Lymphovenous Canada: A Canadian in Washington - The Genetics of Rare Diseases Conference

The timing of The Genetics of Rare Diseases, Window to Common Disorders conference in Washington, D.C. (sponsored by the National Disease Research Interchange (NDRI), the National Institutes of Health (NIH), and the Office of Rare Diseases) on March 25 - just days after the war in Iraq was declared - could have been better.

But only a handful of delegates of rare disease and genetic research bodies stayed away at such an auspicious time: 50 years after the discovery of the double helix as scientists completed the sequencing the human genome and 20 years after the enactment of the U.S.'s Orphan Drug Act.

The conference included representatives from Canada's Hospital for Sick Children, which has been a leader in disease related work to decode the human genome. Indeed two weeks after the conference, the media was awash with news of their work in completing the DNA sequence of the human chromosome 7 of the human genome which is associated with such diseases as cystic fibrosis, leukemia and autism.

The research, which involved an international collaboration of 90 scientists from 10 countries, also discovered sites along the chromosome where invading viruses integrate, "fragile" regions prone to breakage, areas called "gene jungles" and "gene deserts", as well as primate-specific genes. For more information on this discovery see the Chromosome 7 web site at: www.chr7.org

Speakers at many of the round tables returned to the dominating theme/revelation of the conference: as genetic research proceeds it is becoming increasing apparent that genetic disorders associated with rare diseases may be related to more common diseases or disorders of our bodies. Thus, treatments for malfunction of systems affecting rare disorders may ultimately be used in more common conditions.

Why should the genetics of rare diseases be of interest to people with lymphedema? Lymphedema is both a rare disease - for those who are born with it - and a common disease for the vast majority of people with secondary lymphedema who acquire it as a result of treatment for breast cancer or other causes.

Most current genetic treatments have focussed on rare diseases which involve one gene. One such example has been the use of a genetically-engineered virus (retrovirus) to treat "bubble boy disease" where boys with fragile immunity systems are required to live in sterile bubbles.

Unlike some rare diseases, however, lymphedema is not a single gene disease. A number of genes are associated with lymphedema. The existence of more than one gene responsible for the same condition is called genetic heterogeneity. An understanding of how these genes work will not only help us understand the specific lymphedema related disorder they are associated with, but also how the lymphatic system generally works.

The FOXC2 gene

University of Michigan scientists and their colleagues at the University of Arizona have identified genetic mutations that can lead to a serious medical condition known as hereditary lymphedema-distichiasis or LD. Discovering the gene is the first step toward a future diagnostic test for LD and a fuller understanding of its impact on early development of the heart and lymphatic system.

The mutations responsible for LD are located in the FOXC2 gene on chromosome 16. FOXC2 genes are part of the forkhead/winged helix family which serve as master control switches that regulate the activity of other genes. People with the mutated FOXC2 gene often develop severe lymphedema, or fluid retention in their arms and legs. They also have double rows of eyelashes, a condition known as distichiasis. Some members of LD families have other complications - including heart defects, spinal abnormalities and cleft palate.

VEGFR-3 and VEGF-D receptors

As with other organs, the development of the lymph system is tightly regulated. One protein involved in the process is VEGF-C, which binds to its receptor, VEGFR3, on the surface of cells lining lymph vessels. This cell receptor is critical for the growth of lymph vessels that are responsible for draining tissues of extracellular fluid. VEGFR3 changes shape and triggers events within a cell that lead to the development of the lymph system.

Scientists at the University of Pittsburgh have found that people with hereditary lymphedema produce an abnormal version of VEGFR3 that fails to trip the sequence of events leading to normal development. These investigators believe that variations in the VEGFR3 gene that are commonly found in the general population may increase the risk of developing secondary lymphedema. Scientists at the University of Pittsburgh believe that other genes are responsible for lymphedema and continue to do further research in this area.

Researchers from Finland, Australia and Germany report that VEGFR3 promotes the growth of lymphatic vessels and enhance the metastatic spread of cancer cells in tumors.

Investigators at the Royal Melbourne Hospital in Victoria, Australia have found that VEGF-D expression is required for the growth and establishment of lymphatic vessels in the tumor mass. Moreover, VEGF-D-expressing tumors developed metastasis to local lymph nodes in 14 of 23 animals, whereas tumors without VEGF-D metastasized in none of 30 animals.

