can sue, and the doctor faces the possibility of not only having to pay out compensation, but even spending time in prison.

Under such unfavorable circumstances, it is understandable that Taiwan's physicians are reluctant to cooperate with R&D teams and perform human trials. This situation has greatly hindered the development of biomedical technology in Taiwan.

Goal: gene therapy

After the successful development of a treatment for the once-untreatable Pompe disease, National Taiwan University Hospital has led the way in screening newborns for Pompe disease.

Chen points out that recently Dr. Hu Wu-liang of NTUH has discovered two babies with Pompe disease was discovered using this screening process. Fortunately, on the 20th day after birth, both children began to receive treatment so that the adverse effects of the disease could be minimized.

Chen's part of the work in developing a treatment for Pompe disease is complete, yet the final objective has not been reached. He points out that though a drug to treat patients now exists, they must still continue their treatment for their entire lives. Even if Taiwan's National Health Insurance scheme currently covers part of the cost, the time and monetary burdens on patients and their families are still formidable. The only hope for eliminating this burden is developing a workable gene therapy in the future.

Like research on gene therapies for other diseases, research for such a treatment for Pompe disease faces the twin dilemmas of short persistence times and poor therapeutic effectiveness after genes are introduced into the patient's body.

"Current animal experiments show that healthy genes can be successfully introduced to replace defective genes. The problem is that after outside genes are introduced, they are attacked by the patient's own immune cells, so that their therapeutic effect is maintained for only around six months before weakening and then disappearing," Chen explains, admitting that there is still a long way to go before gene therapy for Pompe disease is available.

Besides its efforts in finding treatments for Pompe disease, the Academia Sinica's Institute of Biomedical Sciences, led by Chen, is also working with universities and medical centers on research programs on diseases caused by non-single-gene defects and affected by environmental factors--including diabetes, bipolar disorder, early-onset hypertension, degenerative arthritis of the hand, and obesity, as well as 12 types of adverse drug reactions. The population affected by these conditions is large and represents an enormous potential market. The diseases themselves are likely to have a lasting impact, and will be the institute's focus over the next few years.

Myozyme is simply a beginning. It heralds the arrival of Taiwan's biomedical technology as a force to be reckoned with, and in the future advances can be anticipated.

Pompe disease

Pompe disease is a rare and serious genetic disorder also known as acid maltase deficiency or glycogen storage disease. Because those afflicted lack an enzyme needed to break down glycogen, an excess accumulates in the body, damaging muscular function throughout the body.

The exact prevalence of Pompe disease is unknown, and racial groups differ in their susceptibility. Roughly one in every 40,000 newborns has Pompe disease.

There are two types of Pompe disease: infantile, and late-onset. Infantile Pompe disease is the more serious, and often fatal. Because the young victims do not have the muscular strength to move normally, they are called "floppy babies".

Late-onset Pompe disease may occur at any time from childhood to old age, and progresses more slowly. The course of the disease in different patients varies widely, with some suffering only muscle weakness, while others need a wheelchair or respirator.

Symptoms of infantile Pompe disease include severe muscle weakness, enlarged heart, swollen tongue, enlarged internal organs, and difficulty in breathing. Death usually occurs within one year after symptoms appear, with the immediate cause being cardiopulmonary failure.

The main symptoms of late-onset Pompe disease are muscle weakness, and difficulty in walking or breathing. Heart function is usually normal.

Future research directions for the Institute of Biomedical Sciences

The primary research focus at the Academia Sinica's Institute of Biomedical Sciences is disease affecting humans, with research conducted by eight teams:
  Cancer
  Cardiovascular
  Infectious Disease and Immunology
  Neuroscience
  Epidemiology and Genetics
  Structural Biology
  Cell Biology and Signal Transduction
  Bioinformatics

The institute's future efforts will be directed toward drawing on the results of many years of accumulated research findings, and coordinating efforts in pathology and genetic research. In the next five years, the institute's genomic medicine research program will focus on three steps:
Screening for new genes and markers for diseases
Determination and analysis of genetic causes of disease
Exploring genes as tools for treating disease