One of the fastest translations of a basic research discovery into a promising clinical trial for an "untreatable" and fatal disorder will be discussed publicly for the first time by the key players in this remarkable research story, on Dec. 14, at the American Society for Cell Biology (ASCB)'s annual meeting in San Francisco.
The disease is Progeria, or Hutchinson-Gilford Progeria Syndrome (HGPS), a rare, accelerated aging disease that afflicts children.
The discovery of the gene responsible for the disease five years ago led scientists to the experimental drug that is now being evaluated in 28 children with this "premature aging" disease.
Speaking at the special ASCB session will be the physician heading the clinical trial, the gene-hunter whose research team pinpointed the DNA mutation, and the cell biologist who conducted the basic research on the protein structures in the cell nucleus that were subsequently found to be abnormal in HGPS.
Also on the panel will be the medical director of the Progeria Research Foundation who is both a scientist and the mother of a child with HGPS.
In addition to describing this bench-to-bedside story, the ASCB special symposium will spotlight new research suggesting that the basic cellular mechanism defective in children with HGPS may be at work in "normal" aging disorders, particularly in cardiovascular disease.
HGPS is estimated to affect about one child in 4 million. At birth, children with the disease appear normal. However, their growth soon slows, and children with HGPS begin to show signs of accelerated aging, such as hair loss, wrinkled skin, and loss of body fat. A 10-year-old child with HGPS typically looks like an 80-year-old adult.
HGPS' lethal damage occurs within the major blood vessels. The children develop premature cardiovascular disease, which typically leads to death from heart attack or stroke at about the age of 13. There currently are no treatments for the disease.
The 28 children enrolled in the clinical trial range in age from 3 to 15 years old and come from 16 countries. The two and one-half year phase 2 clinical trial, which began in 2007, is evaluating the FTI drug lonafarnib. In clinical studies in people with myeloid leukemia, neurofibromatosis and other conditions, FTIs' side effects were minimal.
The 2003 discovery of the HGPS gene, named lamin A (LMNA), laid the groundwork for the clinical trial. Indeed, in 2003, Dr. Collins was quoted as saying, "This genetic discovery represents the first piece in solving the tragic puzzle of Progeria. Without such information, we in the medical community were at loss about where to focus our efforts to help these children and their families. Now, we finally know where to begin."
They began by zeroing in on the LMNA gene and the HGPS genetic mutation, a single-letter "misspelling" in the LMNA gene located on chromosome 1. This gene carries the DNA recipe for lamin A, the protein glue that holds together the cell's nucleus. The mutated LMNA gene generates an abnormal Lamin A protein (also called progerin) that disrupts the cell's nuclear membrane. Because progerin wreaks havoc, cells become unstable and abnormal. The resulting gross disfigurement of the cell's nucleus is described as "blebbed," or lobular in shape.
(Recent research indicates that all people, not just children with HGPS, produce small amounts of progerin, and that this mutant protein may play roles in aging or longevity.)
Studying cells from HGPS patients, the NHGRI scientists found that the minute change in the LMNA gene's DNA sequence dramatically changed the way in which the sequence was spliced by the cell's protein-making machinery. The end result was the production of an abnormal lamin A protein that is missing a stretch of 50 amino acids near one of its ends.
Even before Dr. Francis Collins, M.D., Ph.D., the former National Human Genome Research Institute, and his research team tracked down the genetic mutation responsible for HGPS, Dr. Goldman had earned a stellar reputation for his cutting-edge basic research on the Lamin proteins in the cell nucleus.
Lamins were first described in the 1950s, and their protein structure was unraveled in the 1970s. The biochemistry of lamin A/C processing was characterized in the 1980s.
Until the late 1990s, however, funding for nuclear lamina research was sparse. Still, the link to HGPS in 2003 electrified the field, since Dr. Goldman and other lamin researchers had a good hunch about what might be going wrong in this children's disease of accelerated aging.
Years of basic research studies showed that the Lamin A protein production depends on the farnesyl group molecules' attaching themselves to the pre-lamin A protein. This attachment – and progerin production – can be blocked by a FTI drug, NHGRI scientists soon discovered in their studies of laboratory cultures of cells from HGPS patients.
And, the laboratory research continues. In October, the Proceedings of the National Academy of Sciences published findings that the experimental FTI cancer drug, tipifarnib, can prevent -- and even reverse -- potentially fatal cardiovascular damage in a transgenetic mouse model of HGPS. Dr. Collins and Elizabeth Nabel, M.D., director of the National Heart, Lung and Blood Institute (NHLBI), headed these studies. Dr. Collins has continued to conduct research as a special volunteer in the Genome Technology Branch of NHGRI's Division of Intramural Research.
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