Neurofibromatosis is a genetic disorder of the nervous system that causes tumors to grow on or about the nerves anywhere in the body. It can also affect non-nervous tissue such as bone and skin. This autosomal dominant disorder is found in both sexes and in all ethnic groups. These tumors affect people’s lives through disfigurement, loss of hearing, blindness, bone deformation, and, in some cases, death. Fifty percent of people with neurofibromatosis have learning disabilities. A parent with neurofibromatosis has a 50% chance that expression of the disease will occur in his/her child. Surgical intervention can provide palliative relief; however, at this time there is no cure.

The Department of Defense (DOD) Neurofibromatosis Research Program (NFRP) was established in fiscal year 1996 (FY96) by an $8M Congressional appropriation to promote research directed toward the understanding and treatment of neurofibromatosis.¹ The overall goal of the NFRP is to decrease the impact of neurofibromatosis. Appropriations for the FY96-99 NFRP total $37.3M. Ten awards were made with the FY96 appropriation of $8M. The NFRP funded two projects and three investigator awards in FY97 with an appropriation of $8M and funded nine projects in FY98 with an appropriation of $9.8M. Congress has continued to support the DOD NFRP by appropriating an additional $11.5M in FY99.

In FY96-99, Congress appropriated $37.3M for peer-reviewed neurofibromatosis research. Table B-4 in Appendix B summarizes the directions from Congress for the NFRP appropriations, the program’s withholds and management costs, and the investment strategy executed by the program. Prior to receipt of funds by the office of the Congressionally Directed Medical Research Programs (CDMRP), Congress and the DOD withhold funds for designated initiatives. In addition, the CDMRP sets aside funds for program development, scientific peer review, programmatic review, and the administration of grants/contracts through the entire period of performance up to 7 years (see Appendix B). The investment strategy executed is consistent with Congressional language and reflects the program’s vision.

The vision of the NFRP is to decrease the impact of neurofibromatosis. The program’s mission is to support extramural research directed toward the diagnosis, treatment, and understanding of neurofibromatosis types I and II (NF1 and NF2), as well as enhancing the quality of life for individuals with the disease. Scientific ventures that represent underinvestigated avenues of research or novel applications of existing technologies are highly sought.

——FY96-97 Programs

The Investigator-Initiated Award category was used to sponsor basic and clinical research relevant to neurofibromatosis. Emphasis areas within basic research included studies on the normal functions of NF1 and NF2 proteins, studies investigating how abnormal function or lack of function in these proteins leads to pathogenesis, and delineation of genotype-phenotype correlation. Emphasis areas within clinical research were preclinical/clinical trials of treatments for NF1 and NF2, development of technologies that improve the ability to assess outcomes, studies that improve the ability to diagnose neurofibromatosis and predict prognosis, and development of new modalities for noninvasive diagnosis. Ten Investigator-Initiated Awards were funded with the FY96 appropriation and three were funded with the FY97 appropriation.

Funding for FY97 was used to develop natural history studies of tumor growth in NF1 and NF2 that can be readily translated into clinical trials. Two awards were made to fund natural history studies—one study will produce quantitative data on the growth rates of plexiform neurofibromas in NF1 patients, and a second will produce quantitative data on the growth rates of vestibule schwannomas in NF2 patients.

——FY98 Program

Investigator-Initiated Awards were used in FY98 to sponsor basic research leading to clinical trials relevant to neurofibromatosis that will result in substantial improvements in the understanding, diagnosis, and treatment of neurofibromatosis, and that will enhance the quality of life for persons living with the disease. Emphasis areas within basic research include: cellular and biochemical studies investigating how abnormal functions of NF1 and NF2 lead to pathogenesis; molecular and cellular level studies; and studies of normal, cellular biological functions of NF1 and NF2 proteins in a variety of cell types. Nine Investigator-Initiated Awards were funded with the FY98 appropriations.

——FY99 Program

The programmatic strategy for the FY99 NFRP was implemented by a solicitation in the 4 June 1999 Program Announcement for proposals in four subcategories: Investigator-Initiated Awards, New Investigator Awards, Idea Development Awards, and Clinical Trial Awards. Investigator-Initiated Awards have been used by NFRP in FY96, FY98, and FY99 to sponsor basic research leading to clinical trials. The intent of the New Investigator Award category was to support innovative approaches to neurofibromatosis treatment that may be untested but that are expected to reveal breakthroughs or new avenues of investigation. The intent of the Idea Award category was to give established neurofibromatosis investigators and those established investigators who want to move into the neurofibromatosis field the opportunity to undertake underinvestigated avenues of research using innovative scientific approaches. The intent of the Clinical Trial Awards is to sponsor clinical pharmacologic or gene therapy studies that look at toxicities (Phase 1) or investigate the efficacy (Phase 2) of any novel therapeutic approach for NF1 or NF2.

——FY00 Program Plans

The Joint Conference Committee Report 106-371 specifies $15M for peer-reviewed neurofibromatosis research. Vision setting for the FY00 program will occur in January 2000. At that time, an investment strategy will be developed that takes into account Congressional language, recommendations from scientific and advocacy groups, and gaps in research funding.

——Nested Postdoctoral Traineeships

The NFRP initially offered Investigator-Initiated Awards. Embedded in this award category were nested postdoctoral traineeships. This mechanism was designed to encourage postdoctoral trainees to continue careers in neurofibromatosis research under the mentorship of a principal investigator (PI). The FY98 program also funded Investigator-Initiated Awards with nested postdoctoral traineeships.

——Natural History Studies

In FY97, in an effort to build an infrastructure on which future research could be developed, the NFRP supported natural history studies. This award category developed a consortia of investigators who are collaborating on these studies as well as other research endeavors.

——Clinical Trials

In FY99, Clinical Trial Awards were developed in an effort to encourage preclinical/clinical trials of treatments for NF1 and NF2; development of technologies that improve the ability to assess outcomes; studies that improve the ability to diagnose neurofibromatosis and predict prognosis; and development of new modalities for noninvasive diagnosis.

A total of 24 awards have been made in the FY96-98 NFRP. Two of these awards support large, multidisciplinary consortia. Research funded by this relatively new program is already showing signs of productivity and promise. Several insights into tumor formation, metastatic disease, and animal model development are published in the scientific literature.

——Infrastructure

During FY97, two Natural History Awards were made in an effort to build an infrastructure on which future research could be developed. One award was to Children’s Hospital in Boston, Massachusetts, for a natural history study that will produce quantitative data on growth rates of plexiform neurofibromatosis in NF1 patients. The second award was to the House Ear Institute in Los Angeles, California for a natural history study that will produce quantitative data on growth rates of vestibule schwannomas in NF2 patients. Most of the work regarding standardization of data collection for MRIs; neurophysiological and audiological data; and molecular, pathological, and clinical features for the NF2 study has been completed. Recruitment of the 100 NF2 patients planned for the study is ongoing.

——Training

To support and encourage new investigators working in neurofibromatosis research, the FY96 NFRP implemented nested institutional postdoctoral traineeships. At least 15 postdoctoral trainees have been funded by this program. Six of the nine awards in the FY98 program are for Investigator-Initiated Awards with nested postdoctoral traineeships. The FY99 NFRP is offering New Investigator Awards to bring talented new investigators to the field of neurofibromatosis.

——Scientific Achievements

The following scientific achievement summaries represent a small portion of the NFRP-funded portfolio.

Natural History Studies. NFRP-funded researchers are studying the natural history of neurofibromatosis in the hopes of improving the lives of persons living with this disease and, ultimately, eradicating this disease. For example, researchers at the House Ear Institute in Los Angeles, California are studying the growth rates and clinical course of vestibular schwannomas (i.e., tumors affecting the nerves of the ear) in NF2 affected individuals. All NF2 patients eventually develop vestibular schwannomas, which can lead to deafness and death if untreated. The PI of this study is developing an international consortium of clinical centers and expertise in NF2. From individuals with NF2, the PI is collecting data on (1) the size of the schwannomas, (2) the effects of the schwannomas on patients’ auditory systems, and (3) the molecular and pathological features of the schwannomas that might predict tumor behavior in any particular patient. This study should be helpful to newly diagnosed patients and should lead to a better understanding of the natural history/clinical course of these tumors.

Additionally, researchers at Children’s Hospital in Boston are studying plexiform neurofibromas, which are tumors that grow along the length of nerves and often involve multiple branches of a nerve. In patients with NF1, these tumors cause disfigurement and impaired nerve function and can lead to death. The PI of this study is developing a scheme that will permit the accurate assessment of the size and growth rate of plexiform neurofibromas and developing a consortium of clinical centers with the resources needed to perform clinical trials in the future. Individuals with NF1 and plexiform neurofibromas are being recruited for the study. The PI is imaging tumors at defined intervals and collecting DNA (to analyze tumor mutation) and clinical information from the patients. This study will help elucidate the patterns of neurofibroma growth and lead to the development of centers that can perform clinical trials of potential treatments.

Molecular and Genetic Factors. Several studies funded by the NFRP will examine the molecular and genetic mechanisms underlying neurofibromatosis, with the overall goal of identifying methods to arrest the development and progression of this disease. For example, researchers at the Chicago Association for Research and Education in Science are investigating the role of neurofibromin in human Schwann cells, using modern molecular biological techniques. Neurofibromin is a protein that is presumed to suppress the formation of neurofibromas (the main tumor type found in NF1 patients) and is absent in NF1 individuals. This study should lead to a better understanding of the molecular mechanisms underlying the formation of neurofibromas.

Additionally, researchers at the University of North Carolina at Chapel Hill are attempting to identify inhibitors of the Ras signaling pathway in cells. Ras is a gene that is normally kept in control by proteins encoded by neurofibromatosis genes NF1 and NF2. When NF1 and NF2 are mutated in persons with neurofibromatosis, these genes no longer effectively regulate the Ras gene and cells can become transformed (i.e., malignant). The PI of this study is developing novel compounds that block the Ras pathway and is determining their abilities to inhibit the growth of NF1- and NF2-deficient tumor cells. This study may lead to the development of drugs for the treatment of both NF1- and NF2-deficient tumors.

Researchers at the University of Washington have been studying the NF1 gene in detail in an attempt to find regions on the gene that predispose affected individuals to an early onset and/or large numbers of cutaneous neurofibromas. The PI of the study has determined that patients with facial abnormalities and an early age onset of cutaneous neurofibromas often carry a germline microdeletion of 1-2 Mb in size that spanned an entire NF1 allele. The PI has recently developed an assay that can be used to screen for additional NF1 microdeletions.

Chair, James F. Gusella, Ph.D.: Director, Molecular Neurogenetics Unit, Massachusetts General Hospital; Bullard Professor of Neurogenetics, Harvard Medical School. Has received numerous awards and served on a variety of national committees in the area of neurogenetics, including the Scientific Advisory Board of the National Neurofibromatosis Foundation. Discipline(s): Genetics/Molecular Biology.

Peter Adamson, M.D.: Chief, Division of Clinical Pharmacology and Therapeutics at Children’s Hospital of Philadelphia. Discipline(s): Chemotherapy, Experimental Therapeutics.

Peter R.W. Bellermann: President, National Neurofibromatosis Foundation; Chairman, International Neurofibromatosis Association. Member of the Management Committee of the British Neurofibromatosis Association and advisor to the World Health Organization on ethical, social, economic, and political issues in genetics. Discipline(s): Consumer.

Neal Copeland, Ph.D.: Director, Mammalian Genetics Laboratory, National Cancer Institute, Frederick Cancer Research Center. Discipline(s): Molecular Biology, Genetics.

Kurt Fischbeck, M.D.: Chief, Neurogenetics Branch, National Institutes of Health, National Institute of Neurological Disorders and Strokes. Discipline(s): Molecular Genetics.

Zach Hall, Ph.D.: Vice Chancellor of Research, University of California, San Francisco. Discipline(s): Neurobiology.

Robert F. Murray, Jr., M.D., Ph.D.: Professor and Chairman, Graduate Department of Genetics and Human Genetics, Professor, Pediatrics and Medicine, Chief, Division of Medical Genetics, Department of Pediatrics and Child Health, Howard University College of Medicine. Member, Institute of Medicine, National Academy of Sciences. Discipline(s): Medical Genetics/Bioethics.

David Pleasure, M.D.: Professor of Neurology, Pediatrics, and Orthopaedic Surgery, University of Pennsylvania. Serves as Director of Neurology and Neuroscience Research at Children’s Hospital of Philadelphia. Discipline(s): Neurology.

Allen Rubenstein, M.D.: Director, Mount Sinai Neurofibromatosis Research and Treatment Center, Department of Neurology, Mount Sinai Hospital. Helped co-found the National Neurofibromatosis Foundation, is currently its Medical Director, and serves on the Board of Directors. Discipline(s): Neurogenetics.

Louis-Gilbert Vézina, M.D.: Director of Neuroradiology, Department of Diagnostic Imaging and Radiology, and Medical Director, Pediatric Imaging Center, Children’s National Medical Center, Washington, DC. Discipline(s): Neuroradiology.

Mary Ann Wilson: Chair, Education Committee of Neurofibromatosis, Incorporated. Currently works as Consumer Staff Representative for the Alliance of Genetic Support Groups. Has a grown son with NF1 and was a founder of the neurofibromatosis support group in the Metropolitan Washington, DC area. Discipline(s): Consumer.