Submitted to the United States Senate Appropriations Subcommittee on Labor, Health, And Human Services, Education and Related Agencies.
REGARDING FY12 APPROPRIATIONS FOR THE DEPARTMENT OF HEALTH AND HUMAN SERVICES.
Chairman Tom Harkin, Chairman, and Richard Shelby, Ranking Member, and members of the Subcommittee: the Coalition of Heritable Disorders of Connective Tissue thanks you for the opportunity to submit testimony regarding the FY2012 budget for the National Heart, Lung and Blood Institute (NHLBI), the National Institute of Arthritis, Musculoskeletal and Skin Diseases, (NIAMS), and the NIH Office of Research Information Services/Office of Extramural Research. We are extremely grateful for the Subcommittee's strong support of the NIH, particularly as it relates to life threatening genetic disorders such as Heritable Disorders of Connective Tissue. Thanks to your leadership, we are at a time of unprecedented hope for patients with these diseases.
It is estimated that over one million people in the United States are affected by Heritable Disorders of Connective Tissue (HDCT). These disorders manifest themselves in many areas of the body, including the heart, eyes, skeleton, lungs and blood vessels. Connective tissue is the "glue" that holds the body together. These disorders are progressive conditions caused by genetic mutations and cause deterioration in each of these body systems. The most life-threatening are those which affect the aorta and the heart; the most disabling are orthopedic and ophthalmological.
Some 60 years ago, Victor McKusick, the "father" of modern medical genetics, described and coined the term "heritable disorders of connective tissues." These disorders included over 200 such rare disorders, among which were the Marfan syndrome, Weill-Marchesani syndrome, Ehlers-Danlos syndrome, Cutis Laxa, Osterogenesis imperfecta, the chondrodysplasias, and Pseudoxanthoma elasticum (Heritable Disorders of Connective Tissue, McKusick, Va 1972).
Awareness of these disorders has grown through the years due to collaborative research. Clues to the underlying causes of these diseases were obtained from the major manifestations found in the connective tissue and elaboration of connective tissue pathways involving identified disease genes and their protein products uncovered additional disease genes with related connective tissue manifestations. Identification of disease genes have led to surprising new information regarding important connective tissue pathways depending on the history of the particular disorder. Thus, the concept of the heritable disorders of connective tissue have reiterated and epitomized important lessons regarding how the connective tissue integrates cellular and organ function.
NATIONAL HEART LUNG AND BLOOD INSTITUTE
Thanks to research funded by the NHLBI, we have seen amazing responses to hdct disorders with cardiovascular disease. In the 1960s there was no intervention available, not even surgery for heart defects and dissection, this before the development of the "heart-lung" machine. It was not so long ago, when in the early 1960s, a 13 year old girl with Marfan syndrome was sent home from the hospital to die since there was no surgical intervention possible for her dissecting aneurysm. Early on, surgery required replacing the aortic valve with an animal's heart, further research used a mechanical valve, and then came the sturdy composite graft, which became the "Cadillac" of surgical repair. Although the valve sparing method was used throughout this time, it has been continually improved to address the compromised tissue regarding longevity. Now we are seeing additional "translational" clinical trials, which look at therapies for prevention as well as surgical response. It is important to remember these amazing leaps and bounds in medical, surgical and technological advancement.
NHLBI support has been essential in promoting research collaboration. The Pediatric Heart Network, a cooperative network of pediatric cardiovascular clinical research centers, serves as a data coordinating center to promote the exchange of information to evaluate therapeutic and management strategies for children and adults with congenital and genetic heart defects.
NHLBI funded Clinical Trials in the use of Losarton have led to exciting new findings and pointed the way in future research directions. It has inspired current concepts of architectural and signaling pathways underlying the various heritable disorders of connective tissue in order to integrate these concepts in new productive ways. For example, can the recent advances in treating Marfan syndrome with TGF beta inhibitors and Losarton be applied to other heritable disorders of connective tissue? Does TGF beta signaling play pathological roles in other disorders? For another example, is there an important adhesion junction of architectural pathway that connects the vascular smooth muscle cell to the extracellular matrix? And, again: How do cell surface receptors (integrin and growth factor receptors) coordinate architectural and signaling pathways in connective tissue disorders? All pointing to future research avenues.