Drug therapy in the treatment of rare disorders - The U.S. Orphan Drug Act

One of the most positive impacts of genetic research has been the improved use and development of existing drugs and biological products. Speakers at the conference spent much of the conference talking about what could be done in the U.S. to create better conditions for drug research for rare disorders. Participants discussed greater sharing of genetic and basic research between academic institutions and drug companies as well as making more dollars available for basic and applied research into drug products for rare disorders.

Despite incentives provided by the U.S. Orphan Drug Act (ODA) to fund research into drugs for rare disorders such as: tax credits for clinical investigation expenses; 7 years of marketing exclusitivity for an orphan-designated drug or biological product with FDA approval; and the award of grant funding for early phase one research, participants from all sectors agreed that these measures needed to be enhanced.

238 drug orphan designated products have been released since the program came into being in 1983 to encourage drug companies to do research into products without a large market, but the cost of drug development related to the small number of patients remains a problem, even though many orphan drugs have ultimately been used for common disorders.

For Canadians like Maureen Gatz-Faubert, founder of the Canadian Organization for Rare Diseases (CORD), the U.S. Orphan Drug legislation, for all its flaws, is better than no legislation at all - which is the case in Canada. Indeed, the European Union, Japan, Singapore and Australia all have orphan drug legislation to encourage drug companies to do research and development into treatments for rare disorders. (see http://www.cord.ca/ for more information about CORD)

Orphan drugs developed in the United States aren't always available in Canada, and when they are Canadians often have to pay very high prices for them. (see: Rare Diseases' Troubling Questions by Andrew Duffy, Ottawa Citizen, January 21, 2002).

But with the potential for orphan drugs to be used in a targeted way on common disorders that may have genetic links with rare disorders, there may be more incentives for drug companies to do research in this area in the future.

Panelists talked about how to deal with the coming genetic avalanche

The final round table of the day focussed on social issues and rare disease science. To their credit, the National Institutes of Health and the National Center for Human Genome Research in the U.S. have proactively held a number of conferences and forums to encourage researchers to address the difficult ethical issues related to genetic research.

Speakers of the Social Issues Round Table at the Genetics and Rare Diseases conference

Speakers at this round table included representatives of drug companies, the Genetic Alliance, a consumer organization dedicated to protecting the genetic rights of individuals in this rapidly changing environment, a consumer personally affected by a rare disorder and the father of a two children with a fatal rare disease, continued this tradition of dialogue and debate.

Everyone agreed that the issues are complex and there are no easy answers. The path is not clear but we must take advantage of this opportunity to advance the health of society. The NIH has taken the high road by attempting to strike a balance between public safety and the contribution that these discoveries can make in the lives of people with no options.

• Francis Collins, chair and director of the National Human Genome Research Institute, urged participants to be electrified by "these grand challenges" and not to be defeated by them.
• Thomas Murray, president of the Hastings Center and adjunct professor of bioethics at University School for Medicine in Cleveland, Ohio suggested that simplistic views of genetics by the public are one of the greatest dangers.
• Brad Margus, CEO of Perlegen Sciences and the father of two small sons with Ataxia-Telangiectasia, so far an untreatable and lethal disorder, spoke emotionally of his mission to raise money to fund research into this rare disorder.
• Sharon Fontaine-Terry of the Genetic Alliance pointed out that while privacy cannot be always be assured in our society, confidentiality can be protected in the midst of genetic research and treatments. She noted that informed consumers are better able to participate in research and raised concerns related to access, availability and affordability. Fontaine-Terry asked: if common diseases become rare, will the disparities in our society become more evident?
• Finally, decrying the dangers of genetic discrimination and complimenting President George Bush for his promise to introduce legislation to prohibit genetic discrimination, Paul Miller, an articulate lawyer and commissioner with the Equal Opportunity Commission - and a person of small stature - made a startling observation: rare diseases can be stigmatizing but as we discover the connection between rare diseases and common disorders through genetic mapping our society may better understand that we all have the potential for disabilities. Perhaps people with disabilities will no longer be thought of as the other. An interesting thought.

For information on the conference visit the National Disease Research Interchange at: http://www.ndriresource.org/