NATIONAL INSTITUTE OF ARTHRITIS, MUSCULOSKELETAL AND SKIN DISEASES
The collaboration of NHLBI and NIAMS has provided an even greater overview of the information gleaned from the Losarton clinical trial and a global view of these mult-system disorders. The muscular and orthopedic involvement is being addressed by the NIAMS. Through NIAMS support, there is a meeting in July, which is devoted to "Translational" avenues grown of current research progress in the understanding of heritable disorders of connective tissue. Great progress in the understanding of HDCT has been made over the past 15 years through NIAMS supported workshops on Heritable Disorders of Connective Tissue. Symposia have been convened in 1990, 1995, and 2000. In 1990 and 1995, the emphasis was on finding the genes for the various heritable disorders and understanding whether mutations could be correlated with specific phenotypes. Many of these goals have been met, due to research supported in large part by the NIAMS. In 2000, meeting themes were intentionally broader, focusing on multidisciplinary approaches and common themes in matrix biology in order to (1) promote a better understanding of pathogenesis of connective tissue disorders, (2) stimulate new collaborations between investigators, and (3) identify areas in which rapid progress could be made. In the decade since the 2000 Workshop, tremendous progress has been made, leading notably to new therapies. An example of this is Marfan syndrome, for which a clinical trial is underway to test for a therapy, which may prove to play a pivotal role in preventing heart disease. Epidermolysis bullosa is another disease – for which a research has improved prospects for new therapies, as well as for a number of other heritable disorders of connective tissue.
Research has emphasized an understanding of the role of cells in developing treatments for connective tissue disorders. The success of bone marrow transplantation in treating Epidermolysis Bullosa has called attention to this area. While connective tissue researchers have been interested in stem cell treatments - Osteogenesis imperfecta, for example - more discussion and emphasis in this area are needed.
The impact of this collaboration between these similar disease entities in heritable disorders of connective tissue continues to be of major importance. We are moving rapidly from the "bench to the patient," from basic research to the important translational benefit of research findings to treatments which directly benefit the patient. The collaboration between the basic research and clinical studies is what we are able to focus on in these disorders for the benefit of all disease groups.
NIH / OFFICE OF RESEARCH INFORMATION SERVICES/OFFICE OF EXTRAMURAL RESEARCH - RePorter
The National Institute of Health (NIH) has established the NIH RePorter, or research/condition/disease category (RCDC) which provides easy retrieval of information on scientific projects and studies. This excellent new tool provides information on research results, expediting access and the avoidance of duplication and is located in the Office of Research Information Services/ Office of Extramural Research. It provides access to research information on all disease groups. We urge the inclusion of the category "Heritable Disorders of Connective Tissue" (HDCT) in order to facilitate the exchange of information in the research community of these similar disorders.
What is so important about the study of these disorders is their very complexity – with genetic origins, requiring basic science for understanding, and clinical trials in order to maximize the translational advantages of this research. The mutations of HDCT affect all body systems and require particular depth of investigation. This very complexity informs the researcher, as well as contributes to the understanding of other more common disorders. Research on these disorders in all of the body systems, will "spill" over into research into many of the categories identified in both the short range and the long range strategic plans for NHLBI and NIAMS, and provide benefits for many diseases beyond the scope of HDCT.
ABOUT THE COALITION OF HERITABLE DISORDERS OF CONNECTIVE TISSUE (CHDCT)
The CHDCT is a non-profit voluntary health organization founded in 1989, dedicated to saving lives and improving the quality of life for individuals and families affected by any one of the over 200 Heritable Disorders of Connective Tissue. The mission is to raise awareness of these disabling and often deadly disorders and to support and promote research and collaboration between researchers in the field.
We thank you for this opportunity to thank the Committee for its past support and to voice the interests and concerns of the CHCDT member organizations relating to future priorities of NHLBI and the NIAMS.
For more information please contact:
Co-President, Coalition of Heritable Disorders of Connective Tissue (CHDCT)
Co-President, Coalition of Heritable Disorders of Connective Tissue (CHDCT)
Chair emeritus, National Marfan Foundation (NMF)
CHDCT ORGANIZATIONAL MEMBERSHIP - http://www.chdct.org
Children's Brittle Bone Foundation
Corporation for Menkes Disease (CMD)
Dystrophic Epidermolysis Bullosa Research Asso of America (DebRA)
Ehlers-Danlos National Foundation (EDNF)
Little People of america (LPA)
Loeys Dietz Foundation (LFD)
National Association for Pseufoxanthoma Elasticum (NAPE)
National Marfan Foundation (NMF)
Osteogenesis Imperfecta Foundation (OIF)
PXE International, INC (PXE)
Society for Mitral Valve Prolapse Sydrome (SMVP)
Stickler Involved People (SIP)
Williams Syndrome Association (WSA